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.