Mitochondrial dysfunction as a mechanistic biomarker in patients with non-alcoholic fatty liver disease (NAFLD).
Ajaz Saima,McPhail Mark J,Gnudi Luigi,Trovato Francesca M,Mujib Salma,Napoli Salvatore,Carey Ivana,Agarwal Kosh
Mitochondrion
BACKGROUND:Dysfunctional metabolism lies at the centre of the pathogenesis for Non-Alcoholic Fatty Liver Disease (NAFLD) and involves mitochondrial dysfunction, lipid dysmetabolism and oxidative stress. This study, for the first time, explores real-time energy changes in peripheral blood and corresponding metabolite changes, to investigate whether mitochondria-related immunometabolic biomarkers can predict progression in NAFLD. METHODS:Thirty subjects divided into 3 groups were assessed: NAFLD with biopsy-proven mild fibrosis (n = 10), severe fibrosis (n = 10) and healthy controls (HC, n = 10). Mitochondrial functional analysis was performed in a Seahorse XFp analyzer in live peripheral blood mononuclear cells (PBMCs). Global metabolomics quantified a broad range of human plasma metabolites. Mitochondrial carbamoyl phosphate synthase 1(CPS-1), Ornithine transcarbamoylase (OTC), Fibroblast growth factor-21 (FGF-21) and a range of cytokines in plasma were measured by ELISA. RESULTS:NAFLD patients with severe fibrosis demonstrated reduced maximal respiration (106 ± 25 versus 242 ± 62, p < 0.05) and reserve capacity (56 ± 16 versus 184 ± 42, p = 0.006) compared to mild/moderate fibrosis. Comparing mild/moderate vs severe liver fibrosis in patients with NAFLD, 14 out of 493 quantified metabolites were significantly changed (p < 0.05). Most of the amino acids modulated were the urea cycle (UC) components which included citrulline/ornithine ratio, arginine and glutamate. Plasma levels of CPS-1 and FGF-21 were significantly higher mild versus severe fibrosis in NAFLD patients. This novel panel generated an area under the ROC of 0.95, sensitivity of 100% and specificity 80% and p = 0.0007 (F1-F2 versus F3-F4). CONCLUSION:Progression in NAFLD is associated with mitochondrial dysfunction and changes in metabolites associated with the urea cycle. We demonstrate a unique panel of mitochondrial-based, signatures which differentiate between stages of NAFLD. LAY SUMMARY:Mitochondrial dysfunction in peripheral cells along with alterations in metabolites of urea cycle act as a sensor of hepatocyte mitochondrial damage. These changes can be measured in blood and together represent a unique panel of biomarkers for progression of fibrosis in NAFLD.
10.1016/j.mito.2020.12.010
Physalin B ameliorates nonalcoholic steatohepatitis by stimulating autophagy and NRF2 activation mediated improvement in oxidative stress.
Zhang Mei-Hui,Li Jie,Zhu Xiao-Yun,Zhang Yan-Qiu,Ye Sheng-Tao,Leng Ying-Rong,Yang Ting,Zhang Hao,Kong Ling-Yi
Free radical biology & medicine
Non-alcoholic steatohepatitis (NASH) is the progressive stage of non-alcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Physalin B (PB), a withanolide isolated from Physalis species (Solanaceae), exhibits a broad spectrum of biological activities, however, the potential role of PB in NASH has not been evaluated. The present study investigated the protective effects of PB against NASH and further elucidated the mechanisms of PB in hepatic autophagy and oxidative stress in vitro and in vivo. We conducted a series of experiments using methionine-choline deficient (MCD) diet induced NASH mice and cultured L02 cells. Serum markers of liver injury, morphology, and the histology of liver tissues were investigated. Western blot assays and quantitative real-time PCR were used to investigate the hepatoprotective effect of PB. PB significantly ameliorated hepatic injury, including hepatic index, transaminase activities, histology, and inflammation in MCD-induced mice. Moreover, PB markedly increased the expression of P62 and the ratio of LC3Ⅱ/Ⅰ in vitro and in vivo. Furthermore, PB promoted the interaction between endogenous KEAP1 and P62, reduced the interaction between KEAP1 and NRF2, activated the nuclear translocation of NRF2 and NRF2 target gene expression, and ultimately attenuated oxidative stress. In addition, knockdown of P62 blocked PB-mediated activation of NRF2 in L02 cells. These results clearly indicated that PB ameliorated NASH by stimulating autophagy and P62-KEAP1-NRF2 antioxidative signaling, suggesting that PB is expected to become a novel therapeutic drug for NASH.
10.1016/j.freeradbiomed.2020.12.020
Suppression of Hepatic Stellate Cell Death by Toxic Advanced Glycation End-Products.
Takino Jun-Ichi,Sato Takuma,Nagamine Kentaro,Sakasai-Sakai Akiko,Takeuchi Masayoshi,Hori Takamitsu
Biological & pharmaceutical bulletin
Advanced glycation end-products (AGEs) are produced by the non-enzymatic reaction of sugars with proteins. It has been revealed that glyceraldehyde-derived toxic AGEs (TAGE) are elevated in the serum of non-alcoholic steatohepatitis (NASH) patients. NASH causes liver fibrosis and progresses to cirrhosis and hepatocellular carcinoma. However, the impact of TAGE in liver fibrosis caused by extracellular matrix accumulation remains poorly understood. In this study, we examined the effect of TAGE on the activation of hepatic stellate cells that are involved in liver fibrosis. LX-2 cells treated with transforming growth factor-β1 (TGF-β1) significantly reduced cell viability by apoptosis. However, the decrease in cell viability with TGF-β1 treatment was significantly suppressed by TAGE co-treatment. The levels of α-smooth muscle actin (α-SMA) and platelet-derived growth factor (PDGF)-Rβ and its ligand PDGF-B were increased in LX-2 cells following TGF-β1 treatment, suggesting that these cells were activated; however, these increases were unaffected by TAGE co-treatment. Moreover, collagen I level was increased with TGF-β1 treatment, and this increase was further increased by TAGE co-treatment. These results suggested that the suppression of apoptosis in activated LX-2 cells by TGF-β1 and TAGE co-treatment is related to an increase in the production of the extracellular matrix such as collagen I. Therefore, it was suggested that TAGE might aggravate the liver fibrosis of chronic hepatitis, such as NASH.
10.1248/bpb.b20-00708
Inulin Exerts Beneficial Effects on Non-Alcoholic Fatty Liver Disease via Modulating gut Microbiome and Suppressing the Lipopolysaccharide-Toll-Like Receptor 4-Mψ-Nuclear Factor-κB-Nod-Like Receptor Protein 3 Pathway via gut-Liver Axis in Mice.
Bao Ting,He Fang,Zhang Xiaoxia,Zhu Lili,Wang Zhen,Lu Haixia,Wang Ting,Li Yiwei,Yang Shaoqi,Wang Hao
Frontiers in pharmacology
Non-alcoholic fatty liver disease (NAFLD) is a common metabolic disease worldwide with chronic low-grade inflammation and alteration of gut microbiota. Inulin (INU) has been confirmed to exhibit benefit for metabolic diseases. The aim of this study was to clarify the effects and mechanism of INU on NAFLD inflammation via gut-liver axis. C57BL/6 mice were randomly divided into four groups: normal diet group (ND); high-fat diet group (HFD); ND with INU group (ND-INU); HFD with INU group (HFD-INU). After 14 weeks of feeding, mice were sacrificed and associated indications were investigated. Significant increases of body weight, liver weight, liver biochemical aspartate aminotransferase, alanine aminotransferase, triglyceride, total cholesterol and pro-inflammatory indicators (Lipopolysaccharide, interleukin (IL)-18, IL-1β, TNF-α and IL-6), as well as a reduction of plasma IL-10 were observed in HFD group, while INU treatment restored these abnormal indicators. The ratio of hepatic macrophages (Mψs) and Toll-like receptor 4 Mψs were both reduced with INU intervention. Nuclear factor-κB, nod-like receptor protein 3, apoptosis-associated speck-like protein and caspase-1 were decreased in HFD-INU group. Additionally, the results of 16S rRNA sequencing and analysis showed that INU administration modulated the composition of gut microbial community in NAFLD mice by up-regulating the abundances of and as well as down-regulating the abundances of and the ratio of . Short-chain fatty acids including acetic acid, propionic acid and butyric acid, were increased with INU treatment. Correlation analysis revealed close relationships among inflammatory indicators, metabolic indicators as well as gut microbiota/its metabolite short-chain fatty acids. INU prevents NAFLD via modulating gut microbiota and suppressing Lipopolysaccharide-Toll-like receptor 4-Mψ-Nuclear factor-κB-nod-like receptor protein 3 inflammatory pathway via the gut-liver axis.
