Deficient Endoplasmic Reticulum-Mitochondrial Phosphatidylserine Transfer Causes Liver Disease. Hernández-Alvarez María Isabel,Sebastián David,Vives Sara,Ivanova Saška,Bartoccioni Paola,Kakimoto Pamela,Plana Natalia,Veiga Sónia R,Hernández Vanessa,Vasconcelos Nuno,Peddinti Gopal,Adrover Anna,Jové Mariona,Pamplona Reinald,Gordaliza-Alaguero Isabel,Calvo Enrique,Cabré Noemí,Castro Rui,Kuzmanic Antonija,Boutant Marie,Sala David,Hyotylainen Tuulia,Orešič Matej,Fort Joana,Errasti-Murugarren Ekaitz,Rodrígues Cecilia M P,Orozco Modesto,Joven Jorge,Cantó Carles,Palacin Manuel,Fernández-Veledo Sonia,Vendrell Joan,Zorzano Antonio Cell Non-alcoholic fatty liver is the most common liver disease worldwide. Here, we show that the mitochondrial protein mitofusin 2 (Mfn2) protects against liver disease. Reduced Mfn2 expression was detected in liver biopsies from patients with non-alcoholic steatohepatitis (NASH). Moreover, reduced Mfn2 levels were detected in mouse models of steatosis or NASH, and its re-expression in a NASH mouse model ameliorated the disease. Liver-specific ablation of Mfn2 in mice provoked inflammation, triglyceride accumulation, fibrosis, and liver cancer. We demonstrate that Mfn2 binds phosphatidylserine (PS) and can specifically extract PS into membrane domains, favoring PS transfer to mitochondria and mitochondrial phosphatidylethanolamine (PE) synthesis. Consequently, hepatic Mfn2 deficiency reduces PS transfer and phospholipid synthesis, leading to endoplasmic reticulum (ER) stress and the development of a NASH-like phenotype and liver cancer. Ablation of Mfn2 in liver reveals that disruption of ER-mitochondrial PS transfer is a new mechanism involved in the development of liver disease. 10.1016/j.cell.2019.04.010
    Ceramide Signaling and Metabolism in Pathophysiological States of the Lung. Petrache Irina,Berdyshev Evgeny V Annual review of physiology Following the discovery of ceramide as the central signaling and metabolic relay among sphingolipids, studies of its involvement in lung health and pathophysiology have exponentially increased. In this review, we highlight key studies in the context of recent progress in metabolomics and translational research methodologies. Evidence points toward an important role for the ceramide/sphingosine-1-phosphate rheostat in maintaining lung cell survival, vascular barrier function, and proper host response to airway microbial infections. Sphingosine kinase 1 has emerged as an important determinant of sphingosine-1-phosphate lung levels, which, when aberrantly high, contribute to lung fibrosis, maladaptive vascular remodeling, and allergic asthma. New sphingolipid metabolites have been discovered as potential biomarkers of several lung diseases. Although multiple acute and chronic lung pathological conditions involve perturbations in sphingolipid signaling and metabolism, there are specific patterns, unique sphingolipid species, enzymes, metabolites, and receptors, which have emerged that deepen our understanding of lung pathophysiology and inform the development of new therapies for lung diseases. 10.1146/annurev-physiol-021115-105221
    Sphingolipids as targets for inhalation treatment of cystic fibrosis. Becker Katrin Anne,Riethmüller Joachim,Seitz Aaron P,Gardner Aaron,Boudreau Ryan,Kamler Markus,Kleuser Burkhard,Schuchman Edward,Caldwell Charles C,Edwards Michael J,Grassmé Heike,Brodlie Malcolm,Gulbins Erich Advanced drug delivery reviews Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of β1-integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of β1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non-mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation. 10.1016/j.addr.2018.04.015
    Lipid zonation and phospholipid remodeling in nonalcoholic fatty liver disease. Hall Zoe,Bond Nicholas J,Ashmore Tom,Sanders Francis,Ament Zsuzsanna,Wang Xinzhu,Murray Andrew J,Bellafante Elena,Virtue Sam,Vidal-Puig Antonio,Allison Michael,Davies Susan E,Koulman Albert,Vacca Michele,Griffin Julian L Hepatology (Baltimore, Md.) Nonalcoholic fatty liver disease (NAFLD) can progress from simple steatosis (i.e., nonalcoholic fatty liver [NAFL]) to nonalcoholic steatohepatitis (NASH), cirrhosis, and cancer. Currently, the driver for this progression is not fully understood; in particular, it is not known how NAFLD and its early progression affects the distribution of lipids in the liver, producing