PPARgamma activation by antidiabetic thiazolidinediones reduces liver fibrosis and hepatic stellate cells activation in vivo

The ligand-dependent trascription factor PPARgamma is expressed in Hepatic Stellate Cells (HSC), and its transcriptional control is reduced during cell transdifferentiation in culture. PPARgamma transcriptional activation either by specific ligands or by transient forced expression of the receptor decreases PDGF-induced proliferation and inhibits alpha-SMA expression in cultured HSC. Aim of our study was to evaluate whether oral administration of synthetic PPARgamma ligands, thiazolidinediones (TDZs), might affect collagen deposition in animal models of liver fibrosis. The effect of two TDZs (Pioglitazone or Rosiglitazone) was tested on liver fibrosis induced in rats by either dimethylnitrosamine (DMN) or carbon tetrachloride (CC14) administration. In vivo PPARgamma activation was evaluated by gel shift assay using nuclear extracts from HSC isolated from control and treated rats. Oral administration of TDZs reduced extracellular matrix deposition and HSC activation in both rat models of liver fibrosis. PPARgamma specific DNA binding was significantly impaired in nuclear extracts of HSC isolated from DMN- and CClCtreated rats compared to HSC from control rats. TDZ administration restored PPARgamma DNA binding in HSC nuclei. In vitro TDZ-induced PPARgamma activation inhibited collagen and fibronectin synthesis induced by TGF-beta1 in rat and human HSC, as measured by ELISA and northen blotting. TDZs also reduced the betal-induced activity of a 3.5 Kb procollagen type I promoter (pSW3.5-CAT) transfected in human HSC. In conclusion, these findings indicate that PPARgamma activation in HSC hampers fibrosis in vivo and suggest the use of TDZs as valuable drugs for the treatment of liver fibrosis.