β-Catenin pathway is required for TGF-β1 inhibition of PPARγ expression in cultured hepatic stellate cells

Hepatic stellate cell (HSC) activation is a key step in process of liver fibrosis. Transforming growth factor-β1 (TGF-β1) is the most powerful mediator of HSC activation and plays a central role in liver fibrosis. Peroxisome proliferator-activated receptor-γ (PPARγ) is an important regulator of adipocyte differentiation and has been proposed as a crucial factor for inhibition of HSC activation. The effect of TGF-β1 on PPARγ in HSCs is largely unknown. This study is aimed to examine whether TGF-β1 can influence PPARγ expression, focusing on the role of β-catenin pathway, a key pathway linked to adipogenesis, in TGF-β1 regulation of PPARγ in cultured HSCs. