Chronic alcoholic liver disease is associated with hepatic insulin resistance, inflammation, oxidative and ER stress, mitochondrial dysfunction, and DNA damage. Peroxisome-proliferator activated receptor (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 furthered our investigations by characterizing 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-α, PPAR-δ, or PPAR-γ agonist twice weekly by i.p. injection. Ethanol-fed rats developed steatohepatitis with disordered hepatic chord architecture, mega-mitochondria, disruption of the RER, increased apoptosis, and increased 4-hydroxynonenal (HNE) and 3-nitrotyrosine (NTyr) immunoreactivity. PPAR-δ and PPAR-γ agonists reduced the severity of steatohepatitis, and restored the hepatic chord-like architectural, mitochondrial morphology, and RER organization, and the PPAR-δ agonist significantly reduced hepatic HNE. On the other hand, prominent RER tubule dilation, which could reflect ER stress, persisted in ethanol-exposed, PPAR-γ treated but not PPAR-δ treated livers. The PPAR-α 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-δ or PPAR-γ 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.
Keywords: Alcoholic liver disease; ER stress; Electron microscopy; Experimental model; Histopathology; Insulin resistance; PPAR agonists; Steatohepatitis.