10.3389/fphar.2020.558525
Hydrogen Sulfide Attenuates High-Fat Diet-Induced Non-Alcoholic Fatty Liver Disease by Inhibiting Apoptosis and Promoting Autophagy via Reactive Oxygen Species/Phosphatidylinositol 3-Kinase/AKT/Mammalian Target of Rapamycin Signaling Pathway.
Wu Dongdong,Zhong Peiyu,Wang Yizhen,Zhang Qianqian,Li Jianmei,Liu Zhengguo,Ji Ailing,Li Yanzhang
Frontiers in pharmacology
Non-alcoholic fatty liver disease (NAFLD) is a common chronic liver disease worldwide. Hydrogen sulfide (HS) is involved in a wide range of physiological and pathological processes. Nevertheless, the mechanism of action of HS in NAFLD development has not been fully clarified. Here, the reduced level of HS was observed in liver cells treated with oleic acid (OA). Administration of HS increased the proliferation of OA-treated cells. The results showed that HS decreased apoptosis and promoted autophagy through reactive oxygen species (ROS)-mediated phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) cascade in OA-treated cells. In addition, administration of HS relieved high-fat diet (HFD)-induced NAFLD via inhibition of apoptosis and promotion of autophagy. These findings suggest that HS could ameliorate HFD-induced NAFLD by regulating apoptosis and autophagy through ROS/PI3K/AKT/mTOR signaling pathway. Novel HS-releasing donors may have therapeutic potential for the treatment of NAFLD.
10.3389/fphar.2020.585860
A Mineralocorticoid Receptor Deficiency in Myeloid Cells Reduces Liver Steatosis by Impairing Activation of CD8 T Cells in a Nonalcoholic Steatohepatitis Mouse Model.
Muñoz-Durango Natalia,Arrese Marco,Hernández Alejandra,Jara Evelyn,Kalergis Alexis M,Cabrera Daniel
Frontiers in immunology
Background and Aims:The mineralocorticoid receptor (MR) and renin-angiotensin-aldosterone system (RAAS) are implicated in non-alcoholic liver fatty disease (NALFD). However, inflammatory mechanisms linking MR and RAAS with disease pathology remain unclear. Here we aimed to evaluate the contribution of myeloid MR to the inflammatory response in an animal model of non-alcoholic steatohepatitis (NASH), induced with a methionine-choline deficient diet (MCD). Methods:Mice with a conditional deficiency of MR in myeloid cells (MyMRKO) and their counterpart floxed control mice (FC) were fed for 18 days with MCD or chow diet, respectively. Serum levels of aminotransferases and aldosterone levels were measured and hepatic steatosis, inflammation and fibrosis scored histologically. Hepatic triglyceride content (HTC) and hepatic mRNA levels of pro-inflammatory pro-fibrotic-associated genes were also assessed. Deep flow cytometric analysis was used to dissect the immune response during NASH development. Results:MyMRKO mice fed with an MCD diet exhibited reduced hepatic inflammation and lower HTC than controls. Absolute number and percentage of liver inflammatory infiltrate cells (except for CD8 T lymphocytes) were similar in both MyMRKO and control mice fed with an MCD diet but expression of the costimulatory molecule CD86 by dendritic cells and the CD25 activation marker in CD8 T cells were significantly reduced in MyMRKO. Conclusions:Proinflammatory cells are functionally suppressed in the absence of MR. We hypothesized that loss of MR in myeloid cells reduces lipid accumulation in the liver, in part through modulating the adaptive immune response, which is pivotal for the development of steatosis.
10.3389/fimmu.2020.563434
Deletion of KLF10 Leads to Stress-Induced Liver Fibrosis upon High Sucrose Feeding.
Lee Junghoon,Oh Ah-Reum,Lee Hui-Young,Moon Young-Ah,Lee Ho-Jae,Cha Ji-Young
International journal of molecular sciences
Liver fibrosis is a consequence of chronic liver injury associated with chronic viral infection, alcohol abuse, and nonalcoholic fatty liver. The evidence from clinical and animal studies indicates that transforming growth factor-β (TGF-β) signaling is associated with the development of liver fibrosis. Krüppel-like factor 10 (KLF10) is a transcription factor that plays a significant role in TGF-β-mediated cell growth, apoptosis, and differentiation. In recent studies, it has been reported to be associated with glucose homeostasis and insulin resistance. In the present study, we investigated the role of KLF10 in the progression of liver disease upon a high-sucrose diet (HSD) in mice. Wild type (WT) and 10 knockout (KO) mice were fed either a control chow diet or HSD (50% sucrose) for eight weeks. 10 KO mice exhibited significant hepatic steatosis, inflammation, and liver injury upon HSD feeding, whereas the WT mice exhibited mild hepatic steatosis with no apparent liver injury. The livers of HSD-fed 10 KO mice demonstrated significantly increased endoplasmic reticulum stress, oxidative stress, and proinflammatory cytokines. 10 deletion led to the development of sucrose-induced hepatocyte cell death both in vivo and in vitro. Moreover, it significantly increased fibrogenic gene expression and collagen accumulation in the liver. Increased liver fibrosis was accompanied by increased phosphorylation and nuclear localization of Smad3. Here, we demonstrate that HSD-fed mice develop a severe liver injury in the absence of KLF10 due to the hyperactivation of the endoplasmic reticulum stress response and CCAAT/enhance-binding protein homologous protein (CHOP)-mediated apoptosis of hepatocytes. The current study suggests that KLF10 plays a protective role against the progression of hepatic steatosis into liver fibrosis in a lipogenic state.
10.3390/ijms22010331
The association of the adipokine zinc-alpha2-glycoprotein with non-alcoholic fatty liver disease and related risk factors: A comprehensive systematic review.
International journal of clinical practice
BACKGROUND AND AIM:The adipokine zinc-alpha2-glycoprotein (ZAG), a multidisciplinary protein, is involved in lipid metabolism, glucose homeostasis and energy balance. Accumulating evidence demonstrates that the expression of ZAG is mainly downregulated in obesity and obesity-related conditions. In the present study, we assessed the association of ZAG with non-alcoholic fatty liver disease (NAFLD) and the related risk factors including obesity, metabolic factors and inflammatory parameters, with emphasis on potential mechanisms underlying these associations. METHODS:PRISMA guidelines were followed in this review. Systematic searches were performed using the PubMed/Medline, ScienceDirect, Scopus, EMBASE, ProQuest and Google Scholar databases, up to August 2020 for all relevant published papers. RESULTS:Out of 362 records screened, 34 articles were included in the final analysis. According to the studies reviewed here, ZAG appears to exert a protective effect against NAFLD by enhancing mRNA expression levels of peroxisome proliferator-activated receptor α (PPARα) and PPARγ, promoting mRNA expression levels of the lipolysis-related genes, reducing mRNA expression levels of the lipogenesis-related genes, increasing hepatic fatty acid oxidation, ameliorating hepatic steatosis, promoting the activity of brown adipose tissue and the expression of thermogenesis-related genes, modulating energy balance and glucose homeostasis, and elevating plasma levels of healthy adipokines such as adiponectin. ZAG can also be involved in the regulation of inflammatory responses by attenuation of the expression of pro-inflammatory and pro-fibrotic mediators. CONCLUSION:According to the studies reviewed here, ZAG is suggested to be a promising therapeutic target for NAFLD. However, the favourable effects of ZAG need to be confirmed in prospective cohort studies.
10.1111/ijcp.13985
The role of microRNA-33 as a key regulator in hepatic lipogenesis signaling and a potential serological biomarker for NAFLD with excessive dietary fructose consumption in C57BL/6N mice.
