Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis

Wang, Xiaobo; Cai, Bolin; Xiaoming, Yang; Sonubi, Oluwatoni O.; Zheng, Ze; Ramakrishnan, Rajasekhar; Shi, Hongxue; Valenti, Luca; Pajvani, Utpal B.; Sandhu, Jaspreet; Infante, Rodney E.; Radhakrishnan, Arun; Covey, Douglas F.; Guan, Kun Liang; Buck, Jochen; Levin, Lonny R.; Tontonoz, Peter; Schwabe, Robert F.; Tabas, Ira

doi:10.1016/j.cmet.2020.03.010

Cited by 143 publications

(153 citation statements)

References 76 publications

(108 reference statements)

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“…Intracellular cholesterol directly regulates gene transcription by suppressing SREBP2 activity, or indirectly via activating LXRs and farnesoid X receptor (FXR) by cholesterol-derived metabolites (oxysterols and bile acids, respectively). Moreover, the transcriptional regulator tafazzin (TAZ) has been identified as another cholesterol-sensitive pathway implicated in NASH progression [ 117 ]. Excess intracellular cholesterol stabilizes TAZ, which in turn activates the expression of pro-fibrotic genes in hepatocytes.…”

Section: Dyslipidemia: Linking Hepatic Lipid Metabolism and The Heartmentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

314

161

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Background Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming a global health problem. Cardiovascular diseases (CVD) are the most common cause of mortality in NAFLD patients. NAFLD and CVD share several common risk factors including obesity, insulin resistance, and type 2 diabetes (T2D). Atherogenic dyslipidemia, characterized by plasma hypertriglyceridemia, increased small dense low-density lipoprotein (LDL) particles, and decreased high-density lipoprotein cholesterol (HDL-C) levels, is often observed in NAFLD patients. Scope of review In this review, we highlight recent epidemiological studies evaluating the link between NAFLD and CVD risk. We further focus on recent mechanistic insights into the links between NAFLD and altered lipoprotein metabolism. We also discuss current therapeutic strategies for NAFLD and their potential impact on NAFLD-associated CVD risk. Major conclusions Alterations in hepatic lipid and lipoprotein metabolism are major contributing factors to the increased CVD risk in NAFLD patients, and many promising NASH therapies in development also improve dyslipidemia in clinical trials.

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Section: Dyslipidemia: Linking Hepatic Lipid Metabolism and The Heartmentioning

confidence: 99%

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Deprince

Haas

Staels

2020

Molecular Metabolism

314

161

View full text Add to dashboard Cite

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“…In a cohort of T2DM patients, a MUFA-rich diet induced a reduction in liver fat content [77], potentially through an increase in hepatic beta-oxidation [78]. In preclinical studies, dietary cholesterol has been shown to promote NASH and fibrosis, and contribute to HCC progression [79,80]. In human studies, high cholesterol levels have been associated mostly with cirrhosis and liver cancer [81].…”

Section: Environmental Factorsmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Fougerat

Montagner

Loiseau

et al. 2020

Cells

103

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Non-alcoholic fatty liver disease (NAFLD) is a major health issue worldwide, frequently associated with obesity and type 2 diabetes. Steatosis is the initial stage of the disease, which is characterized by lipid accumulation in hepatocytes, which can progress to non-alcoholic steatohepatitis (NASH) with inflammation and various levels of fibrosis that further increase the risk of developing cirrhosis and hepatocellular carcinoma. The pathogenesis of NAFLD is influenced by interactions between genetic and environmental factors and involves several biological processes in multiple organs. No effective therapy is currently available for the treatment of NAFLD. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate many functions that are disturbed in NAFLD, including glucose and lipid metabolism, as well as inflammation. Thus, they represent relevant clinical targets for NAFLD. In this review, we describe the determinants and mechanisms underlying the pathogenesis of NAFLD, its progression and complications, as well as the current therapeutic strategies that are employed. We also focus on the complementary and distinct roles of PPAR isotypes in many biological processes and on the effects of first-generation PPAR agonists. Finally, we review novel and safe PPAR agonists with improved efficacy and their potential use in the treatment of NAFLD.

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“…Of note, cholesterol is consistently elevated in human and mouse fibrotic NASH. Its mechanistic link to NASH development has been explored recently [ 59 ]. Cholesterol upregulates the transcriptional regulator TAZ (transcriptional co-activator with PDZ-binding motif) and promotes fibrotic NASH through an adenylyl cyclase-calcium (Ca 2+ )-RhoA pathway.…”

Section: Introductionmentioning

confidence: 99%

“…Cholesterol upregulates the transcriptional regulator TAZ (transcriptional co-activator with PDZ-binding motif) and promotes fibrotic NASH through an adenylyl cyclase-calcium (Ca 2+ )-RhoA pathway. The importance of this cholesterol–TAZ pathway remains to be demonstrated in human NASH [ 59 ].…”

Section: Introductionmentioning

confidence: 99%

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

et al. 2020

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Non-alcoholic fatty liver disease (NAFLD) is often the hepatic expression of metabolic syndrome and its comorbidities that comprise, among others, obesity and insulin-resistance. NAFLD involves a large spectrum of clinical conditions. These range from steatosis, a benign liver disorder characterized by the accumulation of fat in hepatocytes, to non-alcoholic steatohepatitis (NASH), which is characterized by inflammation, hepatocyte damage, and liver fibrosis. NASH can further progress to cirrhosis and hepatocellular carcinoma. The etiology of NAFLD involves both genetic and environmental factors, including an unhealthy lifestyle. Of note, unhealthy eating is clearly associated with NAFLD development and progression to NASH. Both macronutrients (sugars, lipids, proteins) and micronutrients (vitamins, phytoingredients, antioxidants) affect NAFLD pathogenesis. Furthermore, some evidence indicates disruption of metabolic homeostasis by food contaminants, some of which are risk factor candidates in NAFLD. At the molecular level, several models have been proposed for the pathogenesis of NAFLD. Most importantly, oxidative stress and mitochondrial damage have been reported to be causative in NAFLD initiation and progression. The aim of this review is to provide an overview of the contribution of nutrients and food contaminants, especially pesticides, to oxidative stress and how they may influence NAFLD pathogenesis.

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Cholesterol Stabilizes TAZ in Hepatocytes to Promote Experimental Non-alcoholic Steatohepatitis

Cited by 143 publications

References 76 publications

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Dysregulated lipid metabolism links NAFLD to cardiovascular disease

Peroxisome Proliferator-Activated Receptors and Their Novel Ligands as Candidates for the Treatment of Non-Alcoholic Fatty Liver Disease

Oxidative Stress in NAFLD: Role of Nutrients and Food Contaminants

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