Molecular mechanism of hepatic steatosis: pathophysiological role of autophagy

2016 ◽  
Vol 18 ◽  
Author(s):  
Kewei Wang
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Pathological Condition ◽  
List Type ◽  
Abnormal Metabolism ◽  
Apoptotic Pathways ◽  
Novel Therapeutic

Steatosis is an early characteristic in the pathogenesis of fatty liver disease (FLD). Mechanisms of hepatic steatosis are aetiology-dependent. Activation of autophagy in liver ameliorates hepatic steatosis. A modulation of hepatic autophagy affects the degree of hepatocyte steatosis and the progression of FLD as demonstrated by pre-clinical models and clinical trials. This review summarises recent advances on pathophysiological roles of autophagy in hepatic lipid metabolism. A comprehensive regulation of autophagic networks holds promise for the improvement of hepatic steatosis. Autophagic signalling pathway may be a novel therapeutic target against FLD.Highlights: •Hepatic steatosis is a pathological condition wherein vacuoles of triglyceride (TG) fat are overaccumulated in liver because of abnormal metabolism of lipids.•Hepatic autophagy regulates lipid metabolism as demonstrated by macrolipophagy in response to starvation and hepatic overabundance of TG in obesity.•Autophagic signals are closely associated with apoptotic pathways. There is distinctive relationship between hepatic autophagy and apoptosis, which affects the progression of fatty liver.•Regulation of autophagic process can be a novel therapeutic strategy for fatty liver disease.

scholarly journals The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE−/−FXR−/− Mice

2021 ◽  
Vol 36 (6) ◽  
pp. 1243-1253
Author(s):  
Yenna Lee ◽  
Bo-Rahm Kim ◽  
Geun-Hyung Kang ◽  
Gwan Jae Lee ◽  
Young Joo Park ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Bile Acid ◽  
Fatty Liver ◽  
Mrna Expression ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver ◽  
Ppar Agonists ◽  
Pparα Agonist

Background: Farnesoid X receptor (FXR), a bile acid–activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency.Methods: En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)−/− and ApoE−/−FXR−/− mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice.Results: Compared with ApoE−/− mice, ApoE−/−FXR−/− mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE−/−FXR−/− mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver).Conclusion: Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.

Resveratrol protects against nonalcoholic fatty liver disease by improving lipid metabolism and redox homeostasis via the PPARα pathway

2020 ◽  
Vol 45 (3) ◽  
pp. 227-239 ◽  
Author(s):  
Yujie Huang ◽  
Hedong Lang ◽  
Ka Chen ◽  
Yong Zhang ◽  
Yanxiang Gao ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Protein Kinase ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Hepatic Steatosis ◽  
Hepg2 Cells ◽  
Fatty Liver Disease ◽  
Redox Homeostasis ◽  
Nonalcoholic Fatty Liver

Resveratrol (RSV), a well-known bioactive compound, has been reported to exert a broad range of health benefits. Accumulating evidence suggests that RSV is beneficial for many metabolic diseases, including nonalcoholic fatty liver disease (NAFLD). This study investigated the preventive and therapeutic effects of RSV on high-fat diet (HFD)-induced NAFLD in rats and palmitate acid (PA)-induced hepatocyte steatosis in HepG2 cells. Hepatocytes were incubated with inhibitors of peroxisome proliferator-activated receptor α (PPARα) or short interfering RNAs (siRNAs) targeting PPARα, AMP-activated protein kinase (AMPK), and protein kinase A (PKA) to determine the underlying mechanisms. We found that RSV noticeably ameliorated HFD-induced hepatic steatosis in rats and inhibited PA-induced lipid accumulation in HepG2 cells. Moreover, RSV improved lipid metabolism, enhanced antioxidant capacity, and restored mitochondrial respiratory chain activities. Incubation with inhibitors of PPARα or PPARα siRNA abolished the protective effects of RSV on lipid metabolism and redox homeostasis. Furthermore, RSV activated the PKA/AMPK/PPARα signaling pathway. Our results provided direct evidence for a novel, PPARα-mediated mechanism responsible for the beneficial effects of RSV on hepatic steatosis. These findings may have important theoretical and application prospects for the prevention and treatment of NAFLD. Novelty RSV improved lipid metabolism and redox homeostasis and oxidative stress in NAFLD via the PKA/AMPK/PPARα signaling pathway. RSV may have a greater beneficial effect in the early prevention of hepatic steatosis.

scholarly journals Phosphorylation of eIF2α signaling pathway attenuates obesity-induced non-alcoholic fatty liver disease in an ER stress and autophagy-dependent manner

2020 ◽  
Vol 11 (12) ◽  
Author(s):  
Jie Li ◽  
Xinle Li ◽  
Daquan Liu ◽  
Shiqi Zhang ◽  
Nian Tan ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Er Stress ◽  
Hepatic Steatosis ◽  
Fatty Liver Disease ◽  
Chow Diet ◽  
Dependent Manner ◽  
Alcoholic Fatty Liver ◽  
Alcoholic Fatty Liver Disease