Pan Jeong Hoon,Cha Hanvit,Tang Jingsi,Lee Seoyoon,Lee Suk Hee,Le Brandy,Redding Mersady C,Kim Sangyub,Batish Mona,Kong Byungwhi C,Lee Jin Hyup,Kim Jae Kyeom
Food & function
Limited studies reported mechanisms by which microRNAs (miRNA) are interlinked in the etiology of fructose-induced non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the significance of miRNAs in fructose-induced NAFLD pathogenesis through unbiased approaches. In experiment I, C57BL/6N mice were fed either water or 34% fructose for six weeks ad libitum. In experiment II, time course effects of fructose intervention were monitored using the same conditions; mice were killed at the baseline, fourth, and sixth weeks. Bioinformatic analyses for hepatic proteomics revealed that SREBP1 is the most significant upstream regulator influenced by fructose; miR-33-5p (miR-33) was identified as the key miRNA responsible for SREBP1 regulation upon fructose intake, which was validated by in vitro transfection assay. In experiment II, we confirmed that the longer mice consumed fructose, the more severe liver injury markers (e.g., serum AST) appeared. Moreover, hepatic Srebp1 mRNA expression was increased depending upon the duration of fructose consumption. Hepatic miR-33 was time-dependently decreased by fructose while serum miR-33 expression was increased; these observations indicated that miR-33 from the liver might be released upon cell damage. Finally we observed that fructose-induced ferroptosis might be a cause of liver toxicity, resulting from oxidative damage. Collectively, our findings suggest that fructose-induced oxidative damage induces ferroptosis, and miR-33 could be used as a serological biomarker of fructose-induced NAFLD.
10.1039/d0fo02286a
Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression.
Dallio Marcello,Sangineto Moris,Romeo Mario,Villani Rosanna,Romano Antonino Davide,Loguercio Carmelina,Serviddio Gaetano,Federico Alessandro
International journal of molecular sciences
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the major cause of chronic liver disease, especially in western countries. NAFLD encompasses a wide spectrum of hepatic histological alterations, from simple steatosis to steatohepatitis and cirrhosis with a potential development of hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and fibrosis. Several studies reported that insulin resistance, redox unbalance, inflammation, and lipid metabolism dysregulation are involved in NAFLD progression. However, the mechanisms beyond the evolution of simple steatosis to NASH are not clearly understood yet. Recent findings suggest that different oxidized products, such as lipids, cholesterol, aldehydes and other macromolecules could drive the inflammation onset. On the other hand, new evidence indicates innate and adaptive immunity activation as the driving force in establishing liver inflammation and fibrosis. In this review, we discuss how immunity, triggered by oxidative products and promoting in turn oxidative stress in a vicious cycle, fuels NAFLD progression. Furthermore, we explored the emerging importance of immune cell metabolism in determining inflammation, describing the potential application of trained immune discoveries in the NASH pathological context.
10.3390/ijms22010436
Gut microbiome changes in Nonalcoholic fatty liver disease & alcoholic liver disease.
Kwong Eric K,Puri Puneet
Translational gastroenterology and hepatology
Nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD) are some of the most common liver diseases worldwide. The human gut microbiome is dynamic and shifts in bacterial composition have been implicated in many diseases. Studies have shown that there is a shift in bacterial overgrowth favoring pro-inflammatory mediators in patients with advanced disease progression such as cirrhosis. Further investigation demonstrated that the transplantation of gut microbiota from advanced liver disease patients can reproduce severe liver inflammation and injury in mice. Various techniques in manipulating the gut microbiota have been attempted including fecal transplantation and probiotics. This review focuses on the changes in the gut microbiota as well as emerging lines of microbiome work with respect to NAFLD and ALD.
10.21037/tgh.2020.02.18
Basic science to clinical trials in non-alcoholic fatty liver disease and alcohol-related liver disease: collaboration with industry.
Asgharpour Amon,Dinani Amreen,Friedman Scott L
Translational gastroenterology and hepatology
Non-alcoholic fatty liver disease (NAFLD) and alcohol-related liver disease (ALD) are highly prevalent forms of chronic liver diseases globally, associated with rising all-cause morbidity and mortality. While distinct diseases, NAFLD and ALD share several similarities; both can result in fatty liver disease, steatohepatitis, associated hepatic fibrosis and cirrhosis-related complications, including hepatocellular carcinoma (HCC). Our understanding of the pathophysiology and manifestations of these diseases has advanced significantly, which has established a new foundation to identify therapeutic targets and test new treatments. This review underscores emerging pathogenic pathways that establish a template for target identification and clinical trials. Success is critically dependent upon productive interactions between academic investigators and industry to address unmet therapeutic needs in NAFLD and ALD.
10.21037/tgh.2020.01.04
Berbamine induced activation of the SIRT1/LKB1/AMPK signaling axis attenuates the development of hepatic steatosis in high-fat diet-induced NAFLD rats.
Sharma Ankita,Anand Sumit Kr,Singh Neha,Dwarkanath Akshay,Dwivedi Upendra Nath,Kakkar Poonam
Food & function
Non-alcoholic fatty liver disease (NAFLD), a chronic metabolic disorder is concomitant with oxidative stress and inflammation. This study aimed to assess the effects of berbamine (BBM), a natural bisbenzylisoquinoline alkaloid with manifold biological activities and pharmacological effects on lipid, cholesterol and glucose metabolism in a rat model of NAFLD, and to explicate the potential mechanisms underlying its activity. BBM administration alleviated the increase in the body weight and liver index of HFD rats. The aberrations in liver function, serum parameters, and microscopic changes in the liver structure of HFD fed rats were significantly improved upon BBM administration. BBM also significantly attenuated oxidative damage and inhibited triglyceride and cholesterol synthesis. The SIRT1 deacetylase activity was also enhanced by BBM through liver kinase B1 and activated AMP-activated protein kinase. Activation of the SIRT1/LKB1/AMPK pathway prevented the downstream target ACC (acetyl-CoA carboxylase) and elevation in the expression of FAS (fatty acid synthase) and SCD1 (steroyl CoA desaturase). BBM also modulated the expression of PPARs maintaining the fatty acid homeostasis regulation. The assessment of berbamine induced ultrastructural changes by TEM analysis and the expression of autophagic markers LC3a/b, Beclin 1 and p62 revealed the induction of autophagy to alleviate fatty liver conditions. These results show novel findings that BBM induced protection against hepatic lipid metabolic disorders is achieved by regulating the SIRT1/LKB1/AMPK pathway, and thus it emerges as an effective phyoconstituent for the management of NAFLD.
10.1039/d0fo02501a
The interplay between host cellular and gut microbial metabolism in NAFLD development and prevention.
Yu S-Y,Xu L
Journal of applied microbiology
Metabolism regulation centred on insulin resistance is increasingly important in nonalcoholic fatty liver disease (NAFLD). This review focuses on the interactions between the host cellular and gut microbial metabolism during the development of NAFLD. The cellular metabolism of essential nutrients, such as glucose, lipids and amino acids, is reconstructed with inflammation, immune mechanisms and oxidative stress, and these alterations modify the intestinal, hepatic and systemic environments, and regulate the composition and activity of gut microbes. Microbial metabolites, such as short-chain fatty acids, secondary bile acids, protein fermentation products, choline and ethanol and bacterial toxicants, such as lipopolysaccharides, peptidoglycans and bacterial DNA, play vital roles in NAFLD. The microbe-metabolite relationship is crucial for the modulation of intestinal microbial composition and metabolic activity. The intestinal microbiota and their metabolites participate in epithelial cell metabolism via a series of cell receptors and signalling pathways and remodel the metabolism of various cells in the liver via the gut-liver axis. Microbial metabolic manipulation is a promising strategy for NAFLD prevention, but larger-sampled clinical trials are required for future application.
10.1111/jam.14992
Obesity-induced upregulation of microRNA-183-5p promotes hepatic triglyceride accumulation by targeting the B-cell translocation gene 1.