lipotoxicity and inflammation. In this study, we used dietary and genetic mouse models of NAFL and NASH and translated the results to humans by correlating the spatial distribution of lipids in liver tissue with disease progression using advanced mass spectrometry imaging technology. We identified several lipids with distinct zonal distributions in control and NAFL samples and observed partial to complete loss of lipid zonation in NASH. In addition, we found increased hepatic expression of genes associated with remodeling the phospholipid membrane, release of arachidonic acid (AA) from the membrane, and production of eicosanoid species that promote inflammation and cell injury. The results of our immunohistochemistry analyses suggest that the zonal location of remodeling enzyme LPCAT2 plays a role in the change in spatial distribution for AA-containing lipids. This results in a cycle of AA-enrichment in pericentral hepatocytes, membrane release of AA, and generation of proinflammatory eicosanoids and may account for increased oxidative damage in pericentral regions in NASH. CONCLUSION:NAFLD is associated not only with lipid enrichment, but also with zonal changes of specific lipids and their associated metabolic pathways. This may play a role in the heterogeneous development of NAFLD. (Hepatology 2017;65:1165-1180). 10.1002/hep.28953
    LPIAT1/MBOAT7 depletion increases triglyceride synthesis fueled by high phosphatidylinositol turnover. Tanaka Yuki,Shimanaka Yuta,Caddeo Andrea,Kubo Takuya,Mao Yanli,Kubota Tetsuya,Kubota Naoto,Yamauchi Toshimasa,Mancina Rosellina Margherita,Baselli Guido,Luukkonen Panu,Pihlajamäki Jussi,Yki-Järvinen Hannele,Valenti Luca,Arai Hiroyuki,Romeo Stefano,Kono Nozomu Gut OBJECTIVE:Non-alcoholic fatty liver disease (NAFLD) is a common prelude to cirrhosis and hepatocellular carcinoma. The genetic variant in the lysophosphatidylinositol acyltransferase 1 (, which incorporates arachidonic acid into phosphatidylinositol (PI), is associated with the entire spectrum of NAFLD. In this study, we investigated the mechanism underlying this association in mice and cultured human hepatocytes. DESIGN:We generated the hepatocyte-specific knockout mice to investigate the function of Lpiat1 in vivo. We also depleted in cultured human hepatic cells using CRISPR-Cas9 systems or siRNA. The effect of LPIAT1-depletion on liver fibrosis was examined in mice fed high fat diet and in liver spheroids. Lipid species were measured using liquid chromatography-electrospray ionisation mass spectrometry. Lipid metabolism was analysed using radiolabeled glycerol or fatty acids. RESULTS:The hepatocyte-specific knockout mice developed hepatic steatosis spontaneously, and hepatic fibrosis on high fat diet feeding. Depletion of in cultured hepatic cells and in spheroids caused triglyceride accumulation and collagen deposition. The increase in hepatocyte fat content was due to a higher triglyceride synthesis fueled by a non-canonical pathway. Indeed, reduction in the PI acyl chain remodelling caused a high PI turnover, by stimulating at the same time PI synthesis and breakdown. The degradation of PI was mediated by a phospholipase C, which produces diacylglycerol, a precursor of triglyceride. CONCLUSION:We found a novel pathway fueling triglyceride synthesis in hepatocytes, by a direct metabolic flow of PI into triglycerides. Our findings provide an insight into the pathogenesis and therapeutics of NAFLD. 10.1136/gutjnl-2020-320646
    Recombinant Acid Ceramidase Reduces Inflammation and Infection in Cystic Fibrosis. Gardner Aaron I,Haq Iram J,Simpson A John,Becker Katrin A,Gallagher John,Saint-Criq Vinciane,Verdon Bernard,Mavin Emily,Trigg Alexandra,Gray Michael A,Koulman Albert,McDonnell Melissa J,Fisher Andrew J,Kramer Elizabeth L,Clancy John P,Ward Christopher,Schuchman Edward H,Gulbins Erich,Brodlie Malcolm American journal of respiratory and critical care medicine In cystic fibrosis the major cause of morbidity and mortality is lung disease characterized by inflammation and infection. The influence of sphingolipid metabolism is poorly understood with a lack of studies using human airway model systems. To investigate sphingolipid metabolism in cystic fibrosis and the effects of treatment with recombinant human acid ceramidase on inflammation and infection. Sphingolipids were measured using mass spectrometry in fully differentiated cultures of primary human airway