Activation of hepatic stellate cells (HSC), the major effectors of hepatic fibrogenesis, is coupled with sequential alterations in gene expression, including an increase in receptors for transforming growth factor- (TGF-) and a dramatic reduction in the peroxisome proliferator-activated receptor-gamma (PPAR). Curcumin induces gene expression of PPAR and inhibits HSC activation. The underlying molecular mechanisms are largely unknown. We recently observed that stimulation of PPAR activation suppressed gene expression of TGF- receptors in activated HSC, leading to the interruption of TGF- signaling. This observation supported our assumption of an antagonistic relationship between PPAR activation and TGF- signaling in HSC. In this study, we further hypothesize that TGF- signaling might negatively regulate gene expression of PPAR in activated HSC. The present report demonstrates that exogenous TGF-1 inhibits gene expression of PPAR in activated HSC. Blocking TGF- signaling by dominant negative type II TGF- receptor increases the promoter activity of PPAR gene. Promoter deletion assays, site-directed mutageneses and gel shift assays localize two Smad binding elements (SBEs) in the PPAR gene promoter, acting as curcumin response elements and negatively regulating the promoter activity in passaged HSC. The Smad3/4 protein complex specifically binds to the SBEs. Over-expression of Smad4 dose-dependently eliminates the inhibitory effects of curcumin on the PPAR gene promoter and TGF- signaling. Taken together, these results demonstrate that the interruption of TGF- signaling by curcumin induces gene expression of PPAR in activated HSC in vitro.