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

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.