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    Reversal of hepatic fibrosis -- fact or fantasy? Friedman Scott L,Bansal Meena B Hepatology (Baltimore, Md.) The prospect of reversing hepatic fibrosis has generated great interest now that basic science advances are being translated into promising new antifibrotic therapies. It is appropriate to recognize both the historical advances that created the framework for these successes, and the important role that Hepatology has played in disseminating them. A sense of urgency underlies this effort as the epidemics of HCV and NASH are becoming associated with advancing fibrosis. To maintain progress and minimize confusion among investigators and clinicians it is essential to standardize terms referring to fibrosis 'reversal' and 'regression.' There must also be rapid optimization of non-invasive markers of fibrosis to relieve this current bottleneck to conducting clinical trials. Progress in identifying genetic determinants of fibrosis could further refine patient selection for clinical trials and shorten their duration, as well as unearthing new directions of scientific inquiry. Realistic expectations for successful anti-fibrotic therapies reflect solid evidence of fibrosis regression in patients treated effectively for viral liver disease, as well as growing clarity in the understanding mechanisms of extracellular matrix production and degradation. The paradigms of stellate cell activation and apoptosis remain valuable frameworks for understanding pathways of hepatic fibrogenesis and fibrosis regression, respectively. Continued progress is essential in order to identify the determinants and dynamics of fibrosis reversibility, to discover additional targets for anti-fibrotic therapy, and to develop customized multi-drug regimens. These advances are sure to be captured in the next 25 years by Hepatology , and to profoundly impact the prognosis of patients with chronic liver disease. 10.1002/hep.20974
    Apoptosis and necroptosis in the liver: a matter of life and death. Schwabe Robert F,Luedde Tom Nature reviews. Gastroenterology & hepatology Cell death represents a basic biological paradigm that governs outcomes and long-term sequelae in almost every hepatic disease condition. Acute liver failure is characterized by massive loss of parenchymal cells but is usually followed by restitution ad integrum. By contrast, cell death in chronic liver diseases often occurs at a lesser extent but leads to long-term alterations in organ architecture and function, contributing to chronic hepatocyte turnover, the recruitment of immune cells and activation of hepatic stellate cells. These chronic cell death responses contribute to the development of liver fibrosis, cirrhosis and cancer. It has become evident that, besides apoptosis, necroptosis is a highly relevant form of programmed cell death in the liver. Differential activation of specific forms of programmed cell death might not only affect outcomes in liver diseases but also offer novel opportunities for therapeutic intervention. Here, we summarize the underlying molecular mechanisms and open questions about disease-specific activation and roles of programmed cell death forms, their contribution to response signatures and their detection. We focus on the role of apoptosis and necroptosis in acute liver injury, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and liver cancer, and possible translations into clinical applications. 10.1038/s41575-018-0065-y
    Inflammasome activation and function in liver disease. Szabo Gyongyi,Petrasek Jan Nature reviews. Gastroenterology & hepatology Inflammation contributes to the pathogenesis of most acute and chronic liver diseases. Inflammasomes are multiprotein complexes that can sense danger signals from damaged cells and pathogens and assemble to mediate caspase-1 activation, which proteolytically activates the cytokines IL-1β and IL-18. In contrast to other inflammatory responses, inflammasome activation uniquely requires two signals to induce inflammation, therefore setting an increased threshold. IL-1β, generated upon caspase-1 activation, provides positive feed-forward stimulation for inflammatory cytokines, thereby amplifying inflammation. Inflammasome activation has been studied in different human and experimental liver diseases and has been identified as a major contributor to hepatocyte damage, immune cell activation and amplification of liver inflammation. In this Review, we discuss the different types of inflammasomes, their activation and biological functions in the context of liver injury and disease progression. Specifically, we focus on the triggers of inflammasome activation in alcoholic steatohepatitis and NASH, chronic HCV infection, ischaemia-reperfusion injury and paracetamol-induced liver injury. The application and translation of these discoveries into therapies promises novel approaches in the treatment of inflammation in liver disease. 10.1038/nrgastro.2015.94
    Progression of NAFLD to diabetes mellitus, cardiovascular disease or cirrhosis. Anstee Quentin M,Targher Giovanni,Day Christopher P Nature reviews. Gastroenterology & hepatology NAFLD is a spectrum of progressive liver disease that encompasses simple steatosis, NASH, fibrosis and, ultimately, cirrhosis. NAFLD is recognized as the hepatic component of the metabolic syndrome, as these conditions have insulin resistance as a common pathophysiological mechanism. Therefore, NAFLD is strongly associated with type 2 diabetes mellitus and abdominal obesity. As lifestyles have become increasingly sedentary and dietary patterns have changed, the worldwide prevalence of NAFLD has increased dramatically and is projected to be the principal aetiology for liver transplantation within the next decade. Importantly, a growing body of clinical and epidemiological evidence suggests that NAFLD is associated not only with liver-related morbidity and mortality, but also with an increased risk of developing both cardiovascular disease and type 2 diabetes mellitus. This article reviews the evidence that suggests NAFLD is a multisystem disease and the factors that might determine interindividual variation in the development and progression of its major hepatic and extrahepatic manifestations (principally type 2 diabetes mellitus and cardiovascular disease). 10.1038/nrgastro.2013.41
    Liver transplantation: past, present and future. Zarrinpar Ali,Busuttil Ronald W Nature reviews. Gastroenterology & hepatology The first human liver transplant operation was performed by Thomas Starzl in 1963. The next two decades were marked by difficulties with donor organ quality, recipient selection, operative and perioperative management, immunosuppression and infectious complications. Advances in each of these areas transformed liver transplantation from an experimental procedure to a standard treatment for end-stage liver disease and certain cancers. From the handful of pioneering programmes, liver transplantation has expanded to hundreds of programmes in >80 countries. 1-year patient survival rates have exceeded 80% and outcomes continue to improve. This success has created obstacles. Ongoing challenges of liver transplantation include those concerning donor organ shortages, recipients with more advanced disease at transplant, growing need for retransplantation, toxicities and adverse effects associated with long-term immunosuppression, obesity and NASH epidemics, HCV recurrence and the still inscrutable biology of hepatocellular carcinoma. This Perspectives summarizes this transformation over time and details some of the challenges ahead. 10.1038/nrgastro.2013.88
    Macrophage p38α promotes nutritional steatohepatitis through M1 polarization. Zhang Xiang,Fan Lina,Wu Jianfeng,Xu Hongzhi,Leung Wing Yan,Fu Kaili,Wu Jingtong,Liu Ken,Man Kwan,Yang Xiaoyong,Han Jiahuai,Ren Jianlin,Yu Jun Journal of hepatology BACKGROUND & AIMS:p38 mitogen-activated protein kinases are important inflammatory factors. p38α alteration has been implicated in both human and mouse inflammatory disease models. Therefore, we aimed to characterize the cell type-specific role of p38α in non-alcoholic steatohepatitis (NASH). METHODS:Human liver tissues were obtained from 27 patients with non-alcoholic fatty liver disease (NAFLD) and 20 control individuals. NASH was established and compared between hepatocyte-specific p38α knockout (p38α), macrophage-specific p38α knockout (p38α) and wild-type (p38α) mice fed with high-fat diet (HFD), high-fat/high-cholesterol diet (HFHC), or methionine-and choline-deficient diet (MCD). p38 inhibitors were administered to HFHC-fed wild-type mice for disease treatment. RESULTS:p38α was significantly upregulated in the liver tissues of patients with NAFLD. Compared to p38α littermates, p38α mice developed significant nutritional steatohepatitis induced by HFD, HFHC or MCD. Meanwhile, p38α mice exhibited less severe steatohepatitis and insulin resistance than p38α mice in response to a HFHC or MCD. The effect of macrophage p38α in promoting steatohepatitis was mediated by the induction of pro-inflammatory factors (CXCL2, IL-1β, CXCL10 and IL-6) secreted by M1 macrophages and associated signaling pathways. p38α mice exhibited M2 anti-inflammatory polarization as demonstrated by increased CD45F4/80CD11bCD206 M2 macrophages and enhanced arginase activity in liver tissues. Primary hepatocytes from p38α mice showed decreased steatosis and inflammatory damage. In a co-culture system, p38α deleted macrophages attenuated steatohepatitic changes in hepatocytes through decreased secretion of pro-inflammatory cytokines (TNF-α, CXCL10 and IL-6), which mediate M1 macrophage polarization in p38α mice. Restoration of TNF-α, CXCL10 or IL-6 induced lipid accumulation and inflammatory responses in p38α hepatocytes co-cultured with p38α macrophages. Moreover, pharmacological p38 inhibitors suppressed HFHC-induced steatohepatitis. CONCLUSIONS:Macrophage p38α promotes the progression of steatohepatitis by inducing pro-inflammatory cytokine secretion and M1 polarization. p38 inhibition protects against steatohepatitis. LAY SUMMARY: p38 mitogen-activated protein kinases are important inflammatory factors. In the present study, we demonstrated that p38α is upregulated in liver tissues of patients with non-alcoholic fatty liver diseases. Genetic deletion of p38α in macrophages led to ameliorated nutritional steatohepatitis in mice through decreased pro-inflammatory cytokine secretion and increased M2 macrophage polarization. 10.1016/j.jhep.2019.03.014
    Non-alcoholic fatty liver disease: causes, diagnosis, cardiometabolic consequences, and treatment strategies. Stefan Norbert,Häring Hans-Ulrich,Cusi Kenneth The lancet. Diabetes & endocrinology The prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing worldwide. In some patients with NAFLD, isolated steatosis can progress to advanced stages with non-alcoholic steatohepatitis (NASH) and fibrosis, increasing the risk of cirrhosis and hepatocellular carcinoma. Furthermore, NAFLD is believed to be involved in the pathogenesis of common disorders such as type 2 diabetes and cardiovascular disease. In this Review, we highlight novel concepts related to diagnosis, risk prediction, and treatment of NAFLD. First, because NAFLD is a heterogeneous disease, the advanced stages of which seem to be strongly affected by comorbidities such as insulin resistance and type 2 diabetes, early use of reliable, non-invasive diagnostic tools is needed, particularly in patients with insulin resistance or diabetes, to allow the identification of patients at different disease stages. Second, although the strongest genetic risk alleles for NAFLD (ie, the 148Met allele in PNPLA3 and the 167Lys allele in TM6SF2) are associated with increased liver fat content and progression to NASH and cirrhosis, these alleles are also unexpectedly associated with an apparent protection from cardiovascular disease. If consistent across diverse populations, this discordance in NAFLD-related risk prediction between hepatic and extrahepatic disease might need to be accounted for in the management of NAFLD. Third, drug treatments assessed in NAFLD seem to differ with respect to cardiometabolic and antifibrotic efficacy, suggesting the need to better identify and tailor the most appropriate treatment approach, or to use a combination of approaches. These emerging concepts could contribute to the development of a multidisciplinary approach for endocrinologists and hepatologists working together in the management of NAFLD. 10.1016/S2213-8587(18)30154-2
    NAFLD in Asia--as common and important as in the West. Farrell Geoffrey C,Wong Vincent Wai-Sun,Chitturi Shiv Nature reviews. Gastroenterology & hepatology NAFLD--regarded as a consequence of the modern sedentary, food-abundant lifestyle prevalent in the West--was recorded in Japan nearly 50 years ago and its changing epidemiology during the past three decades is well-documented. NAFLD, and its pathologically more severe form NASH, occur in genetically susceptible people who are over-nourished. Asian people are particularly susceptible, partly owing to body composition differences in fat and muscle. Community prevalence ranges between 20% (China), 27% (Hong Kong), and 15-45% (South Asia, South-East Asia, Korea, Japan and Taiwan). This Review presents emerging data on genetic polymorphisms that predispose Asian people to NAFLD, NASH and cirrhosis, and discusses the clinical and pathological outcomes of these disorders. NAFLD is unlikely to be less severe in Asians than in other populations, but the associated obesity and diabetes pandemics have occurred more recently in Asia than in Europe and the USA, and occur with reduced degrees of adiposity. Cases of cryptogenic cirrhosis and hepatocellular carcinoma have also been attributed to NAFLD. Public health efforts to curb over-nutrition and insulin resistance are needed to prevent and/or reverse NAFLD, as well as its adverse health outcomes of type 2 diabetes, cardiovascular events, cirrhosis and liver cancer. 10.1038/nrgastro.2013.34
    Tumour necrosis factor alpha signalling through activation of Kupffer cells plays an essential role in liver fibrosis of non-alcoholic steatohepatitis in mice. Tomita K,Tamiya G,Ando S,Ohsumi K,Chiyo T,Mizutani A,Kitamura N,Toda K,Kaneko T,Horie Y,Han J-Y,Kato S,Shimoda M,Oike Y,Tomizawa M,Makino S,Ohkura T,Saito H,Kumagai N,Nagata H,Ishii H,Hibi T Gut BACKGROUND:While tumour necrosis factor alpha (TNF-alpha) appears to be associated with the development of non-alcoholic steatohepatitis (NASH), its precise role in the pathogenesis of NASH is not well understood. METHODS:Male mice deficient in both TNF receptors 1 (TNFR1) and 2 (TNFR2) (TNFRDKO mice) and wild-type mice were fed a methionine and choline deficient (MCD) diet or a control diet for eight weeks, maintaining isoenergetic intake. RESULTS:MCD dietary feeding of TNFRDKO mice for eight weeks resulted in attenuated liver steatosis and fibrosis compared with control wild-type mice. In the liver, the number of activated hepatic Kupffer cells recruited was significantly decreased in TNFRDKO mice after MCD dietary feeding. In addition, hepatic induction of TNF-alpha, vascular cell adhesion molecule 1, and intracellular adhesion molecule 1 was significantly suppressed in TNFRDKO mice. While in control animals MCD dietary feeding dramatically increased mRNA expression of tissue inhibitor of metalloproteinase 1 (TIMP-1) in both whole liver and hepatic stellate cells, concomitant with enhanced activation of hepatic stellate cells, both factors were significantly lower in TNFRDKO mice. In primary cultures, TNF-alpha administration enhanced TIMP-1 mRNA expression in activated hepatic stellate cells and suppressed apoptotic induction in activated hepatic stellate cells. Inhibition of TNF induced TIMP-1 upregulation by TIMP-1 specific siRNA reversed the apoptotic suppression seen in hepatic stellate cells. CONCLUSIONS:Enhancement of the TNF-alpha/TNFR mediated signalling pathway via activation of Kupffer cells in an autocrine or paracrine manner may be critically involved in the pathogenesis of liver fibrosis in this NASH animal model. 10.1136/gut.2005.071118
    Molecular basis and mechanisms of progression of non-alcoholic steatohepatitis. Marra Fabio,Gastaldelli Amalia,Svegliati Baroni Gianluca,Tell Gianluca,Tiribelli Claudio Trends in molecular medicine Non-alcoholic steatohepatitis (NASH), a cause of cirrhosis and hepatocellular carcinoma, is characterized by fatty infiltration of the liver, inflammation, hepatocellular damage and fibrosis. Progress has been made in understanding the molecular and cellular mechanisms implicated in the pathogenesis of this condition, therefore, we here review recent developments regarding the basic mechanisms of NASH development. Accumulation of triglycerides in the hepatocytes is the result of increased inflow of free fatty acids and de novo lipogenesis. Steatosis leads to lipotoxicity, which causes apoptosis, necrosis, generation of oxidative stress and inflammation. The resulting chronic injury activates a fibrogenic response that leads eventually to end-stage liver disease. A better understanding of these mechanisms is crucial for the design of novel diagnostic and therapeutic strategies. 10.1016/j.molmed.2007.12.003
    Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPARα. Liang Ning,Damdimopoulos Anastasius,Goñi Saioa,Huang Zhiqiang,Vedin Lise-Lotte,Jakobsson Tomas,Giudici Marco,Ahmed Osman,Pedrelli Matteo,Barilla Serena,Alzaid Fawaz,Mendoza Arturo,Schröder Tarja,Kuiper Raoul,Parini Paolo,Hollenberg Anthony,Lefebvre Philippe,Francque Sven,Van Gaal Luc,Staels Bart,Venteclef Nicolas,Treuter Eckardt,Fan Rongrong Nature communications Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest. 10.1038/s41467-019-09524-z