epithelial cells and cocultures with . activity assays, Western blotting, and quantitative PCR were used to investigate function and expression of ceramidase and sphingomyelinase. Effects of treatment with recombinant human acid ceramidase on sphingolipid profile and inflammatory mediator production were assessed in cell cultures and murine models. Ceramide is increased in cystic fibrosis airway epithelium owing to differential function of enzymes regulating sphingolipid metabolism. Sphingosine, a metabolite of ceramide with antimicrobial properties, is not upregulated in response to by cystic fibrosis airway epithelia. Tumor necrosis factor receptor 1 is increased in cystic fibrosis epithelia and activates NF-κB signaling, generating inflammation. Treatment with recombinant human acid ceramidase, to decrease ceramide, reduced both inflammatory mediator production and susceptibility to infection. Sphingolipid metabolism is altered in airway epithelial cells cultured from people with cystic fibrosis. Treatment with recombinant acid ceramidase ameliorates the two pivotal features of cystic fibrosis lung disease, inflammation and infection, and thus represents a therapeutic approach worthy of further exploration. 10.1164/rccm.202001-0180OC
    Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease. Viglino Damien,Jullian-Desayes Ingrid,Minoves Mélanie,Aron-Wisnewsky Judith,Leroy Vincent,Zarski Jean-Pierre,Tamisier Renaud,Joyeux-Faure Marie,Pépin Jean-Louis The European respiratory journal Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD.We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers.In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI.We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities. 10.1183/13993003.01923-2016
    Metformin induces lipogenic differentiation in myofibroblasts to reverse lung fibrosis. Kheirollahi Vahid,Wasnick Roxana M,Biasin Valentina,Vazquez-Armendariz Ana Ivonne,Chu Xuran,Moiseenko Alena,Weiss Astrid,Wilhelm Jochen,Zhang Jin-San,Kwapiszewska Grazyna,Herold Susanne,Schermuly Ralph T,Mari Bernard,Li Xiaokun,Seeger Werner,Günther Andreas,Bellusci Saverio,El Agha Elie Nature communications Idiopathic pulmonary fibrosis (IPF) is a fatal disease in which the intricate alveolar network of the lung is progressively replaced by fibrotic scars. Myofibroblasts are the effector cells that excessively deposit extracellular matrix proteins thus compromising lung structure and function. Emerging literature suggests a correlation between fibrosis and metabolic alterations in IPF. In this study, we show that the first-line antidiabetic drug metformin exerts potent antifibrotic effects in the lung by modulating metabolic pathways, inhibiting TGFβ1 action, suppressing collagen formation, activating PPARγ signaling and inducing lipogenic differentiation in lung fibroblasts derived from IPF patients. Using genetic lineage tracing in a murine model of lung fibrosis, we show that metformin alters the fate of myofibroblasts and accelerates fibrosis resolution by inducing myofibroblast-to-lipofibroblast transdifferentiation. Detailed pathway analysis revealed a two-arm mechanism by which metformin accelerates fibrosis resolution. Our data report an antifibrotic role for metformin in the lung, thus warranting further therapeutic evaluation. 10.1038/s41467-019-10839-0
    Biochemistry of very-long-chain and long-chain ceramides in cystic fibrosis and other diseases: The importance of side chain. Garić Dušan,De Sanctis Juan B,Shah Juhi,Dumut Daciana Catalina,Radzioch Danuta Progress in lipid research Ceramides, the principal building blocks of all sphingolipids, have attracted the attention of many scientists around the world interested in developing treatments for cystic fibrosis, the most common genetic disease of Caucasians. Many years of fruitful research in this field have produced some fundamentally important, yet controversial results. Here, we aimed to summarize the current knowledge on the role of long- and very-long- chain ceramides, the most abundant species of ceramides in animal cells, in cystic fibrosis and other diseases. We also aim to explain the importance of the length of their side chain in the context of stability of transmembrane proteins through a concise synthesis of their biophysical chemistry, cell biology, and physiology. This review also addresses several remaining riddles in this field. Finally, we discuss the technical challenges associated with the analysis and quantification of ceramides. We provide the evaluation of the antibodies used for ceramide quantification and we demonstrate their lack of specificity. Results and discussion presented here will be of interest to anyone studying these enigmatic lipids. 10.1016/j.plipres.2019.03.001
    Sphingosine 1-phosphate: Lipid signaling in pathology and therapy. Cartier Andreane,Hla Timothy Science (New York, N.Y.) Sphingosine 1-phosphate (S1P), a metabolic product of cell membrane sphingolipids, is bound to extracellular chaperones, is enriched in circulatory fluids, and binds to G protein-coupled S1P receptors (S1PRs) to regulate embryonic development, postnatal organ function, and disease. S1PRs regulate essential processes such as adaptive immune cell trafficking, vascular development, and homeostasis. Moreover, S1PR signaling is a driver of multiple diseases. The past decade has witnessed an exponential growth in this field, in part because of multidisciplinary research focused on this lipid mediator and the application of S1PR-targeted drugs in clinical medicine. This has revealed fundamental principles of lysophospholipid mediator signaling that not only clarify the complex and wide ranging actions of S1P but also guide the development of therapeutics and translational directions in immunological, cardiovascular, neurological, inflammatory, and fibrotic diseases. 10.1126/science.aar5551
    Bile acids and nonalcoholic fatty liver disease: Molecular insights and therapeutic perspectives. Arab Juan P,Karpen Saul J,Dawson Paul A,Arrese Marco,Trauner Michael Hepatology (Baltimore, Md.) Nonalcoholic fatty liver disease (NAFLD) is a burgeoning health problem worldwide and an important risk factor for both hepatic and cardiometabolic mortality. The rapidly increasing prevalence of this disease and of its aggressive form nonalcoholic steatohepatitis (NASH) will require novel therapeutic approaches to prevent disease progression to advanced fibrosis or cirrhosis and cancer. In recent years, bile acids have emerged as relevant signaling molecules that act at both hepatic and extrahepatic tissues to regulate lipid and carbohydrate metabolic pathways as well as energy homeostasis. Activation or modulation of bile acid receptors, such as the farnesoid X receptor and TGR5, and transporters, such as the ileal apical sodium-dependent bile acid transporter, appear to affect both insulin sensitivity and NAFLD/NASH pathogenesis at multiple levels, and these approaches hold promise as novel therapies. In the present review, we summarize current available data on the relationships of bile acids to NAFLD and the potential for therapeutically targeting bile-acid-related pathways to address this growing world-wide disease. (Hepatology 2017;65:350-362). 10.1002/hep.28709
    Molecular mechanism of PPARα action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. Pawlak Michal,Lefebvre Philippe,Staels Bart Journal of hepatology Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor belonging, together with PPARγ and PPARβ/δ, to the NR1C nuclear receptor subfamily. Many PPARα target genes are involved in fatty acid metabolism in tissues with high oxidative rates such as muscle, heart and liver. PPARα activation, in combination with PPARβ/δ agonism, improves steatosis, inflammation and fibrosis in pre-clinical models of non-alcoholic fatty liver disease, identifying a new potential therapeutic area. In this review, we discuss the transcriptional activation and repression mechanisms by PPARα, the spectrum of target genes and chromatin-binding maps from recent genome-wide studies, paying particular attention to PPARα-regulation of hepatic fatty acid and plasma lipoprotein metabolism during nutritional transition, and of the inflammatory response. The role of PPARα, together with other PPARs, in non-alcoholic steatohepatitis will be discussed in light of available pre-clinical and clinical data. 10.1016/j.jhep.2014.10.039
