PPARδ agonist attenuates alcohol-induced hepatic insulin resistance and improves liver injury and repair

Background/Aims: Chronic ethanol exposure impairs liver regeneration due to inhibition of insulin signaling and oxidative injury. PPAR agonists function as insulin sensitizers and anti-inflammatory agents. We investigated whether treatment with a PPAR delta agonist could restore hepatic insulin sensitivity, survival signaling, and regenerative responses vis-a-vis chronic ethanol feeding. Methods: Adult rats were fed isocaloric liquid diets containing 0% or 37% ethanol, and administered a PPAR delta agonist by i.p. injection. We used liver tissue to examine histopathology, gene expression, oxidative stress, insulin signaling, and regenerative responses to 2/3 hepatectomy. Results: Chronic ethanol feeding caused insulin resistance, increased oxidative stress, lipid peroxidation, DNA damage, and hepatocellular injury in liver. These effects were associated with reduced insulin receptor binding and affinity, impaired survival signaling through PI3KAkt/GSK3 beta, and reduced expression of insulin responsive genes mediating energy metabolism and tissue remodeling. PPAR delta agonist treatment reduced ethanol-mediated hepatic injury, oxidative stress, lipid peroxidation, and insulin resistance, increased signaling through PI3K/Akt/GSK3 beta, and enhanced the regenerative response to partial hepatectomy. Conclusions: PPAR delta agonist administration may attenuate the severity of chronic ethanol-induced liver injury and ethanol's adverse effects on the hepatic repair by restoring insulin responsiveness, even in the context of continued high-level ethanol consumption. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.