Life sciences
AIMS:Obesity is recognized as a risk factor for many metabolic disorders, particularly nonalcoholic fatty liver disease (NAFLD). However, the underlying mechanism is still poorly understood. Several lines of evidence indicate that microRNA (miRNA) is a key regulator of lipid metabolism. In this study, we investigated the role of miR-183-5p in the development of NAFLD. METHODS:The expression levels of miR-183-5p and B-cell translocation gene 1 (Btg1) were determined by quantitative real-time PCR and histological analysis in livers of obese mice and cell models induced with palmitic acid (PA), respectively. AML12 cells were treated with PA in the presence or absence of miR-183-5p mimics or inhibitor. Moreover, a Luciferase reporter assay was used to determine whether Btg1 is the direct target of miR-183-5p. Protein levels of BTG1 were estimated using western blotting. KEY FINDINGS:Expression of miR-183-5p was increased in the livers of three murine models and also in the AML12 cell model. Overexpression of miR-183-5p in the cell model and mice led to hepatic triglyceride (TG) accumulation and upregulation of lipogenic genes, whereas inhibition of miR-183-5p in the cell model improved hepatic TG accumulation. Mechanistically, we further identified Btg1 as a direct target gene of miR-183-5p. SIGNIFICANCE:Our findings revealed that miR-183-5p affected the regulation of hepatic TG homeostasis, which may provide a potential therapeutic target for hepatosteatosis.
10.1016/j.lfs.2020.119011
The effect of 1,25-dihydroxyvitamin D3 on liver damage, oxidative stress, and advanced glycation end products in experimental nonalcoholic- and alcoholic- fatty liver disease
Bingül İlknur,Aydın A. Fatih,Küçükgergin Canan,Doğan-Ekici Işın,Doğru-Abbasoğlu Semra,Uysal Müjdat
Turkish journal of medical sciences
Background/aim:Oxidative stress and advanced glycation end products (AGEs) formation are proposed as effective mechanisms in the pathogenesis of nonalcoholic fatty liver disease (NAFLD) and alcoholic liver disease (ALD). 1,25(OH)2D3 was proposed to have antioxidant, antiinflammatory and antiglycation properties. In this study, the effect of 1,25(OH)2D3 treatment on oxidative stress parameters and AGEs levels together with hepatic histopathology was investigated in high fructose (HFr) or ethanol (EtOH)-treated rats. Materials and methods:Rats were treated with fructose (30%) or ethanol (5-20%) in drinking water with and without 1,25(OH)2D3 treatment (5 μg/kg two times a week) for 8 weeks. Insulin resistance (IR), oxidative stress parameters, AGEs, triglyceride (TG), and hydroxyproline (Hyp) levels together with histopathology were investigated in the liver. Results:1,25(OH)2D3 decreased hepatic reactive oxygen species, lipid and protein oxidation products together with histopathological improvements in HFr- and EtOH-treated rats. 1,25(OH)2D3 treatment was observed to decrease significantly serum and hepatic AGEs in HFr group, and hepatic AGEs in EtOH group. Conclusion:Our results clearly show that 1,25(OH)2 D3 treatment may be useful in the alleviation of hepatic lesions by decreasing glycooxidant stress in both NAFLD and ALD models created by HFr- and EtOH-treated rats, respectively.
10.3906/sag-2007-289
Phenolic-rich smoothie consumption ameliorates non-alcoholic fatty liver disease in obesity mice by increasing antioxidant response.
Quitete Fernanda Torres,Almeida Santos Giulia Medeiros,de Oliveira Ribeiro Leilson,Aguiar da Costa Cristiane,Freitas Suely Pereira,Martins da Matta Virgínia,Daleprane Julio Beltrame
Chemico-biological interactions
Consumption of foods rich in phenolic compounds can be beneficial for health. This study aimed to examine whether the consumption of a phenolic-rich smoothie, based on juçara, strawberry and banana, ameliorates metabolic status and liver damage of diet-induced obese mice. Forty male C57BL/6J mice were assigned into four groups (n = 10) and fed control diet with free access to water (C) or phenolic-rich smoothie (C-S), or fed high-fat diet with free access to water (HF) or phenolic-rich smoothie (HF-S) for five weeks. HF and HF-S groups had higher body weight gains than the C group, however the HF had a greater adipose index, higher plasma levels of glucose, insulin and leptin, as well as higher plasma and hepatic steatosis than C, C-S and HF-S groups. The liver oxidative stress markers were reduced in C-S and HF-S groups and the activity of catalase and glutathione peroxidase were higher compared with their counterparts. The present study suggests that regular consumption of a phenolic-rich smoothie improves the liver antioxidant status, prevents metabolic disorders and ameliorates non-alcoholic fatty liver disease caused by high-fat diet consumption.
10.1016/j.cbi.2021.109369
Harnessing Muscle-Liver Crosstalk to Treat Nonalcoholic Steatohepatitis.
Frontiers in endocrinology
Non-alcoholic fatty liver disease (NAFLD) has reached epidemic proportions, affecting an estimated one-quarter of the world's adult population. Multiple organ systems have been implicated in the pathophysiology of NAFLD; however, the role of skeletal muscle has until recently been largely overlooked. A growing body of evidence places skeletal muscle-via its impact on insulin resistance and systemic inflammation-and the muscle-liver axis at the center of the NAFLD pathogenic cascade. Population-based studies suggest that sarcopenia is an effect-modifier across the NAFLD spectrum in that it is tightly linked to an increased risk of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH), and advanced liver fibrosis, all independent of obesity and insulin resistance. Longitudinal studies suggest that increases in skeletal muscle mass over time may both reduce the incidence of NAFLD and improve preexisting NAFLD. Adverse muscle composition, comprising both low muscle volume and high muscle fat infiltration (myosteatosis), is highly prevalent in patients with NAFLD. The risk of functional disability conferred by low muscle volume in NAFLD is further exacerbated by the presence of myosteatosis, which is twice as common in NAFLD as in other chronic liver diseases. Crosstalk between muscle and liver is influenced by several factors, including obesity, physical inactivity, ectopic fat deposition, oxidative stress, and proinflammatory mediators. In this perspective review, we discuss key pathophysiological processes driving sarcopenia in NAFLD: anabolic resistance, insulin resistance, metabolic inflexibility and systemic inflammation. Interventions that modify muscle quantity (mass), muscle quality (fat), and physical function by simultaneously engaging multiple targets and pathways implicated in muscle-liver crosstalk may be required to address the multifactorial pathogenesis of NAFLD/NASH and provide effective and durable therapies.
10.3389/fendo.2020.592373
Nonalcoholic Fatty Liver Disease and Type 2 Diabetes Mellitus: A Bidirectional Relationship.
Muzica Cristina M,Sfarti Catalin,Trifan Anca,Zenovia Sebastian,Cuciureanu Tudor,Nastasa Robert,Huiban Laura,Cojocariu Camelia,Singeap Ana-Maria,Girleanu Irina,Chiriac Stefan,Stanciu Carol
Canadian journal of gastroenterology & hepatology
Worldwide, the leading cause of chronic liver disease is represented by nonalcoholic fatty liver disease (NAFLD) which has now become a global epidemic of the 21st century, affecting 1 in 4 adults, and which appears to be associated with the steadily increasing rates of metabolic syndrome and its components (obesity, type 2 diabetes mellitus (T2DM), and dyslipidemia). NAFLD has been reported to be associated with extrahepatic manifestations such as cardiovascular disease, T2DM, chronic kidney disease, extrahepatic malignancies (e.g., colorectal cancer), endocrine diseases (e.g., hypothyroidism, polycystic ovarian syndrome, psoriasis, and osteoporosis), obstructive sleep apnea, and iron overload. The prevalence of NAFLD is very high, affecting 25-30% of the world population and encloses two steps: (1) nonalcoholic fatty liver (NAFL), which includes steatosis only, and (2) nonalcoholic steatohepatitis (NASH) defined by the presence of steatosis and inflammation with hepatocyte ballooning, with or without fibrosis which can progress to liver fibrosis, hepatocellular carcinoma, and liver transplantation. Current data define a more complex relationship between NAFLD and T2DM than was previously believed, underlining a bidirectional and mutual association between the two entities. This review aims to summarize the current literature regarding the incidence of T2DM among patients with NAFLD and also the prevalence of NAFLD in T2DM patients, highlighting the recent key studies. Clinicians should screen, diagnose, and treat T2DM in patients with NAFLD in order to avoid short- and long-term complications.
10.1155/2020/6638306
and Mixture Improves Disorders of Lipid Metabolism in Nonalcoholic Fatty Liver Disease.
Shin Mi-Rae,Shin Sung Ho,Roh Seong-Soo
Canadian journal of gastroenterology & hepatology
Nonalcoholic fatty liver disease (NAFLD) has been a major cause of a chronic liver disease over recent decades and increasing worldwide in parallel with the remarkable growth of obesity. In the present study, we investigate the ameliorative effects of PCM, a combination of fruit and peel mixture, on high-fat diet- (HFD-) induced NAFLD and clarify the potential mechanisms. PCM in HFD-fed mice was orally administered at a dose of 50 or 100 mg/kg subsequently for 2 months. Thereafter, lipid metabolism parameters and fat synthesis-related genes in the mouse liver were evaluated. Subsequently, body weight changes, liver weight, serum liver function and lipid profiles, and liver pathology were examined, and the relative levels of fatty acid synthesis and -oxidation gene expression were evaluated by western blot. Serum AST, ALT, and TG levels in the HFD control mice were significantly higher than those of normal mice. Compared with HFD control mice, PCM supplementation increased phosphorylation of AMP-activated protein kinase (AMPK). Peroxisome proliferator-activated receptor (PPAR) was significantly increased by PCM administration. Continuously, the activation of PPAR significantly elevated carnitine palmitoyltransferase 1 (CPT-1), a key enzyme in fatty acid -oxidation, and mitochondrial uncoupling protein 2 (UCP-2), thermogenic regulatory genes, in PCM-treated mice compared with those of HFD control mice. Moreover, PCM inhibits lipogenesis and cholesterol synthesis via suppression of sterol regulatory element binding protein-1 (SREBP-1) and SREBP-2 and its target genes such as acetyl-CoA carboxylase (ACC), fatty acid synthase (FAS), stearoyl-CoA desaturase-1 (SCD-1), and 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR). Taken together, these effects were mediated through activation of AMPK. In the conclusion, PCM improved liver damage in HFD-fed mice and attenuated NAFLD by the activation of PPAR and the inhibition of SREBPs expression via AMPK-dependent pathways.
10.1155/2020/8812634
Ferulic acid ameliorates intrahepatic triglyceride accumulation in vitro but not in high fat diet-fed C57BL/6 mice.
Wang Zhenyu,Yang Yang,Zhang Jiawen,Hu Jiamiao,Yan Xin,Zeng Shaoxiao,Huang Xiujuan,Lin Shaoling
Food and chemical toxicology : an international journal published for the British Industrial Biological Research Association
Phenolic acids can improve obesity-related and metabolic syndrome-related conditions including non-alcoholic fatty liver disease (NAFLD). In this study, the effects of ferulic acid (FA) on the metabolic changes related to NAFLD were investigated in oleic acid (OA)-treated HepG2 cells and C57BL/6 mice fed a high fat diet (HFD). In vitro, FA (25 and 50 μg/mL) treatment significantly reduced cellular lipid accumulation with no obvious cytotoxicity, in-part mediated by the suppression of ERK1/2, JNK1/2/3, and HGMB1 expression. However, in vivo administration of FA (20 mg/kg bw·day) for 17 weeks led to no obvious effects on body weight and liver weight gain, blood lipid profiles, or histological abnormalities in obese C57BL/6 mice induced by HFD. Taken together, the positive effects of FA on the reduction of hepatic triglyceride accumulation were therefore demonstrated in cellular model, while its hepatic protective effects might need to be further explored in rodent models and clinical trials.
10.1016/j.fct.2021.111978
Role of necroptosis in chronic hepatic inflammation and fibrosis in a mouse model of increased oxidative stress.
Mohammed Sabira,Nicklas Evan H,Thadathil Nidheesh,Selvarani Ramasamy,Royce Gordon H,Kinter Michael,Richardson Arlan,Deepa Sathyaseelan S
Free radical biology & medicine
Mice deficient in the antioxidant enzyme Cu/Zn-superoxide dismutase (Sod1 or Sod1KO mice) have increased oxidative stress, show accelerated aging and develop spontaneous hepatocellular carcinoma (HCC) with age. Similar to humans, HCC development in Sod1KO mice progresses from non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH) with fibrosis, which eventually progresses to HCC. Oxidative stress plays a role in NAFLD to NASH progression, and liver inflammation is the main mechanism that drives the disease progression from NASH to fibrosis. Because necroptosis is a major source of inflammation, we tested the hypothesis that increased necroptosis in the liver plays a role in increased inflammation and fibrosis in Sod1KO mice. Phosphorylation of MLKL (P-MLKL), a well-accepted marker of necroptosis, and expression of MLKL protein were significantly increased in the livers of Sod1KO mice compared to wild type (WT) mice indicating increased necroptosis. Similarly, phosphorylation of RIPK3 and RIPK3 protein levels were also significantly increased. Markers of pro-inflammatory M1 macrophages, NLRP3 inflammasome, and transcript levels of pro-inflammatory cytokines and chemokines, e.g., TNFα, IL-6, IL-1β, and Ccl2 that are associated with human NASH, were significantly increased. Expression of antioxidant enzymes and heat shock proteins, and markers of fibrosis and oncogenic transcription factor STAT3 were also upregulated and autophagy was downregulated in the livers of Sod1KO mice. Short term treatment of Sod1KO mice with necrostatin-1s (Nec-1s), a necroptosis inhibitor, reversed these conditions. Our data show for the first time that necroptosis-mediated inflammation contributes to fibrosis in a mouse model of increased oxidative stress and accelerated aging, that also exhibits progressive HCC development.
10.1016/j.freeradbiomed.2020.12.449
Induced hepatic stellate cell integrin, α8β1, enhances cellular contractility and TGFβ activity in liver fibrosis.
Nishimichi Norihisa,Tsujino Kazuyuki,Kanno Keishi,Sentani Kazuhiro,Kobayashi Tsuyoshi,Chayama Kazuaki,Sheppard Dean,Yokosaki Yasuyuki
The Journal of pathology
No effective therapy exists for fatal fibrosis. New therapeutic targets are needed for hepatic fibrosis because the incidence keeps increasing. The activation and differentiation of fibroblasts into myofibroblasts that causes excessive matrix deposition is central to fibrosis. Here, we investigated whether (and which) integrin receptors for matrix proteins activate hepatic stellate cells (HSCs). First, integrin α-subunits were investigated systematically for their expression over the course of HSC activation and their distribution on fibroblasts and other systemic primary cells. The most upregulated in plate culture-activated HSCs and specifically expressed across fibroblast linages was the α8 subunit. An anti-α8 neutralizing mAb was evaluated in three different murine fibrosis models: for cytotoxic (CCl treatment), non-alcoholic steatohepatitis-associated and cholestatic fibrosis. In all models, pathology and fibrosis markers (hydroxyproline and α-smooth muscle actin) were improved following the mAb injection. We also CCl -treated mice with inducible Itga8-/-; these mice were protected from increased hydroxyproline levels. Furthermore, ITGA8 was upregulated in specimens from 90 patients with liver fibrosis, indicating the relevance of our findings to liver fibrosis in people. Mechanistically, inhibition or ligand engagement of HSC α8 suppressed and enhanced myofibroblast differentiation, respectively, and HSC/fibroblast α8 activated latent TGFβ. Finally, integrin α8β1 potentially fulfils the growing need for anti-fibrotic drugs and is an integrin not to be ignored. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.
10.1002/path.5618
LECT2 as a hepatokine links liver steatosis to inflammation via activating tissue macrophages in NASH.
Scientific reports
It remains unclear how hepatic steatosis links to inflammation. Leukocyte cell-derived chemotaxin 2 (LECT2) is a hepatokine that senses fat in the liver and is upregulated prior to weight gain. The aim of this study was to investigate the significance of LECT2 in the development of nonalcoholic steatohepatitis (NASH). In human liver biopsy samples, elevated LECT2 mRNA levels were positively correlated with body mass index (BMI) and increased in patients who have steatosis and inflammation in the liver. LECT2 mRNA levels were also positively correlated with the mRNA levels of the inflammatory genes CCR2 and TLR4. In C57BL/6J mice fed with a high-fat diet, mRNA levels of the inflammatory cytokines Tnfa and Nos2 were significantly lower in Lect2 KO mice. In flow cytometry analyses, the number of M1-like macrophages and M1/M2 ratio were significantly lower in Lect2 KO mice than in WT mice. In KUP5, mouse kupffer cell line, LECT2 selectively enhanced the LPS-induced phosphorylation of JNK, but not that of ERK and p38. Consistently, LECT2 enhanced the LPS-induced phosphorylation of MKK4 and TAB2, upstream activators of JNK. Hepatic expression of LECT2 is upregulated in association with the inflammatory signature in human liver tissues. The elevation of LECT2 shifts liver residual macrophage to the M1-like phenotype, and contributes to the development of liver inflammation. These findings shed light on the hepatokine LECT2 as a potential therapeutic target that can dissociate liver steatosis from inflammation.
10.1038/s41598-020-80689-0
Mitochondrial dysfunction in nonalcoholic fatty liver disease and alcohol related liver disease.
Prasun Pankaj,Ginevic Ilona,Oishi Kimihiko
Translational gastroenterology and hepatology
Fatty liver disease constitutes a spectrum of liver diseases which begin with simple steatosis and may progress to advance stages of steatohepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The two main etiologies are-alcohol related fatty liver disease (ALD) and nonalcoholic fatty liver disease (NAFLD). NAFLD is a global health epidemic strongly associated with modern dietary habits and life-style. It is the second most common cause of chronic liver disease in the US after chronic hepatitis C virus (HCV) infection. Approximately 100 million people are affected with this condition in the US alone. Excessive intakes of calories, saturated fat and refined carbohydrates, and sedentary life style have led to explosion of this health epidemic in developing nations as well. ALD is the third most common cause of chronic liver disease in the US. Even though the predominant trigger for onset of steatosis is different in these two conditions, they share common themes in progression from steatosis to the advance stages. Oxidative stress (OS) is considered a very significant contributor to hepatocyte injury in these conditions. Mitochondrial dysfunction contributes to this OS. Role of mitochondrial dysfunction in pathogenesis of fatty liver diseases is emerging but far from completely understood. A better understanding is essential for more effective preventive and therapeutic interventions. Here, we discuss the pathogenesis and therapeutic approaches of NAFLD and ALD from a mitochondrial perspective.
10.21037/tgh-20-125
Major Histocompatibility Complex Class I-Related Chain A Alleles and Histology of Nonalcoholic Fatty Liver Disease.
Hepatology communications
Major histocompatibility complex class I-related chain A (MICA) is a highly polymorphic gene that modulates immune surveillance by binding to its receptor on natural killer cells, and its genetic polymorphisms have been associated with chronic immune-mediated diseases. The progressive form of nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), is characterized by accumulation of fat and inflammatory cells in the hepatic parenchyma, potentially leading to liver cell injury and fibrosis. To date, there are no data describing the potential role of MICA in the pathogenesis of NAFLD. Therefore, our aim was to assess the association between MICA polymorphism and NASH and its histologic features. A total of 134 subjects were included. DNA from patients with biopsy-proven NAFLD were genotyped using polymerase chain reaction-sequence-specific oligonucleotide for MICA alleles. Liver biopsies were assessed for histologic diagnosis of NASH and specific pathologic features, including stage of fibrosis and grade of inflammation. Multivariate analysis was performed to draw associations between MICA alleles and the different variables; ≤ 0.05 was considered significant. Univariate analysis showed that MICA*011 (odds ratio [OR], 7.14; 95% confidence interval [CI], 1.24-41.0; = 0.04) was associated with a higher risk for histologic NASH. Multivariate analysis showed that MICA*002 was independently associated with a lower risk for focal hepatocyte necrosis (OR, 0.24; 95% CI, 0.08-0.74; = 0.013) and advanced fibrosis (OR, 0.11; 95% CI, 0.02-0.70; = 0.019). MICA*017 was independently associated with a higher risk for lymphocyte-mediated inflammation (OR, 5.12; 95% CI, 1.12-23.5; = 0.035). MICA alleles may be associated with NASH and its histologic features of inflammation and fibrosis. Additional research is required to investigate the potential role of MICA in increased risk or protection against NAFLD.
10.1002/hep4.1610
The Natural History of NAFLD, a Community-Based Study at a Large Health Care Delivery System in the United States.
Hepatology communications
Nonalcoholic fatty liver disease (NAFLD) is a global public health problem. However, the natural history of NAFLD is incomplete. This is a retrospective cohort study of patients identified with NAFLD by diagnosis codes in a large, community-based health care delivery system. The objectives were (1) to follow patients from initial NAFLD presentation through progression to cirrhosis and/or decompensated cirrhosis to liver cancer, liver transplant, and death for up to 10 years; and (2) to conduct disease progression analysis restricted to patients with NAFLD identified as having diabetes at baseline. A total of 98,164 patients with full NAFLD and 26,488 with diabetes were divided into three baseline prevalent states: (1) no cirrhosis, (2) compensated cirrhosis, and (3) decompensated cirrhosis. In baseline patients without cirrhosis, annual rates of compensated cirrhosis, decompensated cirrhosis, and death were 0.28%, 0.31%, and 0.63% per year, respectively. With baseline compensated cirrhosis, the annual rates of decompensation and death were 2.4% and 6.7% per year. Finally, in those with decompensated cirrhosis at baseline, the death rate was 8.0% per year. In those without cirrhosis and with cirrhosis at baseline, the rates of liver cancer and death were increased approximately 2-fold in the diabetic subpopulation compared with the full NAFLD cohort. Age and comorbidities increased with increasing disease severity. Cox proportional hazards regression analysis showed that cirrhosis was strongly associated with death and liver cancer, and that diabetes was associated with a significant increase in the hazard of both liver cancer and death (2.56 [2.04-3.20] and 1.43 [1.35-1.52]), respectively. The findings of this community-based study further our understanding of the natural history of NAFLD and demonstrate that diabetes is a major factor in the progression of this disease.
10.1002/hep4.1625
Hydrogen-rich water protects against liver injury in nonalcoholic steatohepatitis through HO-1 enhancement via IL-10 and Sirt 1 signaling.
Li Shao-Wei,Takahara Terumi,Que Weitao,Fujino Masayuki,Guo Wen-Zhi,Hirano Shin-Ichi,Ye Li-Ping,Li Xiao-Kang
American journal of physiology. Gastrointestinal and liver physiology
Nonalcoholic steatohepatitis (NASH) could progress to hepatic fibrosis in the absence of effective control. The purpose of our experiment was to investigate the protective effect of drinking water with a high concentration of hydrogen, namely, hydrogen-rich water (HRW), on mice with nonalcoholic fatty liver disease to elucidate the mechanism underlying the therapeutic action of molecular hydrogen. The choline-supplemented, l-amino acid-defined (CSAA) or the choline-deficient, l-amino acid-defined (CDAA) diet for 20 wk was used to induce NASH and fibrosis in the mice model and simultaneously treated with the high-concentration 7-ppm HRW for different periods (4 wk, 8 wk, and 20 wk). Primary hepatocytes were stimulated by palmitate to mimic liver lipid metabolism during fatty liver formation. Primary hepatocytes were cultured in a closed vessel filled with 21% O + 5% CO + 3.8% H and N as the base gas to verify the response of primary hepatocytes in a high concentration of hydrogen gas in vitro. Mice in the CSAA + HRW group had lower serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) and milder histological damage. The inflammatory cytokines were expressed at lower levels in the HRW group than in the CSAA group. Importantly, HRW reversed hepatocyte fatty acid oxidation and lipogenesis as well as hepatic inflammation and fibrosis in preexisting hepatic fibrosis specimens. Molecular hydrogen inhibits the lipopolysaccharide-induced production of inflammation cytokines through increasing heme oxygenase-1 (HO-1) expression. Furthermore, HRW improved hepatic steatosis in the CSAA + HRW group. Sirtuin 1 (Sirt1) induction by molecular hydrogen via the HO-1/adenosine monophosphate activated protein kinase (AMPK)/peroxisome proliferator-activated receptor α (PPARα)/peroxisome proliferator-activated receptor γ (PPAR-γ) pathway suppresses palmitate-mediated abnormal fat metabolism. Orally administered HRW suppressed steatosis induced by CSAA and attenuated fibrosis induced by CDAA, possibly by reducing oxidative stress and the inflammation response. The mRNA expression of inflammatory cytokines in the HRW group was lower than in the CSAA group. HRW reversed hepatocyte apoptosis as well as hepatic inflammation and fibrosis in NASH specimens. Molecular hydrogen inhibits LPS-induced inflammation via an HO-1/interleukin 10 (IL-10)-independent pathway. HRW improved hepatic steatosis in the CSAA + HRW group. Sirt1 induction by molecular hydrogen via the HO-1/AMPK/PPARα/PPARγ pathway suppresses palmitate-mediated abnormal fat metabolism.