    Bioactive Lipid Species and Metabolic Pathways in Progression and Resolution of Nonalcoholic Steatohepatitis. Musso Giovanni,Cassader Maurizio,Paschetta Elena,Gambino Roberto Gastroenterology The prevalence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, yet there are no effective treatments. A decade has passed since the initial lipidomics analyses of liver tissues from patients with nonalcoholic fatty liver disease. We have learned that liver cells from patients with NASH have an abnormal lipid composition and that the accumulation of lipids leads to organelle dysfunction, cell injury and death, and chronic inflammation, called lipotoxicity. We review the lipid species and metabolic pathways that contribute to the pathogenesis of NASH and potential therapeutic targets, including enzymes involved in fatty acid and triglyceride synthesis, bioactive sphingolipids and polyunsaturated-derived eicosanoids, and specialized pro-resolving lipid mediators. We discuss the concept that NASH is a disease that can resolve and the roles of lipid molecules in the resolution of inflammation and regression of fibrosis. 10.1053/j.gastro.2018.06.031
    Lysophosphatidic acid receptor (LPAR) modulators: The current pharmacological toolbox. Llona-Minguez Sabin,Ghassemian Artin,Helleday Thomas Progress in lipid research Lysophosphatidic acids (LPA) are key lipid-signalling molecules that regulate a remarkably diverse set of cellular events, such as motility, chemotaxis, cell cycle progression, viability, and wound healing. The physiological and pathophysiological consequences of LPA signalling are evident and misregulation of LPA signalling can lead to pathologies like cancer, atherosclerosis, ischaemia, and fibrosis. LPA exerts its biological actions mainly through several types of G protein-coupled receptors, some of which display opposing or redundant effects. For this reason, selective LPA receptor small-molecule ligands can shine light on LPA biology and present an exciting opportunity for drug discovery endeavours. This review provides insights into the detailed chemical nature and pharmacological profile of the small-molecules thus far developed as LPA receptor modulators, as well as information on the preparation of key pharmaceuticals. This summary will facilitate future research efforts and nurture collaboration between chemists and biologists working in this emerging field. 10.1016/j.plipres.2015.01.004
    Effects of iron overload on chronic metabolic diseases. Fernández-Real José Manuel,Manco Melania The lancet. Diabetes & endocrinology Iron can affect the clinical course of several chronic metabolic diseases such as type 2 diabetes, obesity, non-alcoholic fatty liver disease, and atherosclerosis. Iron overload can affect major tissues involved in glucose and lipid metabolism (pancreatic β cells, liver, muscle, and adipose tissue) and organs affected by chronic diabetic complications. Because iron is a potent pro-oxidant, fine-tuned control mechanisms have evolved to regulate entry, recycling, and loss of body iron. These mechanisms include the interplay of iron with transferrin, ferritin, insulin, and hepcidin, as well as with adipokines and proinflammatory molecules. An imbalance of these homoeostatic mechanisms results in systemic and parenchymal siderosis that contributes to organ damage (such as β-cell dysfunction, fibrosis in liver diseases, and atherosclerotic plaque growth and instability). Conversely, iron depletion can exert beneficial effects in patients with iron overload and even in healthy frequent blood donors. Regular assessment of iron balance should be recommended for patients with chronic metabolic diseases, and further research is needed to produce guidelines for the identification of patients who would benefit from iron depletion. 10.1016/S2213-8587(13)70174-8
    Fibrates and cholestasis. Ghonem Nisanne S,Assis David N,Boyer James L Hepatology (Baltimore, Md.) Cholestasis, including primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC), results from an impairment or disruption of bile production and causes intracellular retention of toxic bile constituents, including bile salts. If left untreated, cholestasis leads to liver fibrosis and cirrhosis, which eventually results in liver failure and the need for liver transplantation. Currently, the only therapeutic option available for these patients is ursodeoxycholic acid (UDCA), which slows the progression of PBC, particularly in stage I and II of the disease. However, some patients have an incomplete response to UDCA therapy, whereas other, more advanced cases often remain unresponsive. For PSC, UDCA therapy does not improve survival, and recommendations for its use remain controversial. These considerations emphasize the need for alternative therapies. Hepatic transporters, located