    The Natural History of Advanced Fibrosis Due to Nonalcoholic Steatohepatitis: Data From the Simtuzumab Trials. Sanyal Arun J,Harrison Stephen A,Ratziu Vlad,Abdelmalek Manal F,Diehl Anna Mae,Caldwell Stephen,Shiffman Mitchell L,Aguilar Schall Raul,Jia Catherine,McColgan Bryan,Djedjos C Stephen,McHutchison John G,Subramanian G Mani,Myers Robert P,Younossi Zobair,Muir Andrew J,Afdhal Nezam H,Bosch Jaime,Goodman Zachary Hepatology (Baltimore, Md.) Progression of nonalcoholic steatohepatitis (NASH) is incompletely characterized. We analyzed data on longitudinal changes in liver histology, hepatic venous pressure gradient (HVPG), and serum markers of fibrosis in 475 patients with NASH with bridging fibrosis (F3) or compensated cirrhosis (F4) enrolled in two phase 2b, placebo-controlled trials of simtuzumab. The trials were terminated after 96 weeks because of lack of efficacy, so data from treatment groups were combined. Liver biopsies and HVPG measurements (only for patients with F4 fibrosis) were collected at screening and at weeks 48 and 96. Patients were assessed for Ishak fibrosis stage, hepatic collagen content and alpha-smooth muscle actin (by morphometry), NAFLD Activity Score (NAS), and serum markers of fibrosis. Associations with progression to cirrhosis (in patients with F3 fibrosis) and liver-related clinical events (in patients with F4 fibrosis) were determined. Progression to cirrhosis occurred in 22% (48/217) of F3 patients, and liver-related clinical events occurred in 19% (50/258) of patients with cirrhosis. Factors significantly associated with progression to cirrhosis included higher baseline values of and greater increases in hepatic collagen content, level of alpha-smooth muscle actin, and Enhanced Liver Fibrosis score. Similar factors, plus lack of fibrosis stage improvement (hazard ratio, 9.30; 95% confidence interval, 1.28-67.37), higher HVPG at baseline, and greater increase in HVPG over time, were associated with an increased risk of liver-related clinical events in patients with cirrhosis. Disease progression was not associated with the NAS at baseline or changes in NAS during treatment after adjustment for fibrosis stage. Conclusion: In patients with advanced fibrosis due to NASH, the primary determinant of clinical disease progression is fibrosis and its change over time. 10.1002/hep.30664
    On the Front Line: Obesity and NAFLD. Cell metabolism In February, researchers convened in Banff, Canada, for the 2020 Keystone Symposium on Obesity and NAFLD. As the meeting wrapped up, we spoke with attendees, including key leaders, and they shared what was on the forefront of their minds-from the battle against NASH to emergent single-cell technologies. 10.1016/j.cmet.2020.03.014
    High glucose and hyperinsulinemia stimulate connective tissue growth factor expression: a potential mechanism involved in progression to fibrosis in nonalcoholic steatohepatitis. Paradis V,Perlemuter G,Bonvoust F,Dargere D,Parfait B,Vidaud M,Conti M,Huet S,Ba N,Buffet C,Bedossa P Hepatology (Baltimore, Md.) Nonalcoholic steatohepatitis (NASH) may progress to liver fibrosis and cirrhosis. Mechanisms directly involved in the development of fibrosis have been poorly investigated. Because connective tissue growth factor (CTGF) is an intermediate key molecule involved in the pathogenesis of fibrosing chronic liver diseases and is potentially induced by hyperglycemia, the aims of this study were to (1) study the expression of CTGF in vivo both in human liver biopsy specimens of patients with NASH and in an experimental model of obesity and type II diabetes (Zucker rats); and (2) analyze the effects of hyperglycemia and insulin in vitro on hepatic stellate cells. In vivo, CTGF overexpression was observed in the liver tissue of all of the 16 patients with NASH. CTGF immunostaining was mild in 7 cases (44%) and moderate or strong in 9 cases (56%). Staining was mainly detected in the liver extracellular matrix in parallel with the amount of liver fibrosis. Liver from fa/fa rats also showed CTGF overexpression by comparison with Fa/fa rats both at the messenger RNA (mRNA) level (3-fold increase) and protein level. In vitro, both CTGF mRNA and protein were significantly increased when hepatic stellate cells were incubated with either glucose or insulin. A slight increase in type I procollagen mRNA level was also observed in hepatic stellate cells incubated with glucose. In conclusion, this study suggests that hyperglycemia and insulin are key-factors in the progression of fibrosis in patients with NASH through the up-regulation of CTGF. 10.1053/jhep.2001.28055
    Nonalcoholic fatty liver disease. Brunt Elizabeth M,Wong Vincent W-S,Nobili Valerio,Day Christopher P,Sookoian Silvia,Maher Jacquelyn J,Bugianesi Elisabetta,Sirlin Claude B,Neuschwander-Tetri Brent A,Rinella Mary E Nature reviews. Disease primers Nonalcoholic fatty liver disease (NAFLD) is a disorder characterized by excess accumulation of fat in hepatocytes (nonalcoholic fatty liver (NAFL)); in up to 40% of individuals, there are additional findings of portal and lobular inflammation and hepatocyte injury (which characterize nonalcoholic steatohepatitis (NASH)). A subset of patients will develop progressive fibrosis, which can progress to cirrhosis. Hepatocellular carcinoma and cardiovascular complications are life-threatening co-morbidities of both NAFL and NASH. NAFLD is closely associated with insulin resistance; obesity and metabolic syndrome are common underlying factors. As a consequence, the prevalence of NAFLD is estimated to be 10-40% in adults worldwide, and it is the most common liver disease in children and adolescents in developed countries. Mechanistic insights into fat accumulation, subsequent hepatocyte injury, the role of the immune system and fibrosis as well as the role of the gut microbiota are unfolding. Furthermore, genetic and epigenetic factors might explain the considerable interindividual variation in disease phenotype, severity and progression. To date, no effective medical interventions exist that completely reverse the disease other than lifestyle changes, dietary alterations and, possibly, bariatric surgery. However, several strategies that target pathophysiological processes such as an oversupply of fatty acids to the liver, cell injury and inflammation are currently under investigation. Diagnosis of NAFLD can be established by imaging, but detection of the lesions of NASH still depend on the gold-standard but invasive liver biopsy. Several non-invasive strategies are being evaluated to replace or complement biopsies, especially for follow-up monitoring. 10.1038/nrdp.2015.80
    Nonalcoholic steatohepatitis. Sheth S G,Gordon F D,Chopra S Annals of internal medicine OBJECTIVE:To determine the clinical relevance of nonalcoholic steatohepatitis (NASH) and to review the available literature on the epidemiology, clinical features, histology, pathogenesis, clinical course, and management of this condition. DATA SOURCES:Pertinent articles in English identified through a MEDLINE search (1966 to the present) and the bibliographies of relevant articles. STUDY SELECTION:All studies, including case reports, evaluating the salient features and clinical profile of NASH. DATA EXTRACTION:Data were selected from all articles that fit the study selection criteria. DATA SYNTHESIS:Nonalcoholic steatohepatitis is a distinct clinical entity characterized by elevated plasma liver enzyme levels and liver biopsy findings that are identical to those seen in alcoholic hepatitis; patients with NASH, however, do not consume alcohol in quantities known to cause liver injury. Patients with NASH are typically obese, middle-aged women with asymptomatic hepatomegaly who are diabetic or hyperlipidemic and present with an unrelated medical problem. Analysis of liver biopsy specimens is the cornerstone of diagnosis; hepatic morphologic findings range from mild fatty degeneration and inflammation to cell degeneration, fibrosis, and cirrhosis with or without the presence of Mallory hyaline bodies. Elevated levels of free fatty acids in the liver are thought to be responsible for the development of steatohepatitis. Although NASH is most often a benign disease with an indolent course, patients with this condition occasionally develop cirrhosis, portal hypertension, and hepatic failure. In some cases, NASH may be reversed with weight reduction. CONCLUSION:Nonalcoholic steatohepatitis is an important differential diagnosis for asymptomatic patients with chronically elevated plasma liver enzyme levels, especially if obesity, diabetes, or hyperlipidemia are present. Analysis of liver biopsy specimens is necessary for diagnosis and must be done in all patients with unexplained abnormal liver function and negative results on a noninvasive workup. Prognosis is good in most patients. The precise role of weight reduction and ursodeoxycholic acid therapy in the favorable alteration of the natural history of this disorder needs to be addressed in large, well-controlled studies. 10.7326/0003-4819-126-2-199701150-00008
    Diet, weight loss, and liver health in nonalcoholic fatty liver disease: Pathophysiology, evidence, and practice. Marchesini Giulio,Petta Salvatore,Dalle Grave Riccardo Hepatology (Baltimore, Md.) Fatty liver accumulation results from an imbalance between lipid deposition and removal, driven by the hepatic synthesis of triglycerides and de novo lipogenesis. The habitual diet plays a relevant role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD), and both risky (e.g., fructose) and protective foods (Mediterranean diet) have been described, but the contribution of excess calories remains pivotal. Accordingly, weight loss is the most effective way to promote liver fat removal. Several controlled studies have confirmed that an intense approach to lifestyle changes, carried on along the lines of cognitive-behavior treatment, is able to attain the desired 7%-10% weight loss, associated with reduced liver fat, nonalcoholic steatohepatitis (NASH) remission, and also reduction of fibrosis. Even larger effects are reported after bariatric surgery-induced weight loss in NAFLD, where 80% of subjects achieve NASH resolution at 1-year follow-up. These results provide solid data to evaluate the safety and effectiveness of the pharmacological treatment of NASH. The battle against metabolic diseases, largely fueled by increased liver fat, needs a comprehensive approach to be successful in an obesiogenic environment. In this review, we will discuss the role of hepatic lipid metabolism, genetic background, diet, and physical activity on fatty liver. They are the basis for a lifestyle approach to NAFLD treatment. (Hepatology 2016;63:2032-2043). 10.1002/hep.28392
    The L-α-Lysophosphatidylinositol/G Protein-Coupled Receptor 55 System Induces the Development of Nonalcoholic Steatosis and Steatohepatitis. Fondevila Marcos F,Fernandez Uxia,Gonzalez-Rellan Maria J,Da Silva Lima Natalia,Buque Xabier,Gonzalez-Rodriguez Agueda,Alonso Cristina,Iruarrizaga-Lejarreta Marta,Delgado Teresa C,Varela-Rey Marta,Senra Ana,Garcia-Outeiral Vera,Novoa Eva,Iglesias Cristina,Porteiro Begoña,Beiroa Daniel,Folgueira Cintia,Tojo Marta,Torres Jorge L,Hernández-Cosido Lourdes,Blanco Óscar,Arab Juan Pablo,Barrera Francisco,Guallar Diana,Fidalgo Miguel,López Miguel,Dieguez Carlos,Marcos Miguel,Martinez-Chantar Maria L,Arrese Marco,Garcia-Monzon Carmelo,Mato Jose M,Aspichueta Patricia,Nogueiras Ruben Hepatology (Baltimore, Md.) BACKGROUND AND AIMS:G protein-coupled receptor (GPR) 55 is a putative cannabinoid receptor, and l-α-lysophosphatidylinositol (LPI) is its only known endogenous ligand. Although GPR55 has been linked to energy homeostasis in different organs, its specific role in lipid metabolism in the liver and its contribution to the pathophysiology of nonalcoholic fatty liver disease (NAFLD) remains unknown. APPROACH AND RESULTS:We measured (1) GPR55 expression in the liver of patients with NAFLD compared with individuals without obesity and without liver disease, as well as animal models with steatosis and nonalcoholic steatohepatitis (NASH), and (2) the effects of LPI and genetic disruption of GPR55 in mice, human hepatocytes, and human hepatic stellate cells. Notably, we found that circulating LPI and liver expression of GPR55 were up-regulated in patients with NASH. LPI induced adenosine monophosphate-activated protein kinase activation of acetyl-coenzyme A carboxylase (ACC) and increased lipid content in human hepatocytes and in the liver of treated mice by inducing de novo lipogenesis and decreasing β-oxidation. The inhibition of GPR55 and ACCα blocked the effects of LPI, and the in vivo knockdown of GPR55 was sufficient to improve liver damage in mice fed a high-fat diet and in mice fed a methionine-choline-deficient diet. Finally, LPI promoted the initiation of hepatic stellate cell activation by stimulating GPR55 and activation of ACC. CONCLUSIONS:The LPI/GPR55 system plays a role in the development of NAFLD and NASH by activating ACC. 10.1002/hep.31290
    Activation of LKB1-Akt pathway independent of phosphoinositide 3-kinase plays a critical role in the proliferation of hepatocellular carcinoma from nonalcoholic steatohepatitis. Martínez-López Nuria,Varela-Rey Marta,Fernández-Ramos David,Woodhoo Ashwin,Vázquez-Chantada Mercedes,Embade Nieves,Espinosa-Hevia Luis,Bustamante Francisco Javier,Parada Luis A,Rodriguez Manuel S,Lu Shelly C,Mato José M,Martínez-Chantar Maria L Hepatology (Baltimore, Md.) UNLABELLED:LKB1, originally considered a tumor suppressor, plays an important role in hepatocyte proliferation and liver regeneration. Mice lacking the methionine adenosyltransferase (MAT) gene MAT1A exhibit a chronic reduction in hepatic S-adenosylmethionine (SAMe) levels, basal activation of LKB1, and spontaneous development of nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC). These results are relevant for human health because patients with liver cirrhosis, who are at risk to develop HCC, have a marked reduction in hepatic MAT1A expression and SAMe synthesis. In this study, we isolated a cell line (SAMe-deficient [SAMe-D]) from MAT1A knockout (MAT1A-KO) mouse HCC to examine the role of LKB1 in the development of liver tumors derived from metabolic disorders. We found that LKB1 is required for cell survival in SAMe-D cells. LKB1 regulates Akt-mediated survival independent of phosphoinositide 3-kinase, adenosine monophosphate protein-activated kinase (AMPK), and mammalian target of rapamycin complex (mTORC2). In addition, LKB1 controls the apoptotic response through phosphorylation and retention of p53 in the cytoplasm and the regulation of herpesvirus-associated ubiquitin-specific protease (HAUSP) and Hu antigen R (HuR) nucleocytoplasmic shuttling. We identified HAUSP as a target of HuR. Finally, we observed cytoplasmic staining of p53 and p-LKB1(Ser428) in a NASH-HCC animal model (from MAT1A-KO mice) and in liver biopsies obtained from human HCC derived from both alcoholic steatohepatitis and NASH. CONCLUSION:The SAMe-D cell line is a relevant model of HCC derived from NASH disease in which LKB1 is the principal conductor of a new regulatory mechanism and could be a practical tool for uncovering new therapeutic strategies. 10.1002/hep.23860
    Hepatic lipotoxicity and the pathogenesis of nonalcoholic steatohepatitis: the central role of nontriglyceride fatty acid metabolites. Neuschwander-Tetri Brent A Hepatology (Baltimore, Md.) A significant body of evidence now forces us to rethink the causes of NASH. Once thought to be a disease caused by triglyceride accumulation in hepatocytes with subsequent oxidant stress and lipid peroxidation causing inflammation and fibrosis, new data from animal studies and a limited number of human studies now provide convincing evidence that triglyceride accumulation does not cause insulin resistance or cellular injury in the liver. The lipotoxic liver injury hypothesis for the pathogenesis of NASH suggests that we need to focus our therapeutic efforts on reducing the burden of fatty acids going to the liver or being synthesized in the liver. This can be accomplished by improving insulin sensitivity at the level of adipose tissue to prevent inappropriate peripheral lipolysis and by preventing unnecessary de novo lipogenesis in the liver. Excess carbohydrates are the major substrates for de novo lipogenesis, and thus, reducing carbohydrate consumption through dietary changes and increasing muscle glucose uptake through exercise remain important cornerstones of treatment and prevention of lipotoxic liver injury, a disease hitherto called NASH. 10.1002/hep.23719
    p53/p66Shc-mediated signaling contributes to the progression of non-alcoholic steatohepatitis in humans and mice. Tomita Kengo,Teratani Toshiaki,Suzuki Takahiro,Oshikawa Tetsuya,Yokoyama Hirokazu,Shimamura Katsuyoshi,Nishiyama Kiyoshi,Mataki Norikazu,Irie Rie,Minamino Tohru,Okada Yoshikiyo,Kurihara Chie,Ebinuma Hirotoshi,Saito Hidetsugu,Shimizu Ippei,Yoshida Yohko,Hokari Ryota,Sugiyama Kazuo,Hatsuse Kazuo,Yamamoto Junji,Kanai Takanori,Miura Soichiro,Hibi Toshifumi Journal of hepatology BACKGROUND & AIMS:The tumor suppressor p53 is a primary sensor of stressful stimuli, controlling a number of biologic processes. The aim of our study was to examine the roles of p53 in non-alcoholic steatohepatitis (NASH). METHODS:Male wild type and p53-deficient mice were fed a methionine- and choline-deficient diet for 8 weeks to induce nutritional steatohepatitis. mRNA expression profiles in normal liver samples and liver samples from patients with non-alcoholic liver disease (NAFLD) were also evaluated. RESULTS:Hepatic p53 and p66Shc signaling was enhanced in the mouse NASH model. p53 deficiency suppressed the enhanced p66Shc signaling, decreased hepatic lipid peroxidation and the number of apoptotic hepatocytes, and ameliorated progression of nutritional steatohepatitis. In primary cultured hepatocytes, transforming growth factor (TGF)-β treatment increased p53 and p66Shc signaling, leading to exaggerated reactive oxygen species (ROS) accumulation and apoptosis. Deficient p53 signaling inhibited TGF-β-induced p66Shc signaling, ROS accumulation, and hepatocyte apoptosis. Furthermore, expression levels of p53, p21, and p66Shc were significantly elevated in human NAFLD liver samples, compared with results obtained with normal liver samples. Among NAFLD patients, those with NASH had significantly higher hepatic expression levels of p53, p21, and p66Shc compared with the group with simple steatosis. A significant correlation between expression levels of p53 and p66Shc was observed. CONCLUSIONS:p53 in hepatocytes regulates steatohepatitis progression by controlling p66Shc signaling, ROS levels, and apoptosis, all of which may be regulated by TGF-β. Moreover, p53/p66Shc signaling in the liver appears to be a promising target for the treatment of NASH. 10.1016/j.jhep.2012.05.013