AbstractNon-alcoholic fatty liver disease (NAFLD) is the most common liver disorder and frequently exacerbates in postmenopausal women. In NAFLD, the endoplasmic reticulum (ER) plays an important role in lipid metabolism, in which salubrinal is a selective inhibitor of eIF2α de-phosphorylation in response to ER stress. To determine the potential mechanism of obesity-induced NAFLD, we employed salubrinal and evaluated the effect of ER stress and autophagy on lipid metabolism. Ninety-five female C57BL/6 mice were randomly divided into five groups: standard chow diet, high-fat (HF) diet, HF with salubrinal, HF with ovariectomy, and HF with ovariectomy and salubrinal. All mice except for SC were given HF diet. After the 8-week obesity induction, salubrinal was subcutaneously injected for the next 8 weeks. The expression of ER stress and autophagy markers was evaluated in vivo and in vitro. Compared to the normal mice, the serum lipid level and adipose tissue were increased in obese mice, while salubrinal attenuated obesity by blocking lipid disorder. Also, the histological severity of hepatic steatosis and fibrosis in the liver and lipidosis was suppressed in response to salubrinal. Furthermore, salubrinal inhibited ER stress by increasing the expression of p-eIF2α and ATF4 with a decrease in the level of CHOP. It promoted autophagy by increasing LC3II/I and inhibiting p62. Correlation analysis indicated that lipogenesis in the development of NAFLD was associated with ER stress. Collectively, we demonstrated that eIF2α played a key role in obesity-induced NAFLD, and salubrinal alleviated hepatic steatosis and lipid metabolism by altering ER stress and autophagy through eIF2α signaling.

scholarly journals Human Umbilical Cord-Derived Mesenchymal Stem Cell Therapy Ameliorates Nonalcoholic Fatty Liver Disease in Obese Type 2 Diabetic Mice

2019 ◽  
Vol 2019 ◽  
pp. 1-12 ◽  
Author(s):  
Bing Li ◽  
Yu Cheng ◽  
Songyan Yu ◽  
Li Zang ◽  
Yaqi Yin ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Hepatic Steatosis ◽  
Umbilical Cord ◽  
Fatty Liver Disease ◽  
Human Umbilical Cord ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is increasingly common among patients with type 2 diabetes mellitus (T2DM). The two conditions can act synergistically to produce adverse outcomes. However, the therapeutic options for patients with NAFLD and T2DM are currently limited. Human umbilical cord-derived mesenchymal stem cells (UC-MSCs) have shown therapeutic potential for diabetes and hepatic disorders such as liver cirrhosis and fulminant hepatic failure. The present study is aimed at investigating the effect of human UC-MSCs on a mouse model of NAFLD and T2DM, characterized by obesity-induced hyperglycaemia, dyslipidaemia, hepatic steatosis, and liver dysfunction. Thirty-week-old male C57BL/6 db/db mice were infused with human UC-MSCs or phosphate-buffered saline (PBS) via the tail vein once a week for six weeks. Age-matched male C57BL/6 wild-type db/+ mice were used as controls. Body weight and random blood glucose were measured every week. One week after the sixth infusion, intraperitoneal glucose tolerance tests and insulin tolerance tests were performed and the blood and liver were harvested for biochemical and histopathological examinations. Quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR), immunofluorescence staining, and western blot were performed to monitor the expression of the lipid metabolism- and regulatory pathway-related genes. UC-MSC infusions significantly ameliorated hyperglycaemia, attenuated the elevation of hepatic transaminases, and decreased lipid contents, including triglyceride, total cholesterol, and low-density lipoprotein cholesterol. Moreover, histological lesions in the liver diminished markedly, as evidenced by reduced lipid accumulation and attenuated hepatic steatosis. Mechanistically, UC-MSCs were found to regulate lipid metabolism by increasing the expression of fatty acid oxidation-related genes and inhibiting the expression of lipogenesis-related genes, which were associated with the upregulation of the HNF4α-CES2 pathway. Our results demonstrate that human UC-MSCs can ameliorate NAFLD and reverse metabolic syndrome in db/db mice. Thus, UC-MSCs may serve as a novel therapeutic agent for T2DM patients with NAFLD.

scholarly journals How does hepatic lipid accumulation lead to lipotoxicity in non-alcoholic fatty liver disease?

2021 ◽  
Vol 15 (1) ◽  
pp. 21-35
Author(s):  
Yana Geng ◽  
Klaas Nico Faber ◽  
Vincent E. de Meijer ◽  
Hans Blokzijl ◽  
Han Moshage
Keyword(s):  
Lipid Metabolism ◽  
Liver Disease ◽  
Fatty Liver ◽  
Lipid Accumulation ◽  
Fatty Liver Disease ◽  
Lipid Uptake ◽  
Cellular Mechanisms ◽  
Alcoholic Fatty Liver ◽  
Lipid Species ◽  
Alcoholic Fatty Liver Disease

Abstract Background Non-alcoholic fatty liver disease (NAFLD), characterized as excess lipid accumulation in the liver which is not due to alcohol use, has emerged as one of the major health problems around the world. The dysregulated lipid metabolism creates a lipotoxic environment which promotes the development of NAFLD, especially the progression from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH). Purposeand Aim This review focuses on the mechanisms of lipid accumulation in the liver, with an emphasis on the metabolic fate of free fatty acids (FFAs) in NAFLD and presents an update on the relevant cellular processes/mechanisms that are involved in lipotoxicity. The changes in the levels of various lipid species that result from the imbalance between lipolysis/lipid uptake/lipogenesis and lipid oxidation/secretion can cause organellar dysfunction, e.g. ER stress, mitochondrial dysfunction, lysosomal dysfunction, JNK activation, secretion of extracellular vesicles (EVs) and aggravate (or be exacerbated by) hypoxia which ultimately lead to cell death. The aim of this review is to provide an overview of how abnormal lipid metabolism leads to lipotoxicity and the cellular mechanisms of lipotoxicity in the context of NAFLD.

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