10.1152/ajpgi.00158.2020
The impact of sodium glucose co-transporter 2 inhibitors on non-alcoholic fatty liver disease.
Journal of gastroenterology and hepatology
Affecting one fourth of the global population, non-alcoholic fatty liver disease (NAFLD) is the commonest chronic liver disorder. It encompasses the simple liver fat accumulation to more progressive steatosis, inflammation, and fibrosis characterized as non-alcoholic steatohepatitis (NASH) and in some cases cirrhosis and hepatocellular carcinoma. NAFLD regularly coexists with metabolic disorders, such as obesity and mostly type 2 diabetes mellitus (T2DM). A relatively new class of antidiabetic drugs, the sodium glucose co-transporter 2 (SGLT2) inhibitors exert their action by increasing the urinary glucose and calorie excretion leading to ameliorated plasma glucose levels and lower bodyweight. Recently, several animal studies and human clinical trial have emphasized the possible beneficial impact of SGLT2 inhibitors on NAFLD and its progression to NASH. In this present review, we summarize the current literature regarding the efficacy of the aforementioned category of drugs on anthropometric, laboratory, and histological features of patients with NAFLD. Conclusively, as SGLT2 inhibitors seem to be an appealing therapeutic opportunity for NAFLD management, we identify the open issues and questions to be addressed in order to clarify the impact in choosing antidiabetic medication to treat NAFLD patients associated with T2DM.
10.1111/jgh.15202
Dynamic Shifts in the Composition of Resident and Recruited Macrophages Influence Tissue Remodeling in NASH.
Cell reports
Macrophage-mediated inflammation is critical in the pathogenesis of non-alcoholic steatohepatitis (NASH). Here, we describe that, with high-fat, high-sucrose-diet feeding, mature TIM4 Kupffer cells (KCs) decrease in number, while monocyte-derived Tim4 macrophages accumulate. In concert, monocyte-derived infiltrating macrophages enter the liver and consist of a transitional subset that expresses Cx3cr1/Ccr2 and a second subset characterized by expression of Trem2, Cd63, Cd9, and Gpmnb; markers ascribed to lipid-associated macrophages (LAMs). The Cx3cr1/Ccr2-expressing macrophages, referred to as C-LAMs, localize to macrophage aggregates and hepatic crown-like structures (hCLSs) in the steatotic liver. In C-motif chemokine receptor 2 (Ccr2)-deficient mice, C-LAMs fail to appear in the liver, and this prevents hCLS formation, reduces LAM numbers, and increases liver fibrosis. Taken together, our data reveal dynamic changes in liver macrophage subsets during the pathogenesis of NASH and link these shifts to pathologic tissue remodeling.
10.1016/j.celrep.2020.108626
CNCM I-4035, CNCM I-4034 and CNCM I-4036 Modulate Macrophage Gene Expression and Ameliorate Damage Markers in the Liver of Zucker-Lepr Rats.
Fontana Luis,Plaza-Díaz Julio,Robles-Bolívar Paula,Valente-Godínez Héctor,Sáez-Lara María José,Abadía-Molina Francisco,Gómez-Llorented Carolina,Gil Ángel,Álvarez-Mercado Ana I
Nutrients
Non-alcoholic fatty liver disease (NAFLD) has reached pandemic proportions worldwide. We have previously reported that the probiotic strains CNCM I-4035, CNCM I-4034 and CNCM I-4036 exert anti-inflammatory effects in the intestine of Zucker-Lepr rats. In this work, we focused on their hepatic effects. M1 macrophages are related to inflammation and NAFLD pathogenesis, whereas M2 macrophages release anti-inflammatory mediators. We evaluated the effects of these 3 strains on macrophage polarization, inflammation and liver damage of Zucker-Lepr rats. The animals received either a placebo or 10 CFU of probiotics orally for 30 days. Nos2 and Cd86 mRNA levels were determined as markers of M1 macrophages, and Cd163 and Arg1 as M2 markers, respectively, by qRT-PCR. Liver damage was determined by lipid peroxidation, leukocyte infiltration and myeloperoxidase activity. We evaluated a panoply of circulating chemokines, the hepatic ratio P-Akt/Akt, NF-kB and P-NF-kB protein levels. All 3 probiotic strains modulated macrophage polarization in liver and circulating levels of inflammation-related mediators. CNCM I-4034 increased the ratio P-Akt/Akt and NF-kB protein levels. CNCM I-4035, CNCM I-4034 and CNCM I-4036 decreased both pro-inflammatory macrophage gene expression and leukocyte infiltration in the liver.
10.3390/nu13010202
Mitochondrial dynamics and nonalcoholic fatty liver disease (NAFLD): new perspectives for a fairy-tale ending?
Longo Miriam,Meroni Marica,Paolini Erika,Macchi Chiara,Dongiovanni Paola
Metabolism: clinical and experimental
Nonalcoholic fatty liver disease (NAFLD) includes a broad spectrum of liver dysfunctions and it is predicted to become the primary cause of liver failure and hepatocellular carcinoma. Mitochondria are highly dynamic organelles involved in multiple metabolic/bioenergetic pathways in the liver. Emerging evidence outlined that hepatic mitochondria adapt in number and functionality in response to external cues, as high caloric intake and obesity, by modulating mitochondrial biogenesis, and maladaptive mitochondrial response has been described from the early stages of NAFLD. Indeed, mitochondrial plasticity is lost in progressive NAFLD and these organelles may assume an aberrant phenotype to drive or contribute to hepatocarcinogenesis. Severe alimentary regimen and physical exercise represent the cornerstone for NAFLD care, although the low patients' compliance is urging towards the discovery of novel pharmacological treatments. Mitochondrial-targeted drugs aimed to recover mitochondrial lifecycle and to modulate oxidative stress are becoming attractive molecules to be potentially introduced for NAFLD management. Although the path guiding the switch from bench to bedside remains tortuous, the study of mitochondrial dynamics is providing intriguing perspectives for future NAFLD healthcare.
10.1016/j.metabol.2021.154708
Hepatocyte-Specific Loss of PPARγ Protects Mice From NASH and Increases the Therapeutic Effects of Rosiglitazone in the Liver.
Lee Samuel M,Pusec Carolina M,Norris Gregory H,De Jesus Adam,Diaz-Ruiz Alberto,Muratalla Jose,Sarmento-Cabral Andre,Guzman Grace,Layden Brian T,Cordoba-Chacon Jose
Cellular and molecular gastroenterology and hepatology
BACKGROUND & AIMS:Nonalcoholic steatohepatitis (NASH) is commonly observed in patients with type 2 diabetes, and thiazolidinediones (TZD) are considered a potential therapy for NASH. Although TZD increase insulin sensitivity and partially reduce steatosis and alanine aminotransferase, the efficacy of TZD on resolving liver pathology is limited. In fact, TZD may activate peroxisome proliferator-activated receptor gamma (PPARγ) in hepatocytes and promote steatosis. Therefore, we assessed the role that hepatocyte-specific PPARγ plays in the development of NASH, and how it alters the therapeutic effects of TZD on the liver of mice with diet-induced NASH. METHODS:Hepatocyte-specific PPARγ expression was knocked out in adult mice before and after the development of NASH induced with a high fat, cholesterol, and fructose (HFCF) diet. RESULTS:HFCF diet increased PPARγ expression in hepatocytes, and rosiglitazone further activated PPARγ in hepatocytes of HFCF-fed mice in vivo and in vitro. Hepatocyte-specific loss of PPARγ reduced the progression of HFCF-induced NASH in male mice and increased the benefits derived from the effects of TZD on extrahepatic tissues and non-parenchymal cells. RNAseq and metabolomics indicated that HFCF diet promoted inflammation and fibrogenesis in a hepatocyte PPARγ-dependent manner and was associated with dysregulation of hepatic metabolism. Specifically, hepatocyte-specific loss of PPARγ plays a positive role in the regulation of methionine metabolism, and that could reduce the progression of NASH. CONCLUSIONS:Because of the negative effect of hepatocyte PPARγ in NASH, inhibition of mechanisms promoted by endogenous PPARγ in hepatocytes may represent a novel strategy that increases the efficiency of therapies for NAFLD.