    Yes-Associated Protein in Kupffer Cells Enhances the Production of Proinflammatory Cytokines and Promotes the Development of Nonalcoholic Steatohepatitis. Song Kyoungsub,Kwon Hyunjoo,Han Chang,Chen Weina,Zhang Jinqiang,Ma Wenbo,Dash Srikanta,Gandhi Chandrashekhar R,Wu Tong Hepatology (Baltimore, Md.) BACKGROUND AND AIMS:Yes-associated protein (YAP) plays an important role in hepatocarcinogenesis, although the potential role of YAP in non-neoplastic liver diseases remains largely unknown. We report herein that YAP in Kupffer cells (KCs) enhances the production of proinflammatory cytokines and promotes the development of nonalcoholic steatohepatitis (NASH). Our data show that the expression of YAP is significantly increased in KCs of wild-type mice fed a high-fat diet (HFD). APPROACH AND RESULTS:We generated mice with macrophage/monocyte-specific deletion of YAP (YAP ) or Toll-like receptor 4 (TLR4; TLR4 ), and animals were fed an HFD or treated with lipopolysaccharide (LPS). Our data showed that YAP mice fed an HFD exhibited lower serum alanine aminotransferase (ALT)/aspartate aminotransferase (AST) levels and less hepatic inflammation when compared to their littermate controls. LPS treatment induced accumulation of YAP in KCs in vitro and in mice, which was prevented by macrophage/monocyte-specific deletion of TLR4 (TLR4 ). LPS transcriptionally activates YAP through activator protein 1 in macrophages/KCs. LPS-induced YAP further enhances expression of proinflammatory cytokines (including monocyte chemoattractant protein 1, tumor necrosis factor alpha, and interleukin 6) through YAP association with the TEA domain-binding motif in the promoter region of inflammatory cytokines. Forced overexpression of active YAP (YAP5SA) in KCs enhanced the production of proinflammatory cytokines. Treatment of HFD-fed mice with verteporfin inhibited KC activation, reduced liver inflammation, and decreased serum ALT/AST levels. Analyses of liver tissues from NASH patients reveal that YAP is increased in KCs and that level of YAP in human liver tissues is positively correlated with expression of proinflammatory cytokines. CONCLUSIONS:This study describes an important role of YAP in KCs for regulation of liver inflammation in NASH. Our findings suggest that inhibition of YAP may represent an effective therapeutic strategy for NASH treatment. 10.1002/hep.30990
    Dietary Lipids Differentially Shape Nonalcoholic Steatohepatitis Progression and the Transcriptome of Kupffer Cells and Infiltrating Macrophages. Hepatology (Baltimore, Md.) A crucial component of nonalcoholic fatty liver disease (NAFLD) pathogenesis is lipid stress, which may contribute to hepatic inflammation and activation of innate immunity in the liver. However, little is known regarding how dietary lipids, including fat and cholesterol, may facilitate innate immune activation in vivo. We hypothesized that dietary fat and cholesterol drive NAFLD progression to steatohepatitis and hepatic fibrosis by altering the transcription and phenotype of hepatic macrophages. This hypothesis was tested by using RNA-sequencing methods to characterize and analyze sort-purified hepatic macrophage populations that were isolated from mice fed diets with varying amounts of fat and cholesterol. The addition of cholesterol to a high-fat diet triggered hepatic pathology reminiscent of advanced nonalcoholic steatohepatitis (NASH) in humans characterized by signs of cholesterol dysregulation, generation of oxidized low-density lipoprotein, increased recruitment of hepatic macrophages, and significant fibrosis. RNA-sequencing analyses of hepatic macrophages in this model revealed that dietary cholesterol induced a tissue repair and regeneration phenotype in Kupffer cells (KCs) and recruited infiltrating macrophages to a greater degree than fat. Furthermore, comparison of diseased KCs and infiltrating macrophages revealed that these two macrophage subsets are transcriptionally diverse. Finally, direct stimulation of murine and human macrophages with oxidized low-density lipoprotein recapitulated some of the transcriptional changes observed in the RNA-sequencing study. These findings indicate that fat and cholesterol synergize to alter macrophage phenotype, and they also challenge the dogma that KCs are purely proinflammatory in NASH. Conclusion: This comprehensive view of macrophage populations in NASH indicates mechanisms by which cholesterol contributes to NASH progression and identifies potential therapeutic targets for this common disease. 10.1002/hep.30401
    The role of the gut microbiota in nonalcoholic fatty liver disease. Abu-Shanab Ahmed,Quigley Eamonn M M Nature reviews. Gastroenterology & hepatology Important metabolic functions have been identified for the gut microbiota in health and disease. Several lines of evidence suggest a role for the gut microbiota in both the etiology of nonalcoholic fatty liver disease (NAFLD) and progression to its more advanced state, nonalcoholic steatohepatitis (NASH). Both NAFLD and NASH are strongly linked to obesity, type 2 diabetes mellitus and the metabolic syndrome and, accordingly, have become common worldwide problems. Small intestinal bacterial overgrowth of Gram-negative organisms could promote insulin resistance, increase endogenous ethanol production and induce choline deficiency, all factors implicated in NAFLD. Among the potential mediators of this association, lipopolysaccharide (a component of Gram-negative bacterial cell walls) exerts relevant metabolic and proinflammatory effects. Although the best evidence to support a role for the gut microbiota in NAFLD and NASH comes largely from animal models, data from studies in humans (albeit at times contradictory) is accumulating and could lead to new therapeutic avenues for these highly prevalent conditions. 10.1038/nrgastro.2010.172
    Physical activity: an essential component of lifestyle modification in NAFLD. Rodriguez Benjamin,Torres Dawn M,Harrison Stephen A Nature reviews. Gastroenterology & hepatology NAFLD encompasses a spectrum of liver diseases pertaining to fat accumulation in the liver in the absence of significant alcohol consumption. NASH is the most clinically relevant subset of NAFLD, and patients with NASH have an increased risk of progression to cirrhosis or developing liver cancer. No pharmacotherapy is currently approved for NAFLD, and lifestyle modification via diet and exercise is most commonly recommended. The optimal physical activity regimen in terms of both effectiveness and compliance remains to be determined and is the focus of this Review. 10.1038/nrgastro.2012.200
    Adipose tissue macrophages induce hepatic neutrophil recruitment and macrophage accumulation in mice. Bijnen Mitchell,Josefs Tatjana,Cuijpers Ilona,Maalsen Constantijn J,van de Gaar José,Vroomen Maria,Wijnands Erwin,Rensen Sander S,Greve Jan Willem M,Hofker Marten H,Biessen Erik A L,Stehouwer Coen D A,Schalkwijk Casper G,Wouters Kristiaan Gut OBJECTIVE:Obesity is a risk factor for non-alcoholic steatohepatitis (NASH). This risk has been attributed to visceral adipose tissue (vAT) expansion associated with increased proinflammatory mediators. Accumulation of CD11c proinflammatory adipose tissue macrophages (ATM) is an important driver of vAT inflammation. We investigated the role of ATMs in hepatic inflammation during NASH development. DESIGN:vAT isolated from lean, obese or ATM-depleted (using clodronate liposomes) obese mice was transplanted to lean ldlr acceptor mice. Systemic and hepatic inflammation was assessed either after 2 weeks on standard chow or after 8 weeks on high cholesterol diet (HCD) to induce NASH. RESULTS:Transplanting donor vAT from obese mice increased HCD-induced hepatic macrophage content compared with lean-transplanted mice, worsening liver damage. ATM depletion prior to vAT transplantation reduced this increased hepatic macrophage accumulation. On chow, vAT transplantation induced a more pronounced increase in circulating and hepatic neutrophil numbers in obese-transplanted than lean-transplanted mice, while ATM depletion prior to vAT transplantation reversed this effect. Microarray analysis of fluorescence-activated cell sorting of CD11c and CD11c macrophages isolated from donor adipose tissue showed that obesity resulted in enhanced expression of neutrophil chemotaxis genes specifically in CD11c ATMs. Involvement of the neutrophil chemotaxis proteins, CXCL14 and CXCL16, was confirmed by culturing vAT. In humans, CD11c expression in vAT of obese individuals correlated with vAT expression of neutrophil chemotactic genes and with hepatic expression of neutrophil and macrophage marker genes. CONCLUSION:ATMs from obese vAT induce hepatic macrophage accumulation during NASH development, possibly by enhancing neutrophil recruitment. 10.1136/gutjnl-2016-313654
    NAFLD and diabetes mellitus. Tilg Herbert,Moschen Alexander R,Roden Michael Nature reviews. Gastroenterology & hepatology The liver constitutes a key organ in systemic metabolism, contributing substantially to the development of insulin resistance and type 2 diabetes mellitus (T2DM). The mechanisms underlying these processes are not entirely understood, but involve hepatic fat accumulation, alterations of energy metabolism and inflammatory signals derived from various cell types including immune cells. Lipotoxins, mitochondrial function, cytokines and adipocytokines have been proposed to play a major part in both NAFLD and T2DM. Patients with NAFLD are commonly insulin resistant. On the other hand, a large number of patients with T2DM develop NAFLD with its inflammatory complication, NASH. The high incidence of NASH in patients with T2DM leads to further complications, such as liver cirrhosis and hepatocellular carcinoma, which are increasingly recognized. Therapeutic concepts such as thiazolidinediones (glitazones) for treating T2DM also show some efficacy in the treatment of NASH. This Review will describe the multifaceted and complex interactions between the liver and T2DM. 10.1038/nrgastro.2016.147
    Inflammasome-mediated dysbiosis regulates progression of NAFLD and obesity. Henao-Mejia Jorge,Elinav Eran,Jin Chengcheng,Hao Liming,Mehal Wajahat Z,Strowig Till,Thaiss Christoph A,Kau Andrew L,Eisenbarth Stephanie C,Jurczak Michael J,Camporez Joao-Paulo,Shulman Gerald I,Gordon Jeffrey I,Hoffman Hal M,Flavell Richard A Nature Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome and the leading cause of chronic liver disease in the Western world. Twenty per cent of NAFLD individuals develop chronic hepatic inflammation (non-alcoholic steatohepatitis, NASH) associated with cirrhosis, portal hypertension and hepatocellular carcinoma, yet the causes of progression from NAFLD to NASH remain obscure. Here, we show that the NLRP6 and NLRP3 inflammasomes and the effector protein IL-18 negatively regulate NAFLD/NASH progression, as well as multiple aspects of metabolic syndrome via modulation of the gut microbiota. Different mouse models reveal that inflammasome-deficiency-associated changes in the configuration of the gut microbiota are associated with exacerbated hepatic steatosis and inflammation through influx of TLR4 and TLR9 agonists into the portal circulation, leading to enhanced hepatic tumour-necrosis factor (TNF)-α expression that drives NASH progression. Furthermore, co-housing of inflammasome-deficient mice with wild-type mice results in exacerbation of hepatic steatosis and obesity. Thus, altered interactions between the gut microbiota and the host, produced by defective NLRP3 and NLRP6 inflammasome sensing, may govern the rate of progression of multiple metabolic syndrome-associated abnormalities, highlighting the central role of the microbiota in the pathogenesis of heretofore seemingly unrelated systemic auto-inflammatory and metabolic disorders. 10.1038/nature10809
    Ezetimibe ameliorates steatohepatitis via AMP activated protein kinase-TFEB-mediated activation of autophagy and NLRP3 inflammasome inhibition. Kim Soo Hyun,Kim Gyuri,Han Dai Hoon,Lee Milim,Kim Irene,Kim Bohkyung,Kim Kook Hwan,Song Young-Mi,Yoo Jeong Eun,Wang Hye Jin,Bae Soo Han,Lee Yong-Ho,Lee Byung-Wan,Kang Eun Seok,Cha Bong-Soo,Lee Myung-Shik Autophagy Impairment in macroautophagy/autophagy flux and inflammasome activation are common characteristics of nonalcoholic steatohepatitis (NASH). Considering the lack of approved agents for treating NASH, drugs that can enhance autophagy and modulate inflammasome pathways may be beneficial. Here, we investigated the novel mechanism of ezetimibe, a widely prescribed drug for hypercholesterolemia, as a therapeutic option for ameliorating NASH. Human liver samples with steatosis and NASH were analyzed. For in vitro studies of autophagy and inflammasomes, primary mouse hepatocytes, human hepatoma cells, mouse embryonic fibroblasts with Ampk or Tsc2 knockout, and human or primary mouse macrophages were treated with ezetimibe and palmitate. Steatohepatitis and fibrosis were induced by feeding Atg7 wild-type, haploinsufficient, and knockout mice a methionine- and choline-deficient diet with ezetimibe (10 mg/kg) for 4 wk. Human livers with steatosis or NASH presented impaired autophagy with decreased nuclear TFEB and increased SQSTM1, MAP1LC3-II, and NLRP3 expression. Ezetimibe increased autophagy flux and concomitantly ameliorated lipid accumulation and apoptosis in palmitate-exposed hepatocytes. Ezetimibe induced AMPK phosphorylation and subsequent TFEB nuclear translocation, related to MAPK/ERK. In macrophages, ezetimibe blocked the NLRP3 inflammasome-IL1B pathway in an autophagy-dependent manner and modulated hepatocyte-macrophage interaction via extracellular vesicles. Ezetimibe attenuated lipid accumulation, inflammation, and fibrosis in liver-specific Atg7 wild-type and haploinsufficient mice, but not in knockout mice. Ezetimibe ameliorates steatohepatitis by autophagy induction through AMPK activation and TFEB nuclear translocation, related to an independent MTOR ameliorative effect and the MAPK/ERK pathway. Ezetimibe dampens NLRP3 inflammasome activation in macrophages by modulating autophagy and a hepatocyte-driven exosome pathway. 10.1080/15548627.2017.1356977
    Gene expression of tumor necrosis factor alpha and TNF-receptors, p55 and p75, in nonalcoholic steatohepatitis patients. Crespo J,Cayón A,Fernández-Gil P,Hernández-Guerra M,Mayorga M,Domínguez-Díez A,Fernández-Escalante J C,Pons-Romero F Hepatology (Baltimore, Md.) The main objective of this study was to analyze the pathogenic role of the tumor necrosis factor alpha (TNF-alpha) system in the development of nonalcoholic steatohepatitis (NASH). Fifty-two obese patients were studied. We investigated: (1) the expression of mRNA of TNF-alpha and their p55 and p75-receptors by quantitative reverse-transcriptase polymerase chain reaction (RT-PCR) in hepatic and adipose tissues; and (2) the relationship between TNF-alpha, p55, and p75 and the severity of NASH. Obese patients without NASH were the control group. A remarkable increase in the expression of mRNA of TNF-alpha was found in patients with NASH in hepatic tissue (0.65 +/- 0.54) and in peripheral fat (0.43 +/- 0.45); in the control samples, the mRNA expression was 0.28 +/- 0.32, P <.007, and 0.26 +/- 0.22, P <.018, respectively. Furthermore, we found a significant increase in the mRNA levels of p55 receptor (2.42 +/- 1.81 vs. 1.56 +/- 1.17; P <.05); however, the mRNA expression of the p75 receptor was similar in both patients. Those patients with NASH with significant fibrosis presented an increase in the expression of mRNA TNF-alpha in comparison with those with a slight or nonexistent fibrosis. An overexpression of TNF-alpha mRNA is found in the liver and in the adipose tissue of NASH patients. The levels of mRNA-p55 are increased in the liver tissue of NASH patients. This overexpression is more elevated in patients with more advanced NASH. These findings suggest that the TNF-alpha system may be involved in the pathogenesis of NASH. 10.1053/jhep.2001.29628
    Pathogenesis and novel treatment options for non-alcoholic steatohepatitis. Wong Vincent Wai-Sun,Chitturi Shiv,Wong Grace Lai-Hung,Yu Jun,Chan Henry Lik-Yuen,Farrell Geoffrey C The lancet. Gastroenterology & hepatology Non-alcoholic fatty liver disease affects 20-40% of the population. Its active form, non-alcoholic steatohepatitis (NASH), is characterised by hepatocyte injury, liver inflammation, and progression of fibrosis, and has emerged as one of the most important causes of liver failure and hepatocellular carcinoma. Weight reduction of 10% by dietary restriction and regular exercise is sufficient to reverse NASH in most patients, but in practice this reduction is often not achieved. Available drugs such as vitamin E, pioglitazone, and pentoxifylline have borderline efficacy, but are limited by potential side-effects and toxicities, and do not improve liver fibrosis. However, basic and translational research has improved our understanding of the pathophysiology of NASH, thereby identifying several promising new treatment targets. Several drugs are in phase 2 and 3 development and could enter clinical practice in the near future. In this Review, we discuss the pathogenesis, treatment evaluation, existing therapies, and potential new treatments for NASH. 10.1016/S2468-1253(16)30011-5
