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 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.