10.1016/j.jcmgh.2021.01.003
Targeting Autophagy to Counteract Obesity-Associated Oxidative Stress.
Pietrocola Federico,Bravo-San Pedro José Manuel
Antioxidants (Basel, Switzerland)
Reactive oxygen species (ROS) operate as key regulators of cellular homeostasis within a physiological range of concentrations, yet they turn into cytotoxic entities when their levels exceed a threshold limit. Accordingly, ROS are an important etiological cue for obesity, which in turn represents a major risk factor for multiple diseases, including diabetes, cardiovascular disorders, non-alcoholic fatty liver disease, and cancer. Therefore, the implementation of novel therapeutic strategies to improve the obese phenotype by targeting oxidative stress is of great interest for the scientific community. To this end, it is of high importance to shed light on the mechanisms through which cells curtail ROS production or limit their toxic effects, in order to harness them in anti-obesity therapy. In this review, we specifically discuss the role of autophagy in redox biology, focusing on its implication in the pathogenesis of obesity. Because autophagy is specifically triggered in response to redox imbalance as a quintessential cytoprotective mechanism, maneuvers based on the activation of autophagy hold promises of efficacy for the prevention and treatment of obesity and obesity-related morbidities.
10.3390/antiox10010102
Skeletal Muscle Dysfunction in the Development and Progression of Nonalcoholic Fatty Liver Disease.
Altajar Sarah,Baffy Gyorgy
Journal of clinical and translational hepatology
The association between the pathogenesis and natural course of nonalcoholic fatty liver disease (NAFLD) and skeletal muscle dysfunction is increasingly recognized. These obesity-associated disorders originate primarily from sustained caloric excess, gradually disrupting cellular and molecular mechanisms of the adipose-muscle-liver axis resulting in end-stage tissue injury exemplified by cirrhosis and sarcopenia. These major clinical phenotypes develop through complex organ-tissue interactions from the earliest stages of NAFLD. While the role of adipose tissue expansion and remodeling is well established in the development of NAFLD, less is known about the specific interplay between skeletal muscle and the liver in this process. Here, the relationship between skeletal muscle and liver in various stages of NAFLD progression is reviewed. Current knowledge of the pathophysiology is summarized with the goal of better understanding the natural history, risk stratification, and management of NAFLD.
10.14218/JCTH.2020.00065
Pathophysiology of NASH in endocrine diseases.
Endocrine connections
Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the industrialized world. NAFLD encompasses a whole spectrum ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. The latter can lead to hepatocellular carcinoma. Furthermore, NASH is the most rapidly increasing indication for liver transplantation in western countries and therefore represents a global health issue. The pathophysiology of NASH is complex and includes multiple parallel hits. NASH is notably characterized by steatosis as well as evidence of hepatocyte injury and inflammation, with or without fibrosis. NASH is frequently associated with type 2 diabetes and conditions associated with insulin resistance. Moreover, NASH may also be found in many other endocrine diseases such as polycystic ovary syndrome, hypothyroidism, male hypogonadism, growth hormone deficiency or glucocorticoid excess, for example. In this review, we will discuss the pathophysiology of NASH associated with different endocrinopathies.
10.1530/EC-20-0490
Exposure to high fructose corn syrup during adolescence in the mouse alters hepatic metabolism and the microbiome in a sex-specific manner.
Bhat Shazia F,Pinney Sara E,Kennedy Katherine M,McCourt Cole R,Mundy Miles A,Surette Michael G,Sloboda Deborah M,Simmons Rebecca A
The Journal of physiology
KEY POINTS:The prevalence of obesity and non-alcoholic fatty liver disease in children is dramatically increasing at the same time as consumption of foods with a high sugar content. Intake of high fructose corn syrup (HFCS) is a possible aetiology as it is thought to be more lipogenic than glucose. In a mouse model, HFCS intake during adolescence increased fat mass and hepatic lipid levels in male and female mice. However, only males showed impaired glucose tolerance. Multiple metabolites including lipids, bile acids, carbohydrates and amino acids were altered in liver in a sex-specific manner at 6 weeks of age. Some of these changes were also present in adulthood even though HFCS exposure ended at 6 weeks. HFCS significantly altered the gut microbiome, which was associated with changes in key microbial metabolites. These results suggest that HFCS intake during adolescence has profound metabolic changes that are linked to changes in the microbiome and these changes are sex-specific. ABSTRACT:The rapid increase in obesity, diabetes and fatty liver disease in children over the past 20 years has been linked to increased consumption of high fructose corn syrup (HFCS), making it essential to determine the short- and long-term effects of HFCS during this vulnerable developmental window. We hypothesized that HFCS exposure during adolescence significantly impairs hepatic metabolic signalling pathways and alters gut microbial composition, contributing to changes in energy metabolism with sex-specific effects. C57bl/6J mice with free access to HFCS during adolescence (3-6 weeks of age) underwent glucose tolerance and body composition testing and hepatic metabolomics, gene expression and triglyceride content analysis at 6 and 30 weeks of age (n = 6-8 per sex). At 6 weeks HFCS-exposed mice had significant increases in fat mass, glucose intolerance, hepatic triglycerides (females) and de novo lipogenesis gene expression (ACC, DGAT, FAS, ChREBP, SCD, SREBP, CPT and PPARα) with sex-specific effects. At 30 weeks, HFCS-exposed mice also had abnormalities in glucose tolerance (males) and fat mass (females). HFCS exposure enriched carbohydrate, amino acid, long chain fatty acid and secondary bile acid metabolism at 6 weeks with changes in secondary bile metabolism at 6 and 30 weeks. Microbiome studies performed immediately before and after HFCS exposure identified profound shifts of microbial species in male mice only. In summary, short-term HFCS exposure during adolescence induces fatty liver, alters important metabolic pathways, some of which continue to be altered in adulthood, and changes the microbiome in a sex-specific manner.
10.1113/JP280034
Hypoxia-inducible factor-2 promotes liver fibrosis in non-alcoholic steatohepatitis liver disease via the NF-κB signalling pathway.
Cai Hao,Bai Zhenzhong,Ge Ri-Li
Biochemical and biophysical research communications
Non-alcoholic steatohepatitis (NASH) is one of the most common chronic liver diseases. Chronic hypoxia is related to the pathogenesis of NASH. HIF-2α is the key gene for lipid metabolism, fibrosis, and inflammation in many cells. To identify the molecular mechanism through which hypoxia exposure increases the morbidity of NASH, the expression level of HIF-2α was analysed and was found to be upregulated in human NASH liver. By constructing the NASH model of chronic hypoxia, the mice were housed at an altitude of 4300 m for 4 and 8 weeks, compared to the control groups that were housed at an altitude of 50 m. Histological studies showed that exposure to hypoxia promoted the activation of NF-κB by upregulating the expression of HIF-2α, as well as that of the genes related to inflammation and fibrosis, thereby promoting the development of NASH both in vivo and in vitro. In summary, hypoxia-exposure could upregulate HIF-2α to aggravate tissue fibrosis and inflammation by upregulating inflammation-related genes and fibrosis-related genes metabolites via the activated NF-κB pathway in NASH. Our results suggest that for NASH patients living at high altitudes, drug therapy could focus on treating tissue fibrosis and inflammation, and thus provides a new strategy for NASH treatment.
10.1016/j.bbrc.2021.01.002