    Heme oxygenase-1 levels and oxidative stress-related parameters in non-alcoholic fatty liver disease patients. Malaguarnera Lucia,Madeddu Roberto,Palio Elisabetta,Arena Nicolò,Malaguarnera Mariano Journal of hepatology BACKGROUND/AIMS:Non-alcoholic steatohepatitis (NASH) is a disorder that is histologically characterized by macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and fibrosis. NASH can range from a benign condition to end-stage liver disease. The mechanisms promoting transition from steatosis to NASH appear to involve multiple cellular adaptations to the oxidative stress occurring when fatty acid metabolism is altered. We evaluated the relationship between lipid peroxidation and other oxidative stress biomarkers with changes in expression of heme oxygenase-1 (HO-1) in human hepatic steatosis ranging from simple steatosis to NASH. METHODS:HO-1 expression, lipid peroxidation, ferritin and GSH levels were assayed from liver biopsies obtained from 60 subjects: 35 with NASH, 15 with simple steatosis and 10 controls. RESULTS:The HO-1 expression was significantly increased in NASH patients and the increase reflected the severity of the disease. A significant correlation was observed between the increased levels of HO-1 and ferritin, and between the increased levels of HO-1 and lipid peroxidation. Moreover, NASH patients with lower levels of GSH exhibited higher expression of HO-1. CONCLUSIONS:The induction of HO-1 is an adaptive response against oxidative damage elicited by lipid peroxidation and it may be critical in the progression of the disease. 10.1016/j.jhep.2004.11.040
    A maresin 1/RORα/12-lipoxygenase autoregulatory circuit prevents inflammation and progression of nonalcoholic steatohepatitis. Han Yong-Hyun,Shin Kyong-Oh,Kim Ju-Yeon,Khadka Daulat B,Kim Hyeon-Ji,Lee Yong-Moon,Cho Won-Jea,Cha Ji-Young,Lee Bong-Jin,Lee Mi-Ock The Journal of clinical investigation Retinoic acid-related orphan receptor α (RORα) is considered a key regulator of polarization in liver macrophages that is closely related to nonalcoholic steatohepatitis (NASH) pathogenesis. However, hepatic microenvironments that support the function of RORα as a polarity regulator were largely unknown. Here, we identified maresin 1 (MaR1), a docosahexaenoic acid (DHA) metabolite with a function of specialized proresolving mediator, as an endogenous ligand of RORα. MaR1 enhanced the expression and transcriptional activity of RORα and thereby increased the M2 polarity of liver macrophages. Administration of MaR1 protected mice from high-fat diet-induced NASH in a RORα-dependent manner. Surprisingly, RORα increased the level of MaR1 through transcriptional induction of 12-lipoxygenase (12-LOX), a key enzyme in MaR1 biosynthesis. Furthermore, we demonstrated that modulation of 12-LOX activity enhanced the protective function of DHA against NASH. Together, these results suggest that the MaR1/RORα/12-LOX autoregulatory circuit could offer potential therapeutic strategies for curing NASH. 10.1172/JCI124219
    STING-mediated inflammation in Kupffer cells contributes to progression of nonalcoholic steatohepatitis. Yu Yongsheng,Liu Yu,An Weishuai,Song Jingwen,Zhang Yuefan,Zhao Xianxian The Journal of clinical investigation Innate immune activation contributes to the transition from nonalcoholic fatty liver to nonalcoholic steatohepatitis (NASH). Stimulator of IFN genes (STING, also referred to Tmem173) is a universal receptor that recognizes released DNA and triggers innate immune activation. In this work, we investigated the role of STING in the progression of NASH in mice. Both methionine- and choline-deficient diet (MCD) and high-fat diet (HFD) were used to induce NASH in mice. Strikingly, STING deficiency attenuated steatosis, fibrosis, and inflammation in livers in both murine models of NASH. Additionally, STING deficiency increased fasting glucose levels in mice independently of insulin, but mitigated HFD-induced insulin resistance and weight gain and reduced levels of cholesterol, triglycerides, and LDL in serum; it also enhanced levels of HDL. The mitochondrial DNA (mtDNA) from hepatocytes of HFD-fed mice induced TNF-α and IL-6 expression in cultured Kupffer cells (KCs), which was attenuated by STING deficiency or pretreatment with BAY11-7082 (an NF-κB inhibitor). Finally, chronic exposure to 5,6-dimethylxanthenone-4-acetic acid (DMXAA, a STING agonist) led to hepatic steatosis and inflammation in WT mice, but not in STING-deficient mice. We proposed that STING functions as an mtDNA sensor in the KCs of liver under lipid overload and induces NF-κB-dependent inflammation in NASH. 10.1172/JCI121842
    Resolving inflammation in nonalcoholic steatohepatitis. Spite Matthew The Journal of clinical investigation Chronic unresolved inflammation contributes to the development of nonalcoholic steatohepatitis (NASH), a disorder characterized by lipotoxicity, fibrosis, and progressive liver dysfunction. In this issue of the JCI, Han et al. report that maresin 1 (MaR1), a proresolving lipid mediator, mitigates NASH by reprograming macrophages to an antiinflammatory phenotype. Mechanistically, they identified retinoic acid-related orphan receptor α (RORα) as both a target and autocrine regulator of MaR1 production. Because NASH is associated with many widely occurring metabolic diseases, including obesity and type 2 diabetes, identification of this endogenous protective pathway could have broad therapeutic implications. 10.1172/JCI127583
    Accumulation of natural killer T cells in progressive nonalcoholic fatty liver disease. Syn Wing-Kin,Oo Ye Htun,Pereira Thiago A,Karaca Gamze F,Jung Youngmi,Omenetti Alessia,Witek Rafal P,Choi Steve S,Guy Cynthia D,Fearing Caitlin M,Teaberry Vanessa,Pereira Fausto E L,Adams David H,Diehl Anna Mae Hepatology (Baltimore, Md.) UNLABELLED:Liver inflammation is greater in nonalcoholic steatohepatitis (NASH) than steatosis, suggesting that immune responses contribute to nonalcoholic fatty liver disease (NAFLD) progression. Livers normally contain many natural killer T (NKT) cells that produce factors that modulate inflammatory and fibrogenic responses. Such cells are relatively depleted in steatosis, but their status in more advanced NAFLD is uncertain. We hypothesized that NKT cells accumulate and promote fibrosis progression in NASH. We aimed to determine if livers become enriched with NKT cells during NASH-related fibrosis; identify responsible mechanisms; and assess if NKT cells stimulate fibrogenesis. NKT cells were analyzed in wildtype mice and Patched-deficient (Ptc(+/-)) mice with an overly active Hedgehog (Hh) pathway, before and after feeding methionine choline-deficient (MCD) diets to induce NASH-related fibrosis. Effects of NKT cell-derived factors on hepatic stellate cells (HSC) were examined and fibrogenesis was evaluated in CD1d-deficient mice that lack NKT cells. NKT cells were quantified in human cirrhotic and nondiseased livers. During NASH-related fibrogenesis in wildtype mice, Hh pathway activation occurred, leading to induction of factors that promoted NKT cell recruitment, retention, and viability, plus liver enrichment with NKT cells. Ptc(+/-) mice accumulated more NKT cells and developed worse liver fibrosis; CD1d-deficient mice that lack NKT cells were protected from fibrosis. NKT cell-conditioned medium stimulated HSC to become myofibroblastic. Liver explants were 2-fold enriched with NKT cells in patients with non-NASH cirrhosis, and 4-fold enriched in patients with NASH cirrhosis. CONCLUSION:Hh pathway activation leads to hepatic enrichment with NKT cells that contribute to fibrosis progression in NASH. 10.1002/hep.23599
    ASMase regulates autophagy and lysosomal membrane permeabilization and its inhibition prevents early stage non-alcoholic steatohepatitis. Fucho Raquel,Martínez Laura,Baulies Anna,Torres Sandra,Tarrats Nuria,Fernandez Anna,Ribas Vicente,Astudillo Alma M,Balsinde Jesús,Garcia-Rovés Pablo,Elena Montserrat,Bergheim Ina,Lotersztajn Sophie,Trautwein Christian,Appelqvist Hanna,Paton Adrienne W,Paton James C,Czaja Mark J,Kaplowitz Neil,Fernandez-Checa Jose C,García-Ruiz Carmen Journal of hepatology BACKGROUND & AIMS:Acid sphingomyelinase (ASMase) is activated in non-alcoholic steatohepatitis (NASH). However, the contribution of ASMase to NASH is poorly understood and limited to hepatic steatosis and glucose metabolism. Here we examined the role of ASMase in high fat diet (HFD)-induced NASH. METHODS:Autophagy, endoplasmic reticulum (ER) stress and lysosomal membrane permeabilization (LMP) were determined in ASMase(-/-) mice fed a HFD. The impact of pharmacological ASMase inhibition on NASH was analyzed in wild type mice fed a HFD. RESULTS:ASMase deficiency determined resistance to hepatic steatosis mediated by a HFD or methionine-choline deficient diet. ASMase(-/-) mice were resistant to HFD-induced hepatic ER stress, but sensitive to tunicamycin-mediated ER stress, indicating selectivity in the resistance of ASMase(-/-) mice to ER stress and steatosis. Autophagic flux, determined in the presence of rapamycin and/or chloroquine, was lower in primary mouse hepatocytes (PMH) from ASMase(-/-) mice and accompanied by increased p62 levels, suggesting autophagic impairment. Moreover, autophagy suppression by chloroquine and brefeldin A caused ER stress in PMH from ASMase(+/+) mice but not in ASMase(-/-) mice. ASMase(-/-) PMH exhibited increased lysosomal cholesterol loading, decreased LMP and apoptosis resistance induced by O-methyl-serine dodecylamide hydrochloride or palmitic acid, effects that were reversed by decreasing cholesterol levels by oxysterol 25-hydroxycholesterol. In vivo pharmacological ASMase inhibition by amitriptyline, a widely used tricyclic antidepressant, protected wild type mice against HFD-induced hepatic steatosis, fibrosis, and liver damage, effects indicative of early-stage NASH. CONCLUSIONS:These findings underscore a critical role for ASMase in diet-induced NASH and suggest the potential of amitriptyline as a treatment for patients with NASH. 10.1016/j.jhep.2014.06.009
    The Role of Innate Immune Cells in Nonalcoholic Steatohepatitis. Cai Jingjing,Zhang Xiao-Jing,Li Hongliang Hepatology (Baltimore, Md.) Inflammation and metabolic dysfunction are hallmarks of nonalcoholic steatohepatitis (NASH), which is one of the fastest-growing liver diseases worldwide. Emerging evidence indicates that innate immune mechanisms are pivotal drivers of inflammation and other pathological manifestations observed in NASH, such as hepatosteatosis, insulin resistance (IR), and fibrosis. This robust innate immune reaction is intrinsic to the liver, which is an important immunological organ that contains a coordinated network of innate immune cells, including Kupffer cells (KCs), dendritic cells (DCs), and lymphocytes. Hepatocytes and liver sinusoidal endothelial cells (LSECs) are not formally innate immune cells, but they take on immune cell function when stressed. These cells can sense excess metabolites and bacterial products and translate those signals into immune responses and pathological hepatic changes during the development of NASH. In this review, we take a historical perspective in describing decades of research that aimed to identify the key molecular and cellular players in the innate immune system in the setting of NASH. Furthermore, we summarize the innate immune cells that are involved in the progression of NASH and illustrate how they sense disturbances in circulating metabolic factors by innate immune receptors and subsequently initiate the intercellular signaling cascades that lead to persistent inflammation and progression of hepatic complications. 10.1002/hep.30506
    Nonalcoholic steatohepatitis. Reid A E Gastroenterology Nonalcoholic steatohepatitis (NASH) is a condition characterized by hepatomegaly, elevated serum aminotransferase levels, and a histologic picture similar to alcoholic hepatitis in the absence of alcohol abuse. Most patients with NASH are obese women, and many have diabetes mellitus, hypercholesterolemia, or hypertriglyceridemia. NASH has also been associated with a number of metabolic conditions, surgical procedures, and drug treatments. Most patients are asymptomatic. The most common sign of NASH is hepatomegaly. Stigmata of chronic liver disease are rare. Laboratory abnormalities include a 2-4-fold elevation of serum aminotransferase levels; other liver function test results are usually normal. Histologically, there is moderate to severe macrovesicular steatosis and lobular hepatitis with necrosis or ballooning degeneration and/or fibrosis. The pathogenesis of NASH is poorly understood, but lipid peroxidation and oxidative stress are the leading culprits. The natural history of NASH is unknown, but NASH seems to be a stable disease in most patients. Treatment of NASH is unproven, but weight reduction is recommended in obese patients. Small pilot studies of several drugs have shown promise, but large randomized clinical trials are awaited. Orthotopic liver transplantation is the treatment of choice for end-stage liver disease secondary to NASH. 10.1053/gast.2001.27126
    Osteopontin is induced by hedgehog pathway activation and promotes fibrosis progression in nonalcoholic steatohepatitis. Syn Wing-Kin,Choi Steve S,Liaskou Evaggelia,Karaca Gamze F,Agboola Kolade M,Oo Ye Htun,Mi Zhiyong,Pereira Thiago A,Zdanowicz Marzena,Malladi Padmini,Chen Yuping,Moylan Cynthia,Jung Youngmi,Bhattacharya Syamal D,Teaberry Vanessa,Omenetti Alessia,Abdelmalek Manal F,Guy Cynthia D,Adams David H,Kuo Paul C,Michelotti Gregory A,Whitington Peter F,Diehl Anna Mae Hepatology (Baltimore, Md.) UNLABELLED:Nonalcoholic steatohepatitis (NASH) is a leading cause of cirrhosis. Recently, we showed that NASH-related cirrhosis is associated with Hedgehog (Hh) pathway activation. The gene encoding osteopontin (OPN), a profibrogenic extracellular matrix protein and cytokine, is a direct transcriptional target of the Hh pathway. Thus, we hypothesize that Hh signaling induces OPN to promote liver fibrosis in NASH. Hepatic OPN expression and liver fibrosis were analyzed in wild-type (WT) mice, Patched-deficient (Ptc(+/-) ) (overly active Hh signaling) mice, and OPN-deficient mice before and after feeding methionine and choline-deficient (MCD) diets to induce NASH-related fibrosis. Hepatic OPN was also quantified in human NASH and nondiseased livers. Hh signaling was manipulated in cultured liver cells to assess direct effects on OPN expression, and hepatic stellate cells (HSCs) were cultured in medium with different OPN activities to determine effects on HSC phenotype. When fed MCD diets, Ptc(+/-) mice expressed more OPN and developed worse liver fibrosis (P < 0.05) than WT mice, whereas OPN-deficient mice exhibited reduced fibrosis (P < 0.05). In NASH patients, OPN was significantly up-regulated and correlated with Hh pathway activity and fibrosis stage. During NASH, ductular cells strongly expressed OPN. In cultured HSCs, SAG (an Hh agonist) up-regulated, whereas cyclopamine (an Hh antagonist) repressed OPN expression (P < 0.005). Cholangiocyte-derived OPN and recombinant OPN promoted fibrogenic responses in HSCs (P < 0.05); neutralizing OPN with RNA aptamers attenuated this (P < 0.05). CONCLUSION:OPN is Hh-regulated and directly promotes profibrogenic responses. OPN induction correlates with Hh pathway activity and fibrosis stage. Therefore, OPN inhibition may be beneficial in NASH. 10.1002/hep.23998
    An AMPK-caspase-6 axis controls liver damage in nonalcoholic steatohepatitis. Zhao Peng,Sun Xiaoli,Chaggan Cynthia,Liao Zhongji,In Wong Kai,He Feng,Singh Seema,Loomba Rohit,Karin Michael,Witztum Joseph L,Saltiel Alan R Science (New York, N.Y.) Liver cell death has an essential role in nonalcoholic steatohepatitis (NASH). The activity of the energy sensor adenosine monophosphate (AMP)-activated protein kinase (AMPK) is repressed in NASH. Liver-specific AMPK knockout aggravated liver damage in mouse NASH models. AMPK phosphorylated proapoptotic caspase-6 protein to inhibit its activation, keeping hepatocyte apoptosis in check. Suppression of AMPK activity relieved this inhibition, rendering caspase-6 activated in human and mouse NASH. AMPK activation or caspase-6 inhibition, even after the onset of NASH, improved liver damage and fibrosis. Once phosphorylation was decreased, caspase-6 was activated by caspase-3 or -7. Active caspase-6 cleaved Bid to induce cytochrome c release, generating a feedforward loop that leads to hepatocyte death. Thus, the AMPK-caspase-6 axis regulates liver damage in NASH, implicating AMPK and caspase-6 as therapeutic targets. 10.1126/science.aay0542
    CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis. Zhang Xiang,Shen Jiayun,Man Kwan,Chu Eagle S H,Yau Tung On,Sung Joanne C Y,Go Minnie Y Y,Deng Jun,Lu Liwei,Wong Vincent W S,Sung Joseph J Y,Farrell Geoffrey,Yu Jun Journal of hepatology BACKGROUND & AIMS:Perpetuate liver inflammation is crucial in the pathogenesis of non-alcoholic steatohepatitis (NASH). Expression of CXCL10, a pro-inflammatory cytokine, correlates positively with obesity and type 2 diabetes. Whether CXCL10 plays a role in NASH was unknown. We aimed to investigate the functional and clinical impact of CXCL10 in NASH. METHODS:Cxcl10 gene-deleted (Cxcl10(-/-)) and C57BL/6 wild type (WT) mice were fed a methionine- and choline-deficient (MCD) diet for 4 or 8 weeks. In other experiments, we injected neutralizing anti-CXCL10 mAb into MCD-fed WT mice. Human serum was obtained from 147 patients with biopsy-proven non-alcoholic fatty liver disease and 73 control subjects. RESULTS:WT mice, fed the MCD diet, developed steatohepatitis with higher hepatic CXCL10 expression. Cxcl10(-/-) mice were refractory to MCD-induced steatohepatitis. We further revealed that CXCL10 was associated with the induction of important pro-inflammatory cytokines (TNF-α, IL-1β, and MCP-1) and activation of the NF-κB pathway. CXCL10 was linked to steatosis through upregulation of the lipogenic factors SREBP-1c and LXR, and also to oxidative stress (upregulation of CYP2E1 and C/EBPβ). Blockade of CXCL10 protected against hepatocyte injury in vitro and against steatohepatitis development in mice. We further investigated the clinical impact of CXCL10 and found circulating and hepatic CXCL10 levels were significantly higher in human NASH. Importantly, the circulating CXCL10 level was correlated with the degree of lobular inflammation and was an independent risk factor for NASH patients. CONCLUSIONS:We demonstrate for the first time that CXCL10 plays a pivotal role in the pathogenesis of experimental steatohepatitis. CXCL10 maybe a potential non-invasive biomarker for NASH patients. 10.1016/j.jhep.2014.07.006
