Peroxisome proliferator-activated receptor-α agonist, Wy 14 643, improves metabolic indices, steatosis and ballooning in diabetic mice with non-alcoholic steatohepatitis

2012 ◽  
Vol 27 (2) ◽  
pp. 341-350 ◽  
Author(s):  
Claire Z Larter ◽  
Matthew M Yeh ◽  
Derrick M Van Rooyen ◽  
John Brooling ◽  
Kamaljit Ghatora ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Diabetic Mice ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Steatohepatitis ◽  
Metabolic Indices

Elafibranor interrupts adipose dysfunction-mediated gut and liver injury in mice with alcoholic steatohepatitis

2019 ◽  
Vol 133 (3) ◽  
pp. 531-544 ◽  
Author(s):  
Tzu-Hao Li ◽  
Ying-Ying Yang ◽  
Chia-Chang Huang ◽  
Chih-Wei Liu ◽  
Hung-Cheng Tsai ◽  
...  
Keyword(s):  
Liver Injury ◽  
Energy Homeostasis ◽  
Intestinal Barrier ◽  
Peroxisome Proliferator ◽  
Intestinal Epithelial ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Steatohepatitis ◽  
Ppar Agonists ◽  
Apoptosis And Inflammation ◽  
Adipose Dysfunction

Abstract Background: Reversal of alcohol-induced peroxisome proliferator-activated receptor (PPAR) α (PPARα) and PPARδ dysfunction has been reported to decrease the severity of alcoholic steatohepatitis (ASH). Autophagy is essential for cell survival and tissue energy homeostasis. Emerging evidence indicates that alcohol-induced adipose tissue (AT) autophagy dysfunction contributes to injury in the intestine, liver, and AT of ASH. Methods: The effects and mechanisms of dual PPARα/δ agonist elafibranor on autophagy stimulation were investigated using mice with ASH. Results: C57BL/6 mice on ethanol diet showed AT dysfunction, disrupted intestinal barrier, and ASH, which was accompanied by alcohol-mediated decrease in PPARα, PPARδ, and autophagy levels in intestine, liver, and AT. Chronic treatment with elafibranor attenuated AT apoptosis and inflammation by restoration of tissue PPARα, PPARδ, and autophagy levels. In ASH mice, alcohol-induced AT dysfunction along with increased fatty acid (FA) uptake and decreased free FA (FFA) release from AT was inhibited by elafibranor. The improvement of AT autophagy dysfunction by elafibranor alleviated inflammation and apoptosis-mediated intestinal epithelial disruption in ASH mice. Acute elafibranor incubation inhibited ethanol-induced ASH-mice-sera-enhanced autophagy dysfunction, apoptosis, barrier disruption, and intracellular steatosis in Caco-2 cells and primary hepatocytes (PHs). Conclusion: Altogether, these findings demonstrated that the PPARα/δ agonist, elafibranor, decreased the severity of liver injury by restoration of alcohol-suppressed AT autophagy function and by decreasing the release of apoptotic markers, inflammatory cytokines, and FFA, thereby reducing intestinal epithelium disruption and liver inflammation/apoptosis/steatosis in ASH mice. These data suggest that dual PPAR agonists can serve as potential therapeutic agents for the management of ASH.

scholarly journals Peroxisome proliferator-activated receptor-δ induces insulin-induced gene-1 and suppresses hepatic lipogenesis in obese diabetic mice

Hepatology ◽  
2008 ◽  
Vol 48 (2) ◽  
pp. 432-441 ◽  
Author(s):  
Xiaomei Qin ◽  
Xuefen Xie ◽  
Yanbo Fan ◽  
Jianwei Tian ◽  
Youfei Guan ◽  
...  
Keyword(s):  
Peroxisome Proliferator ◽  
Diabetic Mice ◽  
Hepatic Lipogenesis ◽  
Peroxisome Proliferator Activated Receptor

Hypoxia aggravates non-alcoholic steatohepatitis in mice lacking hepatocellular PTEN

2009 ◽  
Vol 118 (6) ◽  
pp. 401-410 ◽  
Author(s):  
Anne-Christine Piguet ◽  
Deborah Stroka ◽  
Arthur Zimmermann ◽  
Jean-François Dufour
Keyword(s):  
Liver Disease ◽  
Insulin Sensitivity ◽  
Peroxisome Proliferator ◽  
Acetyl Coa Carboxylase ◽  
Acetyl Coa ◽  
Peroxisome Proliferator Activated Receptor ◽  
Alcoholic Fatty Liver ◽  
Lipogenic Genes ◽  
Alcoholic Steatohepatitis ◽  
Obstructive Sleep

The metabolic disorders that predispose patients to NASH (non-alcoholic steatohepatitis) include insulin resistance and obesity. Repeated hypoxic events, such as occur in obstructive sleep apnoea syndrome, have been designated as a risk factor in the progression of liver disease in such patients, but the mechanism is unclear, in particular the role of hypoxia. Therefore we studied the influence of hypoxia on the development and progression of steatohepatitis in an experimental mouse model. Mice with a hepatocellular-specific deficiency in the Pten (phosphatase and tensin homologue deleted on chromosome 10) gene, a tumour suppressor, were exposed to a 10% O2 (hypoxic) or 21% O2 (control) atmosphere for 7 days. Haematocrit, AST (aspartate aminotransferase), glucose, triacylglycerols (triglycerides) and insulin tolerance were measured in blood. Histological lesions were quantified. Expression of genes involved in lipogenesis and mitochondrial β-oxidation, as well as FOXO1 (forkhead box O1), hepcidin and CYP2E1 (cytochrome P450 2E1), were analysed by quantitative PCR. In the animals exposed to hypoxia, the haematocrit increased (60±3% compared with 50±2% in controls; P<0.01) and the ratio of liver weight/body weight increased (5.4±0.2% compared with 4.7±0.3% in the controls; P<0.01). Furthermore, in animals exposed to hypoxia, steatosis was more pronounced (P<0.01), and the NAS [NAFLD (non-alcoholic fatty liver disease) activity score] (8.3±2.4 compared with 2.3±10.7 in controls; P<0.01), serum AST, triacylglycerols and glucose were higher. Insulin sensitivity decreased in mice exposed to hypoxia relative to controls. The expression of the lipogenic genes SREBP-1c (sterol-regulatory-element-binding protein-1c), PPAR-γ (peroxisome-proliferator-activated receptor-γ), ACC1 (acetyl-CoA carboxylase 1) and ACC2 (acetyl-CoA carboxylase 2) increased significantly in mice exposed to hypoxia, whereas mitochondria β-oxidation genes [PPAR-α (peroxisome-proliferator-activated receptor-α) and CPT-1 (carnitine palmitoyltransferase-1)] decreased significantly. In conclusion, the findings of the present study demonstrate that hypoxia alone aggravates and accelerates the progression of NASH by up-regulating the expression of lipogenic genes, by down-regulating genes involved in lipid metabolism and by decreasing insulin sensitivity.

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