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Hepatol Res. 2011 Apr;41(4):386-98. doi: 10.1111/j.1872-034X.2011.00775.x. Epub 2011 Feb 24.

Peroxisome proliferator-activated receptor agonist treatment of alcohol-induced hepatic insulin resistance.

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  • 1Liver Research Center and Departments of Medicine and Pathology, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA.


Aim:  Chronic ethanol exposure impairs insulin signaling in the liver. Peroxisome-proliferator activated receptor (PPAR) agonists function as insulin sensitizers and are used to treat type 2 diabetes mellitus. We examined the therapeutic effectiveness of PPAR agonists in reducing alcoholic hepatitis and hepatic insulin resistance in a model of chronic ethanol feeding. Methods:  Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% (control) or 37% ethanol (caloric content; 9.2% v/v) for 8 weeks. After 3 weeks on the diets, the rats were treated with vehicle, or a PPAR-α, PPAR-δ or PPAR-γ agonist twice weekly by i.p. injection. Livers were harvested for histopathological, gene expression (reverse transcription polymerase chain reaction), protein (western and ELISA) and receptor binding studies. Results:  Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architecture, increased hepatocellular apoptosis, reduced binding to the insulin, insulin-like growth factor (IGF)-1 and IGF-2 receptors, and decreased expression of glyceraldehyde-3-phosphate dehydrogenase and aspartyl-(asparaginyl)-β-hydroxylase (mediating remodeling), which are regulated by insulin/IGF signaling. PPAR-α, PPAR-δ or PPAR-γ agonist treatments reduced the severity of ethanol-mediated liver injury, including hepatic architectural disarray and steatosis. In addition, PPAR-δ and PPAR-γ agonists reduced insulin/IGF resistance and increased insulin/IGF-responsive gene expression. Conclusion:  PPAR agonists may help reduce the severity of chronic ethanol-induced liver injury and insulin/IGF resistance, even in the context of continued high-level ethanol consumption.

© 2011 The Japan Society of Hepatology.

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