    NKT-associated hedgehog and osteopontin drive fibrogenesis in non-alcoholic fatty liver disease. Syn Wing-Kin,Agboola Kolade M,Swiderska Marzena,Michelotti Gregory A,Liaskou Evaggelia,Pang Herbert,Xie Guanhua,Philips George,Chan Isaac S,Karaca Gamze F,Pereira Thiago de Almeida,Chen Yuping,Mi Zhiyong,Kuo Paul C,Choi Steve S,Guy Cynthia D,Abdelmalek Manal F,Diehl Anna Mae Gut OBJECTIVE:Immune responses are important in dictating non-alcoholic steatohepatitis (NASH) outcome. We previously reported that upregulation of hedgehog (Hh) and osteopontin (OPN) occurs in NASH, that Hh-regulated accumulation of natural killer T (NKT) cells promotes hepatic stellate cell (HSC) activation, and that cirrhotic livers harbour large numbers of NKT cells. DESIGN:The hypothesis that activated NKT cells drive fibrogenesis during NASH was evaluated by assessing if NKT depletion protects against NASH fibrosis; identifying the NKT-associated fibrogenic factors; and correlating plasma levels of the NKT cell-associated factor OPN with fibrosis severity in mice and humans. RESULTS:When fed methionine-choline-deficient (MCD) diets for 8 weeks, wild type (WT) mice exhibited Hh pathway activation, enhanced OPN expression, and NASH-fibrosis. Ja18-/- and CD1d-/- mice which lack NKT cells had significantly attenuated Hh and OPN expression and dramatically less fibrosis. Liver mononuclear cells (LMNCs) from MCD diet fed WT mice contained activated NKT cells, generated Hh and OPN, and stimulated HSCs to become myofibroblasts; neutralising these factors abrogated the fibrogenic actions of WT LMNCs. LMNCs from NKT-cell-deficient mice were deficient in fibrogenic factors, failing to activate collagen gene expression in HSCs. Human NASH livers with advanced fibrosis contained more OPN and Hh protein than those with early fibrosis. Plasma levels of OPN mirrored hepatic OPN expression and correlated with fibrosis severity. CONCLUSION:Hepatic NKT cells drive production of OPN and Hh ligands that promote fibrogenesis during NASH. Associated increases in plasma levels of OPN may provide a biomarker of NASH fibrosis. 10.1136/gutjnl-2011-301857
    Adaptation of hepatic mitochondrial function in humans with non-alcoholic fatty liver is lost in steatohepatitis. Koliaki Chrysi,Szendroedi Julia,Kaul Kirti,Jelenik Tomas,Nowotny Peter,Jankowiak Frank,Herder Christian,Carstensen Maren,Krausch Markus,Knoefel Wolfram Trudo,Schlensak Matthias,Roden Michael Cell metabolism The association of hepatic mitochondrial function with insulin resistance and non-alcoholic fatty liver (NAFL) or steatohepatitis (NASH) remains unclear. This study applied high-resolution respirometry to directly quantify mitochondrial respiration in liver biopsies of obese insulin-resistant humans without (n = 18) or with (n = 16) histologically proven NAFL or with NASH (n = 7) compared to lean individuals (n = 12). Despite similar mitochondrial content, obese humans with or without NAFL had 4.3- to 5.0-fold higher maximal respiration rates in isolated mitochondria than lean persons. NASH patients featured higher mitochondrial mass, but 31%-40% lower maximal respiration, which associated with greater hepatic insulin resistance, mitochondrial uncoupling, and leaking activity. In NASH, augmented hepatic oxidative stress (H2O2, lipid peroxides) and oxidative DNA damage (8-OH-deoxyguanosine) was paralleled by reduced anti-oxidant defense capacity and increased inflammatory response. These data suggest adaptation of the liver ("hepatic mitochondrial flexibility") at early stages of obesity-related insulin resistance, which is subsequently lost in NASH. 10.1016/j.cmet.2015.04.004
    Ischaemia-reperfusion injury in non-alcoholic steatohepatitis (NASH) liver: a tough problem to cope with. Xu C,Yu C,Li Y Gut
    The gut-liver-axis: endotoxemia, inflammation, insulin resistance and NASH. Siebler Jürgen,Galle Peter R,Weber Matthias M Journal of hepatology 10.1016/j.jhep.2008.03.007
    Mechanisms of Fibrosis Development in Nonalcoholic Steatohepatitis. Schwabe Robert F,Tabas Ira,Pajvani Utpal B Gastroenterology Nonalcoholic fatty liver disease is the most prevalent liver disease worldwide, affecting 20%-25% of the adult population. In 25% of patients, nonalcoholic fatty liver disease progresses to nonalcoholic steatohepatitis (NASH), which increases the risk for the development of cirrhosis, liver failure, and hepatocellular carcinoma. In patients with NASH, liver fibrosis is the main determinant of mortality. Here, we review how interactions between different liver cells culminate in fibrosis development in NASH, focusing on triggers and consequences of hepatocyte-macrophage-hepatic stellate cell (HSC) crosstalk. We discuss pathways through which stressed and dead hepatocytes instigate the profibrogenic crosstalk with HSC and macrophages, including the reactivation of developmental pathways such as TAZ, Notch, and hedgehog; how clearance of dead cells in NASH via efferocytosis may affect inflammation and fibrogenesis; and insights into HSC and macrophage heterogeneity revealed by single-cell RNA sequencing. Finally, we summarize options to therapeutically interrupt this profibrogenic hepatocyte-macrophage-HSC network in NASH. 10.1053/j.gastro.2019.11.311
    β-Integrin and MAdCAM-1 play opposing roles during the development of non-alcoholic steatohepatitis. Drescher Hannah K,Schippers Angela,Clahsen Thomas,Sahin Hacer,Noels Heidi,Hornef Mathias,Wagner Norbert,Trautwein Christian,Streetz Konrad L,Kroy Daniela C Journal of hepatology BACKGROUND & AIMS:Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease in Western countries. It is unclear how infiltrating leukocytes affect NASH-development. Our study aims to investigate the role of the homing/receptor, pair mucosal addressin cell adhesion molecule-1 (MAdCAM-1)/β-Integrin, on immune cell recruitment and disease progression in a steatohepatitis model. METHODS:Constitutive β-Integrin deficient (β) and MAdCAM-1 deficient (MAdCAM-1) mice were fed a high fat diet (HFD) for 26weeks or methionine-choline-deficient-diet (MCD) for 4weeks. RESULTS:β mice displayed earlier and more progressive steatohepatitis during HFD- and MCD-treatment, while MAdCAM-1 mice showed less histomorphological changes. The anti-oxidative stress response was significantly weaker in β mice as reflected by a significant downregulation of the transcription factors nuclear-factor(erythroid-derived 2)-like 2 (Nrf2) and heme-oxigenase-1 (HO-1). Additionally, stronger dihydroethidium-staining revealed an increased oxidative stress response in β animals. In contrast, MAdCAM-1 mice showed an upregulation of the anti-oxidative stress response. β animals exhibited stronger hepatic infiltration of inflammatory cells, especially neutrophils, reflecting earlier steatohepatitis initiation. Expression of regulatory T cell (T) markers as well as numbers of anti-inflammatory macrophages was significantly enhanced in MAdCAM-1 mice. Those changes finally resulted in earlier and stronger collagen accumulation in β mice, whereas MAdCAM-1 mice were protected from fibrosis initiation. CONCLUSIONS:Adhesion molecule mediated effector cell migration contributes to the outcome of steatohepatitis in the HFD- and the MCD model. While MAdCAM-1 promotes steatohepatitis, β-Integrin unexpectedly exerts protective effects. β mice show earlier steatohepatitis initiation and significantly stronger fibrosis progression. Accordingly, the interaction of β-Integrins and their receptor MAdCAM-1 provide novel targets for therapeutic interventions in steatohepatitis. LAY SUMMARY:The mucosal addressin cell adhesion molecule 1 (MAdCAM-1) is expressed in livers upon diet-induced non-alcoholic steatohepatitis (NASH). Loss of MAdCAM-1 has beneficial effects regarding the development of NASH - manifested by reduced hepatic oxidative stress and decreased inflammation. In contrast, β-Integrin-deficiency results in increased steatohepatitis. 10.1016/j.jhep.2017.02.001
    Inhibition of receptor-interacting protein kinase 1 improves experimental non-alcoholic fatty liver disease. Majdi Amine,Aoudjehane Lynda,Ratziu Vlad,Islam Tawhidul,Afonso Marta B,Conti Filomena,Mestiri Taïeb,Lagouge Marie,Foufelle Fabienne,Ballenghien Florine,Ledent Tatiana,Moldes Marthe,Cadoret Axelle,Fouassier Laura,Delaunay Jean-Louis,Aït-Slimane Tounsia,Courtois Gilles,Fève Bruno,Scatton Olivier,Prip-Buus Carina,Rodrigues Cecília M P,Housset Chantal,Gautheron Jérémie Journal of hepatology BACKGROUND & AIMS:In non-alcoholic fatty liver disease (NAFLD), hepatocytes can undergo necroptosis: a regulated form of necrotic cell death mediated by the receptor-interacting protein kinase (RIPK) 1. Herein, we assessed the potential for RIPK1 and its downstream effector mixed lineage kinase domain-like protein (MLKL) to act as therapeutic targets and markers of activity in NAFLD. METHODS:C57/BL6J-mice were fed a normal chow diet or a high-fat diet (HFD). The effect of RIPA-56, a highly specific inhibitor of RIPK1, was evaluated in HFD-fed mice and in primary human steatotic hepatocytes. RIPK1 and MLKL concentrations were measured in the serum of patients with NAFLD. RESULTS:When used as either a prophylactic or curative treatment for HFD-fed mice, RIPA-56 caused a downregulation of MLKL and a reduction of liver injury, inflammation and fibrosis, characteristic of non-alcoholic steatohepatitis (NASH), as well as of steatosis. This latter effect was reproduced by treating primary human steatotic hepatocytes with RIPA-56 or necrosulfonamide, a specific inhibitor of human MLKL, and by knockout (KO) of Mlkl in fat-loaded AML-12 mouse hepatocytes. Mlkl-KO led to activation of mitochondrial respiration and an increase in β-oxidation in steatotic hepatocytes. Along with decreased MLKL activation, Ripk3-KO mice exhibited increased activities of the liver mitochondrial respiratory chain complexes in experimental NASH. In patients with NAFLD, serum concentrations of RIPK1 and MLKL increased in correlation with activity. CONCLUSION:The inhibition of RIPK1 improves NASH features in HFD-fed mice and reverses steatosis via an MLKL-dependent mechanism that, at least partly, involves an increase in mitochondrial respiration. RIPK1 and MLKL are potential serum markers of activity and promising therapeutic targets in NAFLD. LAY SUMMARY:There are currently no pharmacological treatment options for non-alcoholic fatty liver disease (NAFLD), which is now the most frequent liver disease. Necroptosis is a regulated process of cell death that can occur in hepatocytes during NAFLD. Herein, we show that RIPK1, a gatekeeper of the necroptosis pathway that is activated in NAFLD, can be inhibited by RIPA-56 to reduce not only liver injury, inflammation and fibrosis, but also steatosis in experimental models. These results highlight the potential of RIPK1 as a therapeutic target in NAFLD. 10.1016/j.jhep.2019.11.008
    CD8+ T cells drive adipose tissue inflammation--a novel clue for NASH pathogenesis? Popov Yury,Schuppan Detlef Journal of hepatology 10.1016/j.jhep.2009.10.019
    Nonalcoholic steatohepatitis is the second leading etiology of liver disease among adults awaiting liver transplantation in the United States. Wong Robert J,Aguilar Maria,Cheung Ramsey,Perumpail Ryan B,Harrison Stephen A,Younossi Zobair M,Ahmed Aijaz Gastroenterology BACKGROUND & AIMS:Nonalcoholic steatohepatitis (NASH) has been predicted to become the leading indication for liver transplantation (LT) in the United States. However, few studies have evaluated changes in the etiology of liver diseases among patients awaiting LT, and none have focused on the effects of NASH on liver transplant waitlists in the United States. METHODS:We collected data from the United Network for Organ Sharing and Organ Procurement and Transplantation Network registry from 2004 through 2013, on liver transplant waitlist registrants with hepatitis C virus (HCV) infection, NASH, alcoholic liver disease (ALD), or a combination of HCV infection and ALD. We compared differences in survival within 90 days of registration (90-day survival) and probability of LT among patients with different diseases using Kaplan-Meier and multivariate logistic regression models. RESULTS:Between 2004 and 2013, new waitlist registrants with NASH increased by 170% (from 804 to 2174), with ALD increased by 45% (from 1400 to 2024), and with HCV increased by 14% (from 2887 to 3291); registrants with HCV and ALD decreased by 9% (from 880 to 803). In 2013, NASH became the second-leading disease among liver transplant waitlist registrants, after HCV. Patients with ALD had a significantly higher mean Model for End-Stage Liver Disease score at time of waitlist registration than other registrants. However, after multivariate adjustment, patients with ALD were less likely to die within 90 days when compared with patients with NASH (odds ratio [OR] = 0.77; 95% confidence interval [CI]: 0.67-0.89; P < .001); patients with HCV infection or HCV and ALD had similar odds for 90-day survival compared with NASH patients. Compared with patients with NASH, patients with HCV (OR = 1.45; 95% CI: 1.35-1.55; P < .001), ALD (OR = 1.15; 95% CI: 1.06-1.24; P < .001), or HCV and ALD (OR = 1.29; 95% CI: 1.18-1.42; P < .001) had higher odds for 90-day survival. CONCLUSIONS:Based on data from US adult LT databases, since 2004 the number of adults with NASH awaiting LTs has almost tripled. However, patients with NASH are less likely to undergo LT and less likely to survive for 90 days on the waitlist than patients with HCV, ALD, or HCV and ALD. 10.1053/j.gastro.2014.11.039
    Pathogenesis of Nonalcoholic Steatohepatitis. Machado Mariana Verdelho,Diehl Anna Mae Gastroenterology Nonalcoholic steatohepatitis (NASH) is a necro-inflammatory response that ensues when hepatocytes are injured by lipids (lipotoxicity). NASH is a potential outcome of nonalcoholic fatty liver (NAFL), a condition that occurs when lipids accumulate in hepatocytes. NASH may be reversible, but it can also result in cirrhosis and primary liver cancer. We are beginning to learn about the mechanisms of progression of NAFL and NASH. NAFL does not inevitably lead to NASH because NAFL is a heterogeneous condition. This heterogeneity exists because different types of lipids with different cytotoxic potential accumulate in the NAFL, and individuals with NAFL differ in their ability to defend against lipotoxicity. There are no tests that reliably predict which patients with NAFL will develop lipotoxicity. However, NASH encompasses the spectrum of wound-healing responses induced by lipotoxic hepatocytes. Differences in these wound-healing responses among individuals determine whether lipotoxic livers regenerate, leading to stabilization or resolution of NASH, or develop progressive scarring, cirrhosis, and possibly liver cancer. We review concepts that are central to the pathogenesis of NASH. 10.1053/j.gastro.2016.02.066
    Non-alcoholic fatty liver disease - A global public health perspective. Younossi Zobair M Journal of hepatology As the epidemics of obesity and type 2 diabetes mellitus increase worldwide, the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing proportionately. The subtype of NAFLD which can be characterised as non-alcoholic steatohepatitis (NASH) is a potentially progressive liver disease that can lead to cirrhosis, hepatocellular carcinoma, liver transplantation, and death. NAFLD is also associated with extrahepatic manifestations such as chronic kidney disease, cardiovascular disease and sleep apnoea. NAFLD and NASH carry a large economic burden and create poor health-related quality of life. Despite this important burden, we are only beginning to understand its mechanisms of pathogenesis and the contribution of environmental and genetic factors to the risk of developing a progressive course of disease. Research is underway to identify appropriate non-invasive diagnostic methods and effective treatments. Although the risk of liver-related mortality is increased in patients with NAFLD and liver fibrosis stages F3 or F4, the leading cause of death is cardiovascular disease. Given the rapidly growing global burden of NAFLD and NASH, efforts must continue to find accurate non-invasive diagnostic and prognostic biomarkers, to develop effective treatments for individuals with advanced NASH and prevention methods for individuals at high risk of NAFLD and progressive liver disease. 10.1016/j.jhep.2018.10.033
    Adaptive immunity: an emerging player in the progression of NAFLD. Nature reviews. Gastroenterology & hepatology In the past decade, nonalcoholic fatty liver disease (NAFLD) has become a leading cause of chronic liver disease and cirrhosis, as well as an important risk factor for hepatocellular carcinoma (HCC). NAFLD encompasses a spectrum of liver lesions, including simple steatosis, steatohepatitis and fibrosis. Although steatosis is often harmless, the lobular inflammation that characterizes nonalcoholic steatohepatitis (NASH) is considered a driving force in the progression of NAFLD. The current view is that innate immune mechanisms represent a key element in supporting hepatic inflammation in NASH. However, increasing evidence points to the role of adaptive immunity as an additional factor promoting liver inflammation. This Review discusses data regarding the role of B cells and T cells in sustaining the progression of NASH to fibrosis and HCC, along with the findings that antigens originating from oxidative stress act as a trigger for immune responses. We also highlight the mechanisms affecting liver immune tolerance in the setting of steatohepatitis that favour lymphocyte activation. Finally, we analyse emerging evidence concerning the possible application of immune modulating treatments in NASH therapy. 10.1038/s41575-019-0210-2