along basolateral (sinusoidal) and apical (canalicular) membranes of hepatocytes, are integral determinants of bile formation and secretion. Nuclear receptors (NRs) are critically involved in the regulation of these hepatic transporters and are natural targets for therapy of cholestatic liver diseases. One of these NRs is peroxisome proliferator-activated receptor alpha (PPARα), which plays a central role in maintaining cholesterol, lipid, and bile acid homeostasis by regulating genes responsible for bile acid synthesis and transport in humans, including cytochrome P450 (CYP) isoform 7A1 (CYP7A1), CYP27A1, CYP8B1, uridine 5'-diphospho-glucuronosyltransferase 1A1, 1A3, 1A4, 1A6, hydroxysteroid sulfotransferase enzyme 2A1, multidrug resistance protein 3, and apical sodium-dependent bile salt transporter. Expression of many of these genes is altered in cholestatic liver diseases, but few have been extensively studied or had the mechanism of PPARα effect identified. In this review, we examine what is known about these mechanisms and consider the rationale for the use of PPARα ligand therapy, such as fenofibrate, in various cholestatic liver disorders. 10.1002/hep.27744
    Bile acid receptors as targets for drug development. Schaap Frank G,Trauner Michael,Jansen Peter L M Nature reviews. Gastroenterology & hepatology The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades. These cascades affect the expression of a great number of target genes relevant for bile acid, cholesterol, lipid and carbohydrate metabolism, as well as genes involved in inflammation, fibrosis and carcinogenesis. Pregnane X receptor, vitamin D receptor and constitutive androstane receptor are additional nuclear receptors that respond to bile acids, albeit to a more restricted set of species of bile acids. Recognition of dedicated bile acid receptors prompted the development of semi-synthetic bile acid analogues and nonsteroidal compounds that target these receptors. These agents hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases. This Review discusses the relevant bile acid receptors, the new drugs that target bile acid signalling and their possible applications. 10.1038/nrgastro.2013.151
    Omega-3 fatty acids and non-alcoholic fatty liver disease: Evidence of efficacy and mechanism of action. Scorletti Eleonora,Byrne Christopher D Molecular aspects of medicine For many years it has been known that high doses of long chain omega-3 fatty acids are beneficial in the treatment of hypertriglyceridaemia. Over the last three decades, there has also been a wealth of in vitro and in vivo data that has accumulated to suggest that long chain omega-3 fatty acid treatment might be beneficial to decrease liver triacylglycerol. Several biological mechanisms have been identified that support this hypothesis; notably, it has been shown that long chain omega-3 fatty acids have a beneficial effect: a) on bioactive metabolites involved in inflammatory pathways, and b) on alteration of nuclear transcription factor activities such as peroxisome proliferator-activated receptors (PPARs), sterol regulatory element-binding protein 1c (SREBP-1c) and carbohydrate-responsive element-binding protein (ChREBP), involved in inflammatory pathways and liver lipid metabolism. Since the pathogenesis of non alcoholic fatty liver disease (NAFLD) begins with the accumulation of liver lipid and progresses with inflammation and then several years later with development of fibrosis; it has been thought in patients with NAFLD omega-3 fatty acid treatment would be beneficial in treating liver lipid and possibly also in ameliorating inflammation. Meta-analyses (of predominantly dietary studies and small trials) have tended to support the assertion that omega-3 fatty acids are beneficial in decreasing liver lipid, but recent randomised controlled trials have produced conflicting data. These trials have suggested that omega-3 fatty acid might be beneficial in decreasing liver triglyceride (docosahexanoic acid also possibly being more effective than eicosapentanoic acid) but not in decreasing other features of steatohepatitis (or liver fibrosis). The purpose of this review is to discuss recent evidence regarding biological mechanisms by which long chain omega-3 fatty acids might act to ameliorate liver disease in NAFLD; to consider the recent evidence from randomised trials in both adults and children with NAFLD; and finally to discuss key 'known unknowns' that need to be considered, before planning future studies that are focussed on testing the effects of omega-3 fatty acid treatment in patients with NAFLD. 10.1016/j.mam.2018.03.001
