Thursday, October 11, 2012: 6:50 PM
604 (WSCC)
Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER (endoplasmic reticulum) stress, mitochondrial dysfunction, and DNA damage. Peroxisome Proliferator Activated Receptors (PPAR) agonists are insulin sensitizers that have anti-inflammatory/anti-oxidant effects. We previously showed that PPAR agonists can restore hepatic insulin responsiveness in chronic ethanol-fed rats with steatohepatitis. Herein, we characterize the histological and ultrastructural changes mediated by PPAR agonist rescue of alcohol-induced steatohepatitis. Adult male Long Evans rats were pair fed with isocaloric liquid diets containing 0% or 37% ethanol (caloric) for 8 weeks. After 3 weeks on the diets, rats were treated with vehicle, or a PPAR-alpha, PPAR-delta, or PPAR-gamma agonist twice weekly by intraperitoneal injection. Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architectures, mega-mitochondria, disruption of the RER, increased apoptosis, and increased 4-hydroxynonenal (HNE). PPAR-delta and PPAR-gamma agonists reduced the severity of steatohepatitis, and restored the hepatic chord-like architecture, mitochondrial morphology, and RER organization, and the PPAR-delta agonist significantly reduced hepatic HNE. On the other hand, prominent RER tubule dilation, which could reflect ER stress, persisted in livers of ethanol-exposed, PPAR-gamma agonist treated but not PPAR-delta agonist treated rats. The PPAR-alpha agonist exacerbated both steatohepatitis and formation of mega-mitochondria, and it failed to restore RER architecture or lower biochemical indices of oxidative stress. In conclusion, improved hepatic insulin responsiveness and decreased inflammation resulting from PPAR-delta or PPAR-gamma agonist treatments of alcohol-induced steatohepatitis are likely mediated by enhanced signaling through metabolic pathways with attendant reductions in ER stress, oxidative stress, and mitochondrial dysfunction.