    TGF-β1-driven reduction of cytoglobin leads to oxidative DNA damage in stellate cells during non-alcoholic steatohepatitis. Okina Yoshinori,Sato-Matsubara Misako,Matsubara Tsutomu,Daikoku Atsuko,Longato Lisa,Rombouts Krista,Thanh Thuy Le Thi,Ichikawa Hiroshi,Minamiyama Yukiko,Kadota Mitsutaka,Fujii Hideki,Enomoto Masaru,Ikeda Kazuo,Yoshizato Katsutoshi,Pinzani Massimo,Kawada Norifumi Journal of hepatology BACKGROUND & AIMS:Cytoglobin (CYGB) is a respiratory protein that acts as a scavenger of reactive oxygen species. The molecular role of CYGB in human hepatic stellate cell (HSC) activation and human liver disease remains uncharacterised. The aim of this study was to reveal the mechanism by which the TGF-β1/SMAD2 pathway regulates the human CYGB promoter and the pathophysiological function of CYGB in human non-alcoholic steatohepatitis (NASH). METHODS:Immunohistochemical staining was performed using human NASH biopsy specimens. Molecular and biochemical analyses were performed by western blotting, quantitative PCR, and luciferase and immunoprecipitation assays. Hydroxyl radicals (OH) and oxidative DNA damage were measured using an OH-detectable probe and 8-hydroxy-2'-deoxyguanosine (8-OHdG) ELISA. RESULTS:In culture, TGF-β1-pretreated human HSCs exhibited lower CYGB levels - together with increased NADPH oxidase 4 (NOX4) expression - and were primed for HO-triggered OH production and 8-OHdG generation; overexpression of human CYGB in human HSCs reversed these effects. Electron spin resonance demonstrated the direct OH scavenging activity of recombinant human CYGB. Mechanistically, pSMAD2 reduced CYGB transcription by recruiting the M1 repressor isoform of SP3 to the human CYGB promoter at nucleotide positions 2-13 from the transcription start site. The same repression did not occur on the mouse Cygb promoter. TGF-β1/SMAD3 mediated αSMA and collagen expression. Consistent with observations in cultured human HSCs, CYGB expression was negligible, but 8-OHdG was abundant, in activated αSMApSMAD2- and αSMANOX4-positive hepatic stellate cells from patients with NASH and advanced fibrosis. CONCLUSIONS:Downregulation of CYGB by the TGF-β1/pSMAD2/SP3-M1 pathway brings about OH-dependent oxidative DNA damage in activated hepatic stellate cells from patients with NASH. LAY SUMMARY:Cytoglobin (CYGB) is a respiratory protein that acts as a scavenger of reactive oxygen species and protects cells from oxidative DNA damage. Herein, we show that the cytokine TGF-β1 downregulates human CYGB expression. This leads to oxidative DNA damage in activated hepatic stellate cells. Our findings provide new insights into the relationship between CYGB expression and the pathophysiology of fibrosis in patients with non-alcoholic steatohepatitis. 10.1016/j.jhep.2020.03.051
    The role of macrophages in nonalcoholic fatty liver disease and nonalcoholic steatohepatitis. Kazankov Konstantin,Jørgensen Simon Mark Dahl,Thomsen Karen Louise,Møller Holger Jon,Vilstrup Hendrik,George Jacob,Schuppan Detlef,Grønbæk Henning Nature reviews. Gastroenterology & hepatology Nonalcoholic fatty liver disease (NAFLD) and its inflammatory and often progressive subtype nonalcoholic steatohepatitis (NASH) are becoming the leading cause of liver-related morbidity and mortality worldwide, and a primary indication for liver transplantation. The pathophysiology of NASH is multifactorial and not yet completely understood; however, innate immunity is a major contributing factor in which liver-resident macrophages (Kupffer cells) and recruited macrophages play a central part in disease progression. In this Review, we assess the evidence for macrophage involvement in the development of steatosis, inflammation and fibrosis in NASH. In this process, not only the polarization of liver macrophages towards a pro-inflammatory phenotype is important, but adipose tissue macrophages, especially in the visceral compartment, also contribute to disease severity and insulin resistance. Macrophage activation is mediated by factors such as endotoxins and translocated bacteria owing to increased intestinal permeability, factors released from damaged or lipoapoptotic hepatocytes, as well as alterations in gut microbiota and defined nutritional components, including certain free fatty acids, cholesterol and their metabolites. Reflecting the important role of macrophages in NASH, we also review studies investigating drugs that target macrophage recruitment to the liver, macrophage polarization and their inflammatory effects as potential treatment options for patients with NASH. 10.1038/s41575-018-0082-x
    Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes. Wolf Monika Julia,Adili Arlind,Piotrowitz Kira,Abdullah Zeinab,Boege Yannick,Stemmer Kerstin,Ringelhan Marc,Simonavicius Nicole,Egger Michèle,Wohlleber Dirk,Lorentzen Anna,Einer Claudia,Schulz Sabine,Clavel Thomas,Protzer Ulrike,Thiele Christoph,Zischka Hans,Moch Holger,Tschöp Matthias,Tumanov Alexei V,Haller Dirk,Unger Kristian,Karin Michael,Kopf Manfred,Knolle Percy,Weber Achim,Heikenwalder Mathias Cancer cell Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8(+) T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8(+) T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8(+) and NKT cells cooperatively induce liver damage. Hepatocellular LTβR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development. 10.1016/j.ccell.2014.09.003
    Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2. Ye Dewei,Yang Kangmin,Zang Shufei,Lin Zhuofeng,Chau Hau-Tak,Wang Yudong,Zhang Jialiang,Shi Junping,Xu Aimin,Lin Shaoqiang,Wang Yu Journal of hepatology BACKGROUND & AIMS:Inflammatory cell infiltration in the liver is a hallmark of non-alcoholic steatohepatitis (NASH). However, the pathological events which trigger the infiltration of inflammatory cells to mediate NASH pathogenesis remains poorly understood. This study aims to investigate the role of neutrophil-derived lipocalin 2 (LCN2) in mediating the transition from simple steatosis to NASH. METHODS:Animal models of NASH were induced by high fat high cholesterol (HFHC) diet and methionine- and choline-deficient (MCD) diet in LCN2 knockout mice and wild-type controls. RESULTS:Circulating levels of LCN2 and its hepatic expression were markedly increased in both murine models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of LCN2. In contrast, chronic infusion of recombinant LCN2 exacerbated diet-induced liver injury, inflammation and macrophage accumulation in a neutrophil-dependent manner. Primary mouse neutrophils lacking LCN2 exhibited a defective migration capacity, which can be reversed by replenishment with recombinant LCN2. Mechanistically, LCN2 induced the expression of the chemokine (C-X-C motif) receptor 2 (CXCR2), thereby leading to activation of ERK1/2 and production of proinflammatory chemokines. LCN2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice. CONCLUSIONS:These findings demonstrated that LCN2 acts as a central mediator to facilitate the crosstalk between neutrophils and hepatic macrophages via induction of the chemokine receptor CXCR2, thereby exacerbating steatohepatitis. LAY SUMMARY:Lipocalin-2 levels in blood and the liver were markedly increased in both mouse models and human subjects with NASH, and these changes were associated with increased infiltration of neutrophils in the liver. In diet-induced NASH models, hepatic injury, necroinflammation and infiltration of neutrophils and macrophages were substantially attenuated by genetic depletion of lipocalin-2, but was augmented by chronic infusion of recombinant lipocalin-2. Lipocalin-2 induced the expression of the chemokine receptor CXCR2, thereby leading to activation of the mitogen-activated protein (MAP) kinase ERK1/2 and production of proinflammatory chemokines. Lipocalin-2-induced inflammation, infiltration of macrophages and liver injury was abrogated in CXCR2-deficient mice. 10.1016/j.jhep.2016.05.041
    Impaired Kupffer Cell Self-Renewal Alters the Liver Response to Lipid Overload during Non-alcoholic Steatohepatitis. Tran Sophie,Baba Ines,Poupel Lucie,Dussaud Sébastien,Moreau Martine,Gélineau Adélaïde,Marcelin Geneviève,Magréau-Davy Elissa,Ouhachi Melissa,Lesnik Philippe,Boissonnas Alexandre,Le Goff Wilfried,Clausen Björn E,Yvan-Charvet Laurent,Sennlaub Florian,Huby Thierry,Gautier Emmanuel L Immunity Kupffer cells (KCs) are liver-resident macrophages that self-renew by proliferation in the adult independently from monocytes. However, how they are maintained during non-alcoholic steatohepatitis (NASH) remains ill defined. We found that a fraction of KCs derived from Ly-6C monocytes during NASH, underlying impaired KC self-renewal. Monocyte-derived KCs (MoKCs) gradually seeded the KC pool as disease progressed in a response to embryo-derived KC (EmKC) death. Those MoKCs were partly immature and exhibited a pro-inflammatory status compared to EmKCs. Yet, they engrafted the KC pool for the long term as they remained following disease regression while acquiring mature EmKC markers. While KCs as a whole favored hepatic triglyceride storage during NASH, EmKCs promoted it more efficiently than MoKCs, and the latter exacerbated liver damage, highlighting functional differences among KCs with different origins. Overall, our data reveal that KC homeostasis is impaired during NASH, altering the liver response to lipids, as well as KC ontogeny. 10.1016/j.immuni.2020.06.003
    Nonalcoholic Steatohepatitis: A Review. Sheka Adam C,Adeyi Oyedele,Thompson Julie,Hameed Bilal,Crawford Peter A,Ikramuddin Sayeed JAMA Importance:Nonalcoholic steatohepatitis (NASH) is the inflammatory subtype of nonalcoholic fatty liver disease (NAFLD) and is associated with disease progression, development of cirrhosis, and need for liver transplant. Despite its importance, NASH is underrecognized in clinical practice. Observations:NASH affects an estimated 3% to 6% of the US population and the prevalence is increasing. NASH is strongly associated with obesity, dyslipidemia, type 2 diabetes, and metabolic syndrome. Although a number of noninvasive tests and scoring systems exist to characterize NAFLD and NASH, liver biopsy is the only accepted method for diagnosis of NASH. Currently, no NASH-specific therapies are approved by the US Food and Drug Administration. Lifestyle modification is the mainstay of treatment, including dietary changes and exercise, with the primary goal being weight loss. Substantial improvement in histologic outcomes, including fibrosis, is directly correlated with increasing weight loss. In some cases, bariatric surgery may be indicated to achieve and maintain the necessary degree of weight loss required for therapeutic effect. An estimated 20% of patients with NASH will develop cirrhosis, and NASH is predicted to become the leading indication for liver transplants in the US. The mortality rate among patients with NASH is substantially higher than the general population or patients without this inflammatory subtype of NAFLD, with annual all-cause mortality rate of 25.56 per 1000 person-years and a liver-specific mortality rate of 11.77 per 1000 person-years. Conclusions and Relevance:Nonalcoholic steatohepatitis affects 3% to 6% of the US population, is more prevalent in patients with metabolic disease and obesity, progresses to cirrhosis in approximately 20% of cases, and is associated with increased rates of liver-specific and overall mortality. Early identification and targeted treatment of patients with nonalcoholic steatohepatitis are needed to improve patient outcomes, including directing patients toward intensive lifestyle modification to promote weight loss and referral for bariatric surgery as indicated for management of obesity and metabolic disease. 10.1001/jama.2020.2298
    AMPK regulates macrophage polarization in adipose tissue inflammation and NASH. Weng Shih-Yen,Schuppan Detlef Journal of hepatology 10.1016/j.jhep.2012.09.031
    Hepatocyte Notch activation induces liver fibrosis in nonalcoholic steatohepatitis. Science translational medicine Fibrosis is the major determinant of morbidity and mortality in patients with nonalcoholic steatohepatitis (NASH) but has no approved pharmacotherapy in part because of incomplete understanding of its pathogenic mechanisms. Here, we report that hepatocyte Notch activity tracks with disease severity and treatment response in patients with NASH and is similarly increased in a mouse model of diet-induced NASH and liver fibrosis. Hepatocyte-specific Notch loss-of-function mouse models showed attenuated NASH-associated liver fibrosis, demonstrating causality to obesity-induced liver pathology. Conversely, forced activation of hepatocyte Notch induced fibrosis in both chow- and NASH diet-fed mice by increasing Sox9-dependent Osteopontin (Opn) expression and secretion from hepatocytes, which activate resident hepatic stellate cells. In a cross-sectional study, we found that OPN explains the positive correlation between liver Notch activity and fibrosis stage in patients. Further, we developed a Notch inhibitor [ antisense oligonucleotide ( ASO)] that reduced fibrosis in NASH diet-fed mice. In summary, these studies demonstrate the pathological role and therapeutic accessibility of the maladaptive hepatocyte Notch response in NASH-associated liver fibrosis. 10.1126/scitranslmed.aat0344
    The Hierarchical Model of NAFLD: Prognostic Significance of Histologic Features in NASH. Loomba Rohit,Chalasani Naga Gastroenterology 10.1053/j.gastro.2015.06.016
    Hepatocellular ballooning in NASH. Caldwell Stephen,Ikura Yoshihiro,Dias Daniela,Isomoto Kosuke,Yabu Akito,Moskaluk Christopher,Pramoonjago Patcharin,Simmons Winsor,Scruggs Harriet,Rosenbaum Nicholas,Wilkinson Timothy,Toms Patsy,Argo Curtis K,Al-Osaimi Abdullah M S,Redick Jan A Journal of hepatology BACKGROUND & AIMS:Hepatocellular ballooning is a key finding in nonalcoholic steatohepatitis (NASH). It is conventionally defined by hemotoxylin and eosin (H&E) staining showing enlarged cells with rarefied cytoplasm and recently by changes in the cytoskeleton. Fat droplets are emerging as important organelles in cell metabolism. To address a possible relation between fat droplets and ballooning, we studied fat staining, H&E, and keratin 18 staining in human NASH. METHODS:Sequential staining and high resolution imaging were used to study freshly prepared cryo-sections from 10 patients with histologically confirmed steatohepatitis using oil red O for fat droplet identification, H&E to identify ballooning, and anti-K18 to confirm cytoskeletal changes. High resolution images were captured at each stage using the Aperio Scanscope. To provide ultrastructural correlation, glutaraldehyde-fixed specimens were studied using transmission electron microscopy (TEM) with serial sectioning for localization of ballooned cells by light microscopy and TEM in identical specimens. RESULTS:Serial staining consistently demonstrated that hepatocellular ballooning is associated with fat droplet accumulation evident by oil red O positivity and depletion of cytoplasmic keratin 18 with K-18 positive Mallory-Denk bodies (MDB). TEM confirmed the association between osmium stained fat droplets, MDB formation, and cellular enlargement and suggested droplet-associated dilation of the endoplasmic reticulum. CONCLUSIONS:These results indicate a relationship between cellular ballooning, fat droplet accumulation, and cytoskeletal injury in NASH. We speculate that injury to multiple, organelles including fat droplets and endoplasmic reticulum, contribute to this characteristic finding. 10.1016/j.jhep.2010.04.031
    CD44 is a key player in non-alcoholic steatohepatitis. Patouraux Stéphanie,Rousseau Déborah,Bonnafous Stéphanie,Lebeaupin Cynthia,Luci Carmelo,Canivet Clémence M,Schneck Anne-Sophie,Bertola Adeline,Saint-Paul Marie-Christine,Iannelli Antonio,Gugenheim Jean,Anty Rodolphe,Tran Albert,Bailly-Maitre Béatrice,Gual Philippe Journal of hepatology BACKGROUND & AIMS:Cluster of differentiation (CD)44 regulates adipose tissue inflammation in obesity and hepatic leukocyte recruitment in a lithogenic context. However, its role in hepatic inflammation in a mouse model of steatohepatitis and its relevance in humans have not yet been investigated. We aimed to evaluated the contribution of CD44 to non-alcoholic steatohepatitis (NASH) development and liver injury in mouse models and in patients at various stages of non-alcoholic fatty liver disease (NAFLD) progression. METHODS:The role of CD44 was evaluated in CD44 mice and after injections of an αCD44 antibody in wild-type mice challenged with a methionine- and choline-deficient diet (MCDD). In obese patients, hepatic CD44 (n=30 and 5 NASH patients with a second liver biopsy after bariatric surgery) and serum sCD44 (n=64) were evaluated. RESULTS:Liver inflammation (including inflammatory foci number, macrophage and neutrophil infiltration and CCL2/CCR2 levels), liver injury and fibrosis strongly decreased in CD44 mice compared to wild-type mice on MCDD. CD44 deficiency enhanced the M2 polarization and strongly decreased the activation of macrophages by lipopolysaccharide (LPS), hepatocyte damage-associated molecular patterns (DAMPs) and saturated fatty acids. Neutralization of CD44 in mice with steatohepatitis strongly decreased the macrophage infiltration and chemokine ligand (CCL)2 expression with a partial correction of liver inflammation and injury. In obese patients, hepatic CD44 was strongly upregulated in NASH patients (p=0.0008) and correlated with NAFLD activity score (NAS) (p=0.001), ballooning (p=0.003), alanine transaminase (p=0.005) and hepatic CCL2 (p<0.001) and macrophage marker CD68 (p<0.001) expression. Correction of NASH was associated with a strong decrease in liver CD44 cells. Finally, the soluble form of CD44 increased with severe steatosis (p=0.0005) and NASH (p=0.007). CONCLUSION:Human and experimental data suggest that CD44 is a marker and key player of hepatic inflammation and its targeting partially corrects NASH. LAY SUMMARY:Human and experimental data suggest that CD44, a cellular protein mainly expressed in immune cells, is a marker and key player of non-alcoholic steatohepatitis (NASH). Indeed, CD44 enhances the non-alcoholic fatty liver (NAFL) (hepatic steatosis) to NASH progression by regulating hepatic macrophage polarization (pro-inflammatory phenotype) and infiltration (macrophage motility and the MCP1/CCL2/CCR2 system). Targeting CD44 partially corrects NASH, making it a potential therapeutic strategy. 10.1016/j.jhep.2017.03.003