    Lipid mediators in the resolution of inflammation. Serhan Charles N,Chiang Nan,Dalli Jesmond,Levy Bruce D Cold Spring Harbor perspectives in biology Mounting of the acute inflammatory response is crucial for host defense and pivotal to the development of chronic inflammation, fibrosis, or abscess formation versus the protective response and the need of the host tissues to return to homeostasis. Within self-limited acute inflammatory exudates, novel families of lipid mediators are identified, named resolvins (Rv), protectins, and maresins, which actively stimulate cardinal signs of resolution, namely, cessation of leukocytic infiltration, counterregulation of proinflammatory mediators, and the uptake of apoptotic neutrophils and cellular debris. The biosynthesis of these resolution-phase mediators in sensu stricto is initiated during lipid-mediator class switching, in which the classic initiators of acute inflammation, prostaglandins and leukotrienes (LTs), switch to produce specialized proresolving mediators (SPMs). In this work, we review recent evidence on the structure and functional roles of these novel lipid mediators of resolution. Together, these show that leukocyte trafficking and temporal spatial signals govern the resolution of self-limited inflammation and stimulate homeostasis. 10.1101/cshperspect.a016311
    The Role of Cholesterol in the Pathogenesis of NASH. Ioannou George N Trends in endocrinology and metabolism: TEM Lipotoxicity drives the development of progressive hepatic inflammation and fibrosis in a subgroup of patients with nonalcoholic fatty liver disease (NAFLD), causing nonalcoholic steatohepatitis (NASH) and even progression to cirrhosis and hepatocellular carcinoma (HCC). While the underlying molecular mechanisms responsible for the development of inflammation and fibrosis that characterize progressive NASH remain unclear, emerging evidence now suggests that hepatic free cholesterol (FC) is a major lipotoxic molecule critical in the development of experimental and human NASH. In this review, we examine the effects of excess FC in hepatocytes, Kupffer cells (KCs), and hepatic stellate cells (HSCs), and the subcellular mechanisms by which excess FC can induce cellular toxicity or proinflammatory and profibrotic effects in these cells. 10.1016/j.tem.2015.11.008
    Diseases of pulmonary surfactant homeostasis. Whitsett Jeffrey A,Wert Susan E,Weaver Timothy E Annual review of pathology Advances in physiology and biochemistry have provided fundamental insights into the role of pulmonary surfactant in the pathogenesis and treatment of preterm infants with respiratory distress syndrome. Identification of the surfactant proteins, lipid transporters, and transcriptional networks regulating their expression has provided the tools and insights needed to discern the molecular and cellular processes regulating the production and function of pulmonary surfactant prior to and after birth. Mutations in genes regulating surfactant homeostasis have been associated with severe lung disease in neonates and older infants. Biophysical and transgenic mouse models have provided insight into the mechanisms underlying surfactant protein and alveolar homeostasis. These studies have provided the framework for understanding the structure and function of pulmonary surfactant, which has informed understanding of the pathogenesis of diverse pulmonary disorders previously considered idiopathic. This review considers the pulmonary surfactant system and the genetic causes of acute and chronic lung disease caused by disruption of alveolar homeostasis. 10.1146/annurev-pathol-012513-104644
