Activation of peroxisome proliferator-activated receptor-|[gamma]| by curcumin blocks the signaling pathways for PDGF and EGF in hepatic stellate cells

摘要

During hepatic fibrogenesis, reduction in the abundance of peroxisome proliferator-activated receptor-γ (PPARγ) is accompanied by activation of mitogenic signaling for platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) in hepatic stellate cells (HSCs), the major effector cells. We previously reported that curcumin, the yellow pigment in curry, interrupted PDGF and EGF signaling, stimulated PPARγ gene expression, and enhanced its activity, leading to inhibition of cell proliferation of activated HSC in vitro and in vivo. The aim of this study was to elucidate the underlying mechanisms. We hypothesized that the enhancement of PPARγ activity by curcumin might result in the interruption of PDGF and EGF signaling. Our experiments demonstrated that curcumin, with different treatment strategies, showed different efficiencies in the inhibition of PDGF- or EGF-stimulated HSC proliferation. Further experiments observed that curcumin dose dependently reduced gene expression of PDGF and EGF receptors (ie, PDGF-βR and EGFR), which required PPARγ activation. The activation of PPARγ by its agonist suppressed pdgf-βr and egfr expression in HSC. In addition, curcumin reduced the phosphorylation levels of PDGF-βR and EGFR, as well as their downstream signaling cascades, including ERK1/2 and JNK1/2. Moreover, activation of PPARγ induced gene expression of glutamate–cysteine ligase, the rate-limiting enzyme in de novo synthesis of the major intracellular antioxidant, glutathione. De novo synthesis of glutathione was required for curcumin to suppress pdgf-βr and egfr expression in activated HSCs. Our results collectively demonstrated that enhancement of PPARγ activity by curcumin interrupted PDGF and EGF signaling in activated HSCs by reducing the phosphorylation levels of PDGF-βR and EGFR, and by suppressing the receptor gene expression. These results provide novel insights into the mechanisms of curcumin in the inhibition of HSC activation and the suppression of hepatic fibrogenesis.