    Diagnosis: new noninvasive test to diagnose NASH by analysing exhaled breath. Greenhill Claire Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2012.226
    Arginine and NASH--do macrophages deliver the first hit? Scheja Ludger,Kluwe Johannes Journal of hepatology 10.1016/j.jhep.2014.11.001
    Liver fibrosis in 2012: Convergent pathways that cause hepatic fibrosis in NASH. Friedman Scott L Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2012.256
    NASH: KLF6 activates PPARα signalling in hepatic steatosis. Ray Katrina Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2013.26
    Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. Mouries Juliette,Brescia Paola,Silvestri Alessandra,Spadoni Ilaria,Sorribas Marcel,Wiest Reiner,Mileti Erika,Galbiati Marianna,Invernizzi Pietro,Adorini Luciano,Penna Giuseppe,Rescigno Maria Journal of hepatology BACKGROUND & AIMS:Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. METHODS:C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. RESULTS:We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. CONCLUSIONS:We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. LAY SUMMARY:The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH. 10.1016/j.jhep.2019.08.005
    Blocking integrin αβ-mediated CD4 T cell recruitment to the intestine and liver protects mice from western diet-induced non-alcoholic steatohepatitis. Rai Ravi P,Liu Yunshan,Iyer Smita S,Liu Silvia,Gupta Biki,Desai Chirayu,Kumar Pradeep,Smith Tekla,Singhi Aatur D,Nusrat Asma,Parkos Charles A,Monga Satdarshan P,Czaja Mark J,Anania Frank A,Raeman Reben Journal of hepatology BACKGROUND & AIMS:The heterodimeric integrin receptor αβ regulates CD4 T cell recruitment to inflamed tissues, but its role in the pathogenesis of non-alcoholic steatohepatitis (NASH) is unknown. Herein, we examined the role of αβ-mediated recruitment of CD4 T cells to the intestine and liver in NASH. METHODS:Male littermate F11r (control) and junctional adhesion molecule A knockout F11r mice were fed a normal diet or a western diet (WD) for 8 weeks. Liver and intestinal tissues were analyzed by histology, quantitative reverse transcription PCR (qRT-PCR), 16s rRNA sequencing and flow cytometry. Colonic mucosa-associated microbiota were analyzed using 16s rRNA sequencing. Liver biopsies from patients with NASH were analyzed by confocal imaging and qRT-PCR. RESULTS:WD-fed knockout mice developed NASH and had increased hepatic and intestinal αβ CD4 T cells relative to control mice who developed mild hepatic steatosis. The increase in αβ CD4 T cells was associated with markedly higher expression of the αβ ligand mucosal addressin cell adhesion molecule 1 (MAdCAM-1) in the colonic mucosa and livers of WD-fed knockout mice. Elevated MAdCAM-1 expression correlated with increased mucosa-associated Proteobacteria in the WD-fed knockout mice. Antibiotics reduced MAdCAM-1 expression indicating that the diet-altered microbiota promoted colonic and hepatic MAdCAM-1 expression. αβ blockade in WD-fed knockout mice significantly decreased αβ CD4 T cell recruitment to the intestine and liver, attenuated hepatic inflammation and fibrosis, and improved metabolic indices. MAdCAM-1 blockade also reduced hepatic inflammation and fibrosis in WD-fed knockout mice. Hepatic MAdCAM-1 expression was elevated in patients with NASH and correlated with higher expression of α and β integrins. CONCLUSIONS:These findings establish αβ/MAdCAM-1 as a critical axis regulating NASH development through colonic and hepatic CD4 T cell recruitment. LAY SUMMARY:Non-alcoholic steatohepatitis (NASH) is an advanced and progressive form of non-alcoholic fatty liver disease (NAFLD), and despite its growing incidence no therapies currently exist to halt NAFLD progression. Herein, we show that blocking integrin receptor αβ-mediated recruitment of CD4 T cells to the intestine and liver not only attenuates hepatic inflammation and fibrosis, but also improves metabolic derangements associated with NASH. These findings provide evidence for the potential therapeutic application of αβ antibody in the treatment of human NASH. 10.1016/j.jhep.2020.05.047
    Outcomes of liver transplantation for non-alcoholic steatohepatitis: A European Liver Transplant Registry study. Haldar Debashis,Kern Barbara,Hodson James,Armstrong Matthew James,Adam Rene,Berlakovich Gabriela,Fritz Josef,Feurstein Benedikt,Popp Wolfgang,Karam Vincent,Muiesan Paolo,O'Grady John,Jamieson Neville,Wigmore Stephen J,Pirenne Jacques,Malek-Hosseini Seyed Ali,Hidalgo Ernest,Tokat Yaman,Paul Andreas,Pratschke Johann,Bartels Michael,Trunecka Pavel,Settmacher Utz,Pinzani Massimo,Duvoux Christophe,Newsome Philip Noel,Schneeberger Stefan, Journal of hepatology BACKGROUND & AIMS:Little is known about outcomes of liver transplantation for patients with non-alcoholic steatohepatitis (NASH). We aimed to determine the frequency and outcomes of liver transplantation for patients with NASH in Europe and identify prognostic factors. METHODS:We analysed data from patients transplanted for end-stage liver disease between January 2002 and December 2016 using the European Liver Transplant Registry database. We compared data between patients with NASH versus other aetiologies. The principle endpoints were patient and overall allograft survival. RESULTS:Among 68,950 adults undergoing first liver transplantation, 4.0% were transplanted for NASH - an increase from 1.2% in 2002 to 8.4% in 2016. A greater proportion of patients transplanted for NASH (39.1%) had hepatocellular carcinoma (HCC) than non-NASH patients (28.9%, p <0.001). NASH was not significantly associated with survival of patients (hazard ratio [HR] 1.02, p = 0.713) or grafts (HR 0.99; p = 0.815) after accounting for available recipient and donor variables. Infection (24.0%) and cardio/cerebrovascular complications (5.3%) were the commonest causes of death in patients with NASH without HCC. Increasing recipient age (61-65 years: HR 2.07, p <0.001; >65: HR 1.72, p = 0.017), elevated model for end-stage liver disease score (>23: HR 1.48, p = 0.048) and low (<18.5 kg/m: HR 4.29, p = 0.048) or high (>40 kg/m: HR 1.96, p = 0.012) recipient body mass index independently predicted death in patients transplanted for NASH without HCC. Data must be interpreted in the context of absent recognised confounders, such as pre-morbid metabolic risk factors. CONCLUSIONS:The number and proportion of liver transplants performed for NASH in Europe has increased from 2002 through 2016. HCC was more common in patients transplanted with NASH. Survival of patients and grafts in patients with NASH is comparable to that of other disease indications. LAY SUMMARY:The prevalence of non-alcoholic fatty liver disease has increased dramatically in parallel with the worldwide increase in obesity and diabetes. Its progressive form, non-alcoholic steatohepatitis, is a growing indication for liver transplantation in Europe, with good overall outcomes reported. However, careful risk factor assessment is required to maintain favourable post-transplant outcomes in patients with non-alcoholic steatohepatitis. 10.1016/j.jhep.2019.04.011
    ARRB1 inhibits non-alcoholic steatohepatitis progression by promoting GDF15 maturation. Zhang Zechuan,Xu Xiaoliang,Tian Wenfang,Jiang Runqiu,Lu Yijun,Sun Qikai,Fu Rao,He Qifeng,Wang Jincheng,Liu Yang,Yu Hailong,Sun Beicheng Journal of hepatology BACKGROUND & AIMS:Non-alcoholic steatohepatitis (NASH) is associated with the dysregulation of lipid metabolism and hepatic inflammation. The causal mechanism underlying NASH is not fully elucidated. This study investigated the role of β-Arrestin1 (ARRB1) in the progression of NASH. METHODS:Liver tissue from patients with NASH and controls were obtained to evaluate ARRB1 expression. NASH models were established in Arrb1-knockout and wild-type mice fed either a high-fat diet (HFD) for 26 weeks or a methionine/choline-deficient (MCD) diet for 6 weeks. RESULTS:ARRB1 expression was reduced in liver samples from patients with NASH. Reduced Arrb1 levels were also detected in murine NASH models. Arrb1 deficiency accelerated steatohepatitis development in HFD-/MCD-fed mice (accompanied by the upregulation of lipogenic genes and downregulation of β-oxidative genes). Intriguingly, ARRB1 was found to interact with growth differentiation factor 15 (GDF15) and facilitated the transportation of GDF15 precursor (pro-GDF15) to the Golgi apparatus for cleavage and maturation. Treatment with recombinant GDF15 ablated the lipid accumulation in the presence of Arrb1 deletion both in vitro and in vivo. Re-expression of Arrb1 in the NASH models ameliorated the liver disease, and this effect was greater in the presence of pro-GDF15 overexpression. By contrast, the effect of pro-GDF15 overexpression alone was impaired in Arrb1-deficient mice. In addition, the severity of liver disease in patients with NASH was negatively correlated with ARRB1 expression. CONCLUSION:ARRB1 acts as a vital regulator in the development of NASH by facilitating the translocation of GDF15 to the Golgi apparatus and its subsequent maturation. Thus, ARRB1 is a potential therapeutic target for the treatment of NASH. LAY SUMMARY:Non-alcoholic steatohepatitis (NASH) is associated with the progressive dysfunction of lipid metabolism and a consequent inflammatory response. Decreased ARRB1 is observed in patients with NASH and murine NASH models. Re-expression of Arrb1 in the murine NASH model ameliorated liver disease, an effect which was more pronounced in the presence of pro-GDF15 overexpression, highlighting a promising strategy for NASH therapy. 10.1016/j.jhep.2019.12.004
    Endocrine and liver interaction: the role of endocrine pathways in NASH. Loria Paola,Carulli Lucia,Bertolotti Marco,Lonardo Amedeo Nature reviews. Gastroenterology & hepatology This article reviews evidence that causally links hormonal disorders with hepatobiliary disease, and gives particular focus to nonalcoholic steatohepatitis (NASH). The downstream mechanisms by which endocrine disturbances cause liver disease might be similar to those involved in the development of primary liver disease. Hypothyroidism, for example, might lead to NASH, cirrhosis and potentially liver cancer via the development of hyperlipidemia and obesity. Patients with growth hormone deficiency have a metabolic-syndrome-like phenotype that is also associated with the development of NASH. Polycystic ovary syndrome is a common endocrine disorder that is often associated with insulin resistance, the metabolic syndrome, altered levels of liver enzymes and the development of NASH. Recent findings support a role of dehydroepiandrosterone sulfate deficiency in the development of advanced NASH. In addition, adrenal failure is increasingly reported in patients with end stage liver disease and in patients who have received a liver transplant, which suggests a bidirectional relationship between liver and endocrine functions. Clinicians should, therefore, be aware of the potential role of endocrine disorders in patients with cryptogenic liver disease and of the effects of liver function on the endocrine system. 10.1038/nrgastro.2009.33
    Macrophage MerTK Promotes Liver Fibrosis in Nonalcoholic Steatohepatitis. Cai Bishuang,Dongiovanni Paola,Corey Kathleen E,Wang Xiaobo,Shmarakov Igor O,Zheng Ze,Kasikara Canan,Davra Viralkumar,Meroni Marica,Chung Raymond T,Rothlin Carla V,Schwabe Robert F,Blaner William S,Birge Raymond B,Valenti Luca,Tabas Ira Cell metabolism Nonalcoholic steatohepatitis (NASH) is emerging as a leading cause of chronic liver disease. However, therapeutic options are limited by incomplete understanding of the mechanisms of NASH fibrosis, which is mediated by activation of hepatic stellate cells (HSCs). In humans, human genetic studies have shown that hypomorphic variations in MERTK, encoding the macrophage c-mer tyrosine kinase (MerTK) receptor, provide protection against liver fibrosis, but the mechanisms remain unknown. We now show that holo- or myeloid-specific Mertk targeting in NASH mice decreases liver fibrosis, congruent with the human genetic data. Furthermore, ADAM metallopeptidase domain 17 (ADAM17)-mediated MerTK cleavage in liver macrophages decreases during steatosis to NASH transition, and mice with a cleavage-resistant MerTK mutant have increased NASH fibrosis. Macrophage MerTK promotes an ERK-TGFβ1 pathway that activates HSCs and induces liver fibrosis. These data provide insights into the role of liver macrophages in NASH fibrosis and provide a plausible mechanism underlying MERTK as a genetic risk factor for NASH fibrosis. 10.1016/j.cmet.2019.11.013
    NASH: CX3CR1-a direct line to gut-liver crosstalk? Patman Gillian Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2015.133
    Genetics and epigenetics of NAFLD and NASH: Clinical impact. Eslam Mohammed,Valenti Luca,Romeo Stefano Journal of hepatology Non-alcoholic fatty liver disease (NAFLD) is now recognised as the most common liver disease worldwide. It encompasses a broad spectrum of conditions, from simple steatosis, through non-alcoholic steatohepatitis, to fibrosis and ultimately cirrhosis and hepatocellular carcinoma. A hallmark of NAFLD is the substantial inter-patient variation in disease progression. NAFLD is considered a complex disease trait such that interactions between the environment and a susceptible polygenic host background determine disease phenotype and influence progression. Recent years have witnessed multiple genome-wide association and large candidate gene studies, which have enriched our understanding of the genetic basis of NAFLD. Notably, the I148M PNPLA3 variant has been identified as the major common genetic determinant of NAFLD. Variants with moderate effect size in TM6SF2, MBOAT7 and GCKR have also been shown to have a significant contribution. The premise for this review is to discuss the status of research into important genetic and epigenetic modifiers of NAFLD progression. The potential to translate the accumulating wealth of genetic data into the design of novel therapeutics and the clinical implementation of diagnostic/prognostic biomarkers will be explored. Finally, personalised medicine and the opportunities for future research and challenges in the immediate post genetics era will be illustrated and discussed. 10.1016/j.jhep.2017.09.003
    From NAFLD to NASH to cirrhosis-new insights into disease mechanisms. Wree Alexander,Broderick Lori,Canbay Ali,Hoffman Hal M,Feldstein Ariel E Nature reviews. Gastroenterology & hepatology NAFLD has evolved as a serious public health problem in the USA and around the world. In fact, NASH-the most serious form of NAFLD-is predicted to become the leading cause of liver transplantation in the USA by the year 2020. The pathogenesis of NAFLD and NASH, in particular the mechanisms responsible for liver injury and fibrosis, is the result of a complex interplay between host and environmental factors, and is at the centre of intense investigation. In this Review, we focus on recently uncovered aspects of the genetic, biochemical, immunological and molecular events that are responsible for the development and progression of this highly prevalent and potentially serious disease. These studies bring new insight into this complex disorder and have led to the development of novel therapeutic and diagnostic strategies that might enable a personalized approach in the management of this disease. 10.1038/nrgastro.2013.149
    Liver disease: Conscious uncoupling in NASH. Villanueva M Teresa Nature reviews. Drug discovery 10.1038/nrd.2017.60
    Predicting the future burden of NAFLD and NASH. Mahady Suzanne E,George Jacob Journal of hepatology 10.1016/j.jhep.2018.06.025
    NAFLD: A critical role for the NLRP3 inflammasome in NASH. Thomas Hugh Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2017.21
    NASH: NASH and TLR9. Thomas Hugh Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2016.20
    Predicting NASH response with liver fat: Are we back to square one? Wong Vincent Wai-Sun Journal of hepatology 10.1016/j.jhep.2019.10.024
    NAFLD: Early promise for ASK1 inhibition in NASH. Ray Katrina Nature reviews. Gastroenterology & hepatology 10.1038/nrgastro.2017.144
    β-arrestin: Dr Jekyll and Mr Hyde in NASH and fibrosis. Abe Hiroyuki,Schuppan Detlef Journal of hepatology 10.1016/j.jhep.2020.01.016
    Cytokines and NASH: a pilot study of the effects of lifestyle modification and vitamin E. Kugelmas Marcelo,Hill Daniell B,Vivian Beverly,Marsano Luis,McClain Craig J Hepatology (Baltimore, Md.) There are few data evaluating plasma and/or peripheral blood monocyte cytokine concentrations/production or attempts to manipulate proinflammatory cytokines in nonalcoholic steatohepatitis (NASH). A pilot project in a general clinical research center evaluated the effects of a step 1 American Heart Association diet plus aerobic exercise with or without 800 IU of vitamin E daily on cytokine profiles and liver enzyme levels in 16 patients with biopsy-proven NASH. Biochemical assessment of liver function, lipid profiles, and body mass index significantly improved during the first 6 weeks of therapy and remained stable during the following 6 weeks. Plasma hyaluronic acid (HA) concentrations decreased in parallel with weight loss. Plasma tumor necrosis factor (TNF) concentrations were significantly elevated in patients with NASH and similar to patients with stable alcoholic cirrhosis but not as elevated as in patients with acute alcoholic steatohepatitis (AH). Although plasma TNF, interleukin 8 (IL-8), and IL-6 concentrations were all significantly elevated compared with control values, only plasma IL-6 levels significantly decreased with therapy. Peripheral blood monocyte TNF, IL-8, and IL-6 production was significantly elevated in patients with NASH but did not significantly decrease. Independent effects of vitamin E were not observed in this small sample. In conclusion, patients with NASH have dysregulated cytokine metabolism similar to, but less pronounced than abnormalities documented in AH. Cytokine values generally did not decrease significantly with weight loss with or without vitamin E over the duration of the study. Lifestyle modifications (low-fat diet and exercise) were associated with improvement in liver enzymes, cholesterol, and plasma HA levels in patients with NASH, whereas the level of vitamin E supplementation used in this short-term pilot study provided no apparent added benefit. 10.1053/jhep.2003.50316
