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Background & Aims: Accumulating evidence indicates that acetaldehyde (AcCHO) is one of the main mediators of fibrogenesis in alcoholic liver disease. AcCHO stimulates synthesis of fibrillar collagens in hepatic stellate cells, but the molecular events directly involved in the activation of collagen genes are debatable. Methods: Peroxisome proliferator-activated receptor γ (PPARγ) is a nuclear receptor that is expressed in stellate cells, and its activation by specific ligands inhibits collagen synthesis. In this study, we evaluated the effects of AcCHO on PPARγ transcriptional activity and its correlation with the AcCHO-induced collagen synthesis in hepatic stellate cells. Results: AcCHO treatment inhibited ligand-dependent and -independent PPARγ transcriptional activity, and this effect was correlated with an increased phosphorylation of a mitogen-activated protein kinase site at serine 84 of the human PPARγ. Transfection of the PPARγSer84Ala mutant completely prevented the effect of AcCHO on PPARγ activity and in parallel abrogated the induction of collagen gene expression by AcCHO. The effect of AcCHO on PPARγ activity and phosphorylation was blocked by extracellular signal–regulated kinase (ERK) 1/2 and protein kinase C (PKC)δ inhibitors as well as by catalase, suggesting that hydrogen peroxide is involved in the molecular cascade responsible for PPARγ phosphorylation via activation of the PKCδ/ERK pathway. Furthermore, inhibition of c-Abl completely abrogated the effect of AcCHO on either PPARγ function or collagen synthesis; in addition, expression of the PPARγSer84Ala mutant prevented the profibrogenic signals mediated by c-Abl activation. Conclusions: Our results showed that the induction of collagen expression by AcCHO in stellate cells is dependent on PPARγ phosphorylation induced by a hydrogen peroxide–mediated activation of the profibrogenic c-Abl signaling pathway.

Background & Aims: The ligand-dependent transcription factor peroxisome proliferator-activated receptor γ (PPARγ) is expressed in hepatic stellate cells (HSC), and its transcriptional activity is reduced during cell transdifferentiation in culture. PPARγ transcriptional activation decreases platelet-derived growth factor–induced proliferation and inhibits α-smooth muscle actin expression in cultured HSC. The aim of our study was to evaluate whether oral administration of synthetic PPARγ ligands, thiazolidinediones (TZD), might affect collagen deposition in animal models of liver fibrosis. Methods: The effect of 2 TZD (pioglitazone or rosiglitazone) was tested on liver fibrosis induced in rats by either toxin administration (dimethylnitrosamine or carbon tetrachloride) or bile duct ligation. In vivo PPARγ activation was evaluated by gel shift assay using nuclear extracts from HSC isolated from control and treated rats. Results: Oral administration of TZD reduced extracellular matrix deposition and HSC activation in both toxic and cholestatic models of liver fibrosis. PPARγ-specific DNA binding was significantly impaired in nuclear extracts of HSC isolated from fibrotic rats compared with HSC from control rats. TZD administration restored PPARγ DNA binding in HSC nuclei. In vitro, TZD-induced PPARγ activation inhibited collagen and fibronectin synthesis induced by transforming growth factor (TGF)-β1 in human HSC, as measured by enzyme-linked immunosorbent assay and Northen blotting. TZD also reduced the TGF-β1–induced activity of a 3.5-kilobase procollagen type I promoter transfected in human HSC. Conclusions: These findings indicate that PPARγ activation in HSC retards fibrosis in vivo and suggest the use of TZD for the treatment of liver fibrosis. GASTROENTEROLOGY 2002;122:1924-1940