Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro

Nonalcoholic steatohepatitis with fibrosis is a more severe form of nonalcoholic fatty liver disease, one of the most common liver diseases We have previously shown that peroxisome proliferator-activated receptors gamma (PPAR gamma) ligand, rosiglitazone, prevented the development of the methionine choline deficient (MCD) diet-induced fibrosing steatohepatitis We have now tested whether overexpression of PPAR gamma ameliorates established steatohepatins and fibrosis Male C57BL6 mice fed with MCD diet for 8 weeks developed hepatic fibrosis with increased hepatic expression of collagen1 alpha(1), inhibitors of fibrosis reversal-1, regulator involved in matrix degradation-9 and connective tissue growth factor After 2 weeks of transduction of PPAR gamma through an adenovirus-expressing PPAR gamma (Ad-PPAR gamma), expression of these genes was reduced in a manner that paralleled the reduction in activated hepatic stellate cells (HSCs) and resolution of liver fibrosis. On the in vitro study. PPAR gamma is expressed in primary quiescent HSC, but depleted in culture activated HSC Conversely, ectopic expression of PPAR gamma in activated HSC achieved the phenotypic reversal to the quiescent cell Such induction markedly suppressed cell viability and cell proliferation, downregulated proliferating cell nuclear antigen, and caused cell cycle arrest at G0/G1 phase. Further, introduction of PPAR gamma in HSC increased cell apoptosis, this was confirmed by enhanced expression of FasL, cleaved caspase-3, cleaved caspase-7 and poly ADP-ribose polymerase, indicating an extrinsic apoptosis pathway. In conclusion, the present study shows that MCD diet-Induced fibrosing steatohepatitis can be reversed by overexpression of PPAR gamma. It is likely that PPAR gamma reverses fibrosis by reducing HSCs proliferation, inducing cell cycle arrest and apoptosis. (C) 2010 Elsevier Ltd All rights reserved