    Hypertension, diabetes, atherosclerosis and NASH: Cause or consequence? Lonardo Amedeo,Nascimbeni Fabio,Mantovani Alessandro,Targher Giovanni Journal of hepatology Non-alcoholic fatty liver disease (NAFLD) has become one of the most common forms of chronic liver disease worldwide and its prevalence is expected to continue rising. NAFLD has traditionally been considered a consequence of metabolic syndrome (MetS). However, the link between NAFLD and MetS components, especially type 2 diabetes mellitus (T2DM), hypertension (HTN), and cardiovascular disease (CVD) is more complex than previously thought. Indeed, the adverse effects of NAFLD extend far beyond the liver, with a large body of clinical evidence now suggesting that NAFLD may precede and/or promote the development of T2DM, HTN and atherosclerosis/CVD. The risk of developing these cardiometabolic diseases parallels the underlying severity of NAFLD. Accumulating evidence suggests that the presence and severity of NAFLD is associated with an increased risk of incident T2DM and HTN. Moreover, long-term prospective studies indicate that the presence and severity of NAFLD independently predicts fatal and nonfatal CVD events. In this review, we critically discuss the rapidly expanding body of clinical evidence that supports the existence of a bi-directional relationship between NAFLD and various components of MetS, particularly T2DM and HTN, as well as the current knowledge regarding a strong association between NAFLD and CVD morbidity and mortality. Finally, we discuss the most updated putative biological mechanisms through which NAFLD may contribute to the development of HTN, T2DM and CVD. 10.1016/j.jhep.2017.09.021
    NASH: Understanding how steatosis progresses to NASH. Greenhill Claire Nature reviews. Endocrinology 10.1038/nrendo.2016.187
    P(URI)fying Novel Drivers of NASH and HCC: A Feedforward Loop of IL17A via White Adipose Tissue. Weber Achim,Heikenwalder Mathias Cancer cell How obesity and metabolic syndrome trigger non-alcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC) remains elusive. In this issue, Gomes and colleagues describe that nutrient surplus induces hepatic URI expression, triggering genotoxicity and IL17A expression, thus leading to insulin resistance, NASH, and HCC. IL17A signaling blockers might become a readily translatable therapy. 10.1016/j.ccell.2016.06.010
    Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention. Younossi Zobair,Anstee Quentin M,Marietti Milena,Hardy Timothy,Henry Linda,Eslam Mohammed,George Jacob,Bugianesi Elisabetta Nature reviews. Gastroenterology & hepatology NAFLD is one of the most important causes of liver disease worldwide and will probably emerge as the leading cause of end-stage liver disease in the coming decades, with the disease affecting both adults and children. The epidemiology and demographic characteristics of NAFLD vary worldwide, usually parallel to the prevalence of obesity, but a substantial proportion of patients are lean. The large number of patients with NAFLD with potential for progressive liver disease creates challenges for screening, as the diagnosis of NASH necessitates invasive liver biopsy. Furthermore, individuals with NAFLD have a high frequency of metabolic comorbidities and could place a growing strain on health-care systems from their need for management. While awaiting the development effective therapies, this disease warrants the attention of primary care physicians, specialists and health policy makers. 10.1038/nrgastro.2017.109
    AMPK against NASH. Strzyz Paulina Nature reviews. Molecular cell biology 10.1038/s41580-020-0225-0
    No anti-fibrotic effect of selonsertib in NASH. Dickson Iain Nature reviews. Gastroenterology & hepatology 10.1038/s41575-020-0297-5
    Novel regulatory pathway in NASH identified. Morris Alan Nature reviews. Endocrinology 10.1038/s41574-020-0384-2
    From NASH to HCC: current concepts and future challenges. Nature reviews. Gastroenterology & hepatology Caloric excess and sedentary lifestyle have led to a global epidemic of obesity and metabolic syndrome. The hepatic consequence of metabolic syndrome and obesity, nonalcoholic fatty liver disease (NAFLD), is estimated to affect up to one-third of the adult population in many developed and developing countries. This spectrum of liver disease ranges from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Owing to the high prevalence of NAFLD, especially in industrialized countries but also worldwide, and the consequent burden of progressive liver disease, there is mounting epidemiological evidence that NAFLD has rapidly become a leading aetiology underlying many cases of hepatocellular carcinoma (HCC). In this Review, we discuss NAFLD-associated HCC, including its epidemiology, the key features of the hepatic NAFLD microenvironment (for instance, adaptive and innate immune responses) that promote hepatocarcinogenesis and the management of HCC in patients with obesity and associated metabolic comorbidities. The challenges and future directions of research will also be discussed, including clinically relevant biomarkers for early detection, treatment stratification and monitoring as well as approaches to therapies for both prevention and treatment in those at risk or presenting with NAFLD-associated HCC. 10.1038/s41575-019-0145-7
    NASH and HCC Are Driven by Different Signaling Pathways with a Common Regulator. Mehal Wajahat Cell metabolism Oxidative stress is uniformly present in non-alcoholic steatohepatitis (NASH), but its role in the development of liver inflammation and hepatocellular cancer (HCC) and the relationship between these two pathologies are poorly understood. In a recent issue of Cell, Grohmann et al. (2018) demonstrate a vital role of obesity-induced oxidative stress in deactivating the phosphatase TCPTP, resulting in activation of STAT-1 and STAT-3, which each independently drive the development of NASH and HCC, respectively. 10.1016/j.cmet.2018.12.012
    Noninvasive biomarkers in NAFLD and NASH - current progress and future promise. Wong Vincent Wai-Sun,Adams Leon A,de Lédinghen Victor,Wong Grace Lai-Hung,Sookoian Silvia Nature reviews. Gastroenterology & hepatology Nonalcoholic fatty liver disease (NAFLD) affects 25% of the global adult population and is the most common chronic liver disease worldwide. Nonalcoholic steatohepatitis (NASH) is the active form of NAFLD, with hepatic necroinflammation and faster fibrosis progression. With an increasing number of patients developing NASH-related end-stage liver disease and pharmacological treatments on the horizon, there is a pressing need to develop NAFLD and NASH biomarkers for prognostication, selection of patients for treatment and monitoring. This requirement is particularly true as liver biopsy utility is limited by its invasive nature, poor patient acceptability and sampling variability. This article reviews current and potential biomarkers for different features of NAFLD, namely, steatosis, necroinflammation and fibrosis. For each biomarker, we evaluate its accuracy, reproducibility, responsiveness, feasibility and limitations. We cover biochemical, imaging and genetic biomarkers and discuss biomarker discovery in the omics era. 10.1038/s41575-018-0014-9
    Triggering and resolution of inflammation in NASH. Schuster Susanne,Cabrera Daniel,Arrese Marco,Feldstein Ariel E Nature reviews. Gastroenterology & hepatology Nonalcoholic steatohepatitis (NASH) is considered the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by liver steatosis, inflammation, hepatocellular injury and different degrees of fibrosis. A central issue in this field relates to the identification of those factors that trigger inflammation, thus fuelling the transition from nonalcoholic fatty liver to NASH. These triggers of liver inflammation might have their origins outside the liver (such as in adipose tissue or the gut) as well as inside the organ (for instance, lipotoxicity, innate immune responses, cell death pathways, mitochondrial dysfunction and endoplasmic reticulum stress), both of which contribute to NASH development. In this Review, we summarize the currently available information on the key upstream triggers of inflammation in NASH. We further delineate the mechanisms by which liver inflammation is resolved and the implications of a defective pro-resolution process. A better knowledge of these mechanisms should help to design targeted therapies able to halt or reverse disease progression. 10.1038/s41575-018-0009-6
    Determinants of fibrosis progression and regression in NASH. Schuppan Detlef,Surabattula Rambabu,Wang Xiao Yu Journal of hepatology Cirrhosis has become the major liver-related clinical endpoint in non-alcoholic steatohepatitis (NASH). However, progression to cirrhosis is less predictable in NASH than in other chronic liver diseases. This is due to the complex and multifactorial aetiology of NASH, which is determined by lifestyle and nutrition, multiple genetic and epigenetic factors, and a prominent role of hepatic and extrahepatic comorbidities. Thus, modest changes in these cofactors can also induce fibrosis regression, at least in patients with precirrhotic liver disease. Fibrogenesis in NASH correlates with, but is indirectly coupled to, classical inflammation, since fibrosis progression is driven by repetitive periods of repair. While hepatocyte lipoapoptosis is a key driving force of fibrosis progression, activated hepatic stellate cells, myofibroblasts, cholangiocytes, macrophages and components of the pathological extracellular matrix are major fibrogenic effectors and thus pharmacological targets for therapies aimed at inhibition of fibrosis progression or induction of fibrosis reversal. The advent of novel, highly sensitive and specific serum biomarkers and imaging methods to assess the dynamics of liver fibrosis in NASH will improve detection, stratification and follow-up of patients with progressive NASH . These non-invasive tools will also promote the clinical development of antifibrotic drugs, by permitting the design of lean proof-of-concept studies, and enabling development of a personalised antifibrotic therapy for patients with rapid fibrosis progression or advanced disease. 10.1016/j.jhep.2017.11.012
    Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. Hagström Hannes,Nasr Patrik,Ekstedt Mattias,Hammar Ulf,Stål Per,Hultcrantz Rolf,Kechagias Stergios Journal of hepatology BACKGROUND & AIMS:Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but identifying patients with increased risk of mortality and liver-specific morbidity remains a challenge. Non-alcoholic steatohepatitis (NASH) is thought to enhance this risk; therefore, resolution of NASH is a major endpoint in current pharmacologic studies. Herein, we aim to investigate the long-term prognosis of a large cohort of NAFLD patients, and to study the specific effect of NASH and fibrosis stage on prognosis. METHODS:We conducted a retrospective cohort study of 646 biopsy-proven NAFLD patients. Each case was matched for age, sex and municipality to ten controls. Outcomes on mortality and severe liver disease, defined as cirrhosis, liver decompensation/failure or hepatocellular carcinoma, were evaluated using population-based registers. Cox regression models adjusted for age, sex and type 2 diabetes were used to examine the long-term risk according to fibrosis stage. Likelihood ratio tests were used to assess whether adding NASH to these models increased the predictive capacity. Laplace regression was used to estimate the time to severe liver disease according to stage of fibrosis. RESULTS:During a follow-up of mean 20years (range 0-40) equivalent to 139,163 person-years, 12% of NAFLD patients and 2.2% of controls developed severe liver disease (p<0.001). Compared to controls, the risk of severe liver disease increased per stage of fibrosis (hazard ratio ranging from 1.9 in F0 to 104.9 in F4). Accounting for the presence of NASH did not change these estimates significantly (likelihood ratio test >0.05 for all stages of fibrosis). Similar results were seen for overall mortality. The lower end of the 95% confidence interval for the 10 percentile of time to development of severe liver disease was 22-26years in F0-1, 9.3years in F2, 2.3years in F3, and 0.9years to liver decompensation in F4. CONCLUSIONS:In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. LAY SUMMARY:Non-alcoholic fatty liver disease (NAFLD) is very common in the general population, but reaching an accurate prognosis remains challenging. We investigate the long-term prognosis of a large cohort of NAFLD patients. In this, the largest ever study of biopsy-proven NAFLD, the presence of NASH did not increase the risk of liver-specific morbidity or overall mortality. Knowledge of time to development of severe liver disease according to fibrosis stage can be used in individual patient counselling and for public health decisions. 10.1016/j.jhep.2017.07.027
    NKT-cell subsets: promoters and protectors in inflammatory liver disease. Kumar Vipin Journal of hepatology Natural killer T cells (NKT) are innate-like cells which are abundant in liver sinusoids and express the cell surface receptors of NK cells (e.g., NK1.1 (mouse) or CD161+/CD56+(human)) as well as an antigen receptor (TCR) characteristic of conventional T cells. NKT cells recognize lipid antigens in the context of CD1d, a non-polymorphic MHC class I-like molecule. Activation of NKT cells has a profound influence on the immune response against tumors and infectious organisms and in autoimmune diseases. NKT cells can be categorized into at least two distinct subsets: iNKT or type I use a semi-invariant TCR, whereas type II NKT TCRs are more diverse. Recent evidence suggests that NKT-cell subsets can play opposing roles early in non-microbial liver inflammation in that type I NKT are proinflammatory whereas type II NKT cells inhibit type I NKT-mediated liver injury. 10.1016/j.jhep.2013.02.032
    Defining the human T helper 17 cell phenotype. Annunziato Francesco,Cosmi Lorenzo,Liotta Francesco,Maggi Enrico,Romagnani Sergio Trends in immunology T helper (Th) 17 cells represent a third effector arm of CD4 T cells and complement the function of the Th1 and Th2 cell lineages. Here, we provide an overview of the transcription factors, cytokines, chemokines, and cytokine and chemokine receptors that characterize the Th17 cell phenotype. Data relevant for human Th17 cells are emphasized, with a focus on the function of two markers that have recently been associated with human Th17 cells, CD161 and interleukin-4-induced gene 1 (IL4I1). Also considered is the basis of Th17 cell plasticity towards the Th1 lineage, and we suggest that this plasticity together with the limited expansion of Th17 cells in response to T cell receptor (TCR) triggering accounts for the rarity of human Th17 cells in inflamed tissues. 10.1016/j.it.2012.05.004
    Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Dusseaux Mathilde,Martin Emmanuel,Serriari Nacer,Péguillet Isabelle,Premel Virginie,Louis Delphine,Milder Maud,Le Bourhis Lionel,Soudais Claire,Treiner Emmanuel,Lantz Olivier Blood Mucosal-associated invariant T (MAIT) cells are very abundant in humans and have antimicrobial specificity, but their functions remain unclear. MAIT cells are CD161(hi)IL-18Rα(+) and either CD4(-)CD8(-) (DN) or CD8αβ(int) T cells. We now show that they display an effector-memory phenotype (CD45RA(-)CD45RO(+)CD95(hi)CD62L(lo)), and their chemokine receptor expression pattern (CCR9(int)CCR7(-)CCR5(hi)CXCR6(hi)CCR6(hi)) indicates preferential homing to tissues and particularly the intestine and the liver. MAIT cells can represent up to 45% of the liver lymphocytes. They produce interferon-γ and Granzyme-B as well as high levels of interleukin-17 after phorbol myristate acetate + ionomycin stimulation. Most MAIT cells are noncycling cells (< 1% are Ki-67(+)) and express the multidrug resistance transporter (ABCB1). As expected from this phenotype, MAIT cells are more resistant to chemotherapy than other T-cell populations. These features might also allow MAIT cells to resist the xenobiotics potentially secreted by the gut bacteria. We also show that this population does not appear to have antiviral specificity and that CD8 MAIT cells include almost all the ABCB1(+)CD161(hi) CD8 T cells. Together with their already known abundance and antimicrobial specificity, the gut-liver homing characteristics, high expression of ABCB1, and ability to secrete interleukin-17 probably participate in the antibacterial properties of MAIT cells. 10.1182/blood-2010-08-303339
    Do studies in humans better depict Th17 cells? Annunziato Francesco,Romagnani Sergio Blood CD4(+) T helper (Th) lymphocytes represent a heterogeneous population of cells. In addition to type 1 (Th1) and type 2 (Th2) cells, another subset of CD4(+) effector Th cells has been discovered and named as Th17, because of its unique ability to produce interleukin (IL)-17. Studies in mice initially suggested that Th17 cells are the pathogenic cells in autoimmune disorders, whereas Th1 cells may behave rather as protective. Subsequent studies in humans demonstrated the plasticity of Th17 cells and their possibility to shift to Th1. The plasticity of Th17 to Th1 cells has recently been confirmed in mice, where it was found that Th17 cells seem to be pathogenic only when they shift to Th1 cells. Studies in humans also showed that Th17 cells are different than in mice because all of them express CD161 and exclusively originate from CD161(+) precursors present in umbilical cord blood and newborn thymus. While murine Th17 cells develop in response to IL-6, IL-1, and transforming growth factor (TGF)-beta, human Th17 cells originate from these CD161(+) precursors in response to IL-1beta and IL-23, the need for TGF-beta being controversial. Thus, we believe that studies in humans have better depicted human Th17 cells than studies in mice. 10.1182/blood-2009-03-209189