    Hyaluronan and TLR4 promote surfactant-protein-C-positive alveolar progenitor cell renewal and prevent severe pulmonary fibrosis in mice. Liang Jiurong,Zhang Yanli,Xie Ting,Liu Ningshan,Chen Huaiyong,Geng Yan,Kurkciyan Adrianne,Mena Jessica Monterrosa,Stripp Barry R,Jiang Dianhua,Noble Paul W Nature medicine Successful recovery from lung injury requires the repair and regeneration of alveolar epithelial cells to restore the integrity of gas-exchanging regions within the lung and preserve organ function. Improper regeneration of the alveolar epithelium is often associated with severe pulmonary fibrosis, the latter of which involves the recruitment and activation of fibroblasts, as well as matrix accumulation. Type 2 alveolar epithelial cells (AEC2s) are stem cells in the adult lung that contribute to the lung repair process. The mechanisms that regulate AEC2 renewal are incompletely understood. We provide evidence that expression of the innate immune receptor Toll-like receptor 4 (TLR4) and the extracellular matrix glycosaminoglycan hyaluronan (HA) on AEC2s are important for AEC2 renewal, repair of lung injury and limiting the extent of fibrosis. Either deletion of TLR4 or HA synthase 2 in surfactant-protein-C-positive AEC2s leads to impaired renewal capacity, severe fibrosis and mortality. Furthermore, AEC2s from patients with severe pulmonary fibrosis have reduced cell surface HA and impaired renewal capacity, suggesting that HA and TLR4 are key contributors to lung stem cell renewal and that severe pulmonary fibrosis is the result of distal epithelial stem cell failure. 10.1038/nm.4192
    Air Space Distension Precedes Spontaneous Fibrotic Remodeling and Impaired Cholesterol Metabolism in the Absence of Surfactant Protein C. Ruwisch Jannik,Sehlmeyer Kirsten,Roldan Nuria,Garcia-Alvarez Begoña,Perez-Gil Jesus,Weaver Timothy E,Ochs Matthias,Knudsen Lars,Lopez-Rodriguez Elena American journal of respiratory cell and molecular biology Surfactant protein (SP)-C deficiency is found in samples from patients with idiopathic pulmonary fibrosis, especially in familial forms of this disease. We hypothesized that SP-C may contribute to fibrotic remodeling in aging mice and alveolar lipid homeostasis. For this purpose, we analyzed lung function, alveolar dynamics, lung structure, collagen content, and expression of genes related to lipid and cholesterol metabolism of aging SP-C knockout mice. In addition, experiments with an alveolar macrophage cell line exposed to lipid vesicles with or without cholesterol and/or SP-C were performed. Alveolar dynamics showed progressive alveolar derecruitment with age and impaired oxygen saturation. Lung structure revealed that decreasing volume density of alveolar spaces was accompanied by increasing of the ductal counterparts. Simultaneously, septal wall thickness steadily increased, and fibrotic wounds appeared in lungs from the age of 50 weeks. This remarkable phenotype is unique to the 129Sv strain, which has an increased absorption of cholesterol, linking the accumulation of cholesterol and the absence of SP-C to a fibrotic remodeling process. The findings of this study suggest that overall loss of SP-C results in an age-dependent, complex, heterogeneous phenotype characterized by a combination of overdistended air spaces and fibrotic wounds that resembles combined emphysema and pulmonary fibrosis in patients with idiopathic pulmonary fibrosis. Addition of SP-C to cholesterol-laden lipid vesicles enhanced the expression of cholesterol metabolism and transport genes in an alveolar macrophage cell line, identifying a potential new lipid-protein axis involved in lung remodeling. 10.1165/rcmb.2019-0358OC
    Mitofusins regulate lipid metabolism to mediate the development of lung fibrosis. Chung Kuei-Pin,Hsu Chia-Lang,Fan Li-Chao,Huang Ziling,Bhatia Divya,Chen Yi-Jung,Hisata Shu,Cho Soo Jung,Nakahira Kiichi,Imamura Mitsuru,Choi Mary E,Yu Chong-Jen,Cloonan Suzanne M,Choi Augustine M K Nature communications Accumulating evidence illustrates a fundamental role for mitochondria in lung alveolar type 2 epithelial cell (AEC2) dysfunction in the pathogenesis of idiopathic pulmonary fibrosis. However, the role of mitochondrial fusion in AEC2 function and lung fibrosis development remains unknown. Here we report that the absence of the mitochondrial fusion proteins mitofusin1 (MFN1) and mitofusin2 (MFN2) in murine AEC2 cells leads to morbidity and mortality associated with spontaneous lung fibrosis. We uncover a crucial role for MFN1 and MFN2 in the production of surfactant lipids with MFN1 and MFN2 regulating the synthesis of phospholipids and cholesterol in AEC2 cells. Loss of MFN1, MFN2 or inhibiting lipid synthesis via fatty acid synthase deficiency in AEC2 cells exacerbates bleomycin-induced lung fibrosis. We propose a tenet that mitochondrial fusion and lipid metabolism are tightly linked to regulate AEC2 cell injury and subsequent fibrotic remodeling in the lung. 10.1038/s41467-019-11327-1