Activation of peroxisome proliferator activated receptor alpha ameliorates ethanol mediated liver fibrosis in mice

Background: Peroxisome proliferator activated receptor alpha (PPAR alpha) ameliorates ethanol induced hepatic steatohepatitis. However, its role in alcoholic liver fibrosis has not been fully clarified. The aim of this study was to elucidate the effect and the molecular basis of PPARa in ethanol induced liver fibrosis in mice. Methods: C57BL/6J mice were fed with 4% ethanol-containing Lieber-DeCarli liquid diet for eight weeks, and intraperitoneal injected with 5% carbon tetrachloride (CCl4) for the last four weeks to induce alcoholic liver fibrosis. PPARa agonist WY14643 was administered to mice during the last couple of weeks. The effects of PPARa induction on liver histology, activation of hepatic stellate cells (HSCs), as well as hepatic expression of inflammatory and fibrogenic factors were assessed. Results: The ethanol plus CCl4 treated mice exhibited progressive liver injury including piecemeal necrosis of hepatocytes, severe inflammatory cells infiltration and bridging fibrosis. This was accompanied by down-regulated hepatic expression of PPARa and the protective cytokines adiponectin, heme oxygenase-1 and interleukin-10. Additionally, up-regulation of the proinflammatory cytokine tumor necrosis factor-alpha, as well as the profibrogenic genes osteopontin, transforming growth factor-beta 1, visfatin, phosphatidylinositol 3-kinase, matrix metalloproteinase-2 (MMP-2) and MMP-9 was observed. WY14643 treatment restored expression of cytokines altered by ethanol plus CCl4 treatment and concomitantly ameliorated the liver injury. Conclusions: The present study provides evidence for the protective role of PPAR alpha induction in ameliorating ethanol mediated fibrosis through mediation of inflammatory and fibrogenic factors.