Acetaldehyde inhibits PPARγ via H2O2-mediated c-Abl activation in human hepatic stellate cells

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 gamma (PPAR gamma) 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 PPAR gamma transcriptional activity and its correlation with the AcCHO-induced collagen synthesis in hepatic stellate cells. Results: AcCHO treatment inhibited ligand-dependent and -independent PPAR-gamma transcriptional activity, and this effect was correlated with an increased phosphorylation of a mitogenactivated protein kinase site at serine 84 of the human PPAR gamma. Transfection of the PPAR gamma Ser84Ala mutant completely prevented the effect of AcCHO on PPAR gamma activity and in parallel abrogated the induction of collagen gene expression by AcCHO. The effect of AcCHO on PPAR-y activity and phosphorylation was blocked by extracellular signal-regulated kinase (ERK) 1/2 and protein kinase C (PKC)5 inhibitors as well as by catalase, suggesting that hydrogen peroxide is involved in the molecular cascade responsible for PPAR-y phosphorylation via activation of the PKC delta/ERK pathway. Furthermore, inhibition of c-Abl completely abrogated the effect of AcCHO on either PPAR-y function or collagen synthesis; in addition, expression of the PPAR gamma Ser84Ala 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 PPAR-y phosphorylation induced by a hydrogen peroxide-mediated activation of the profibrogenic c-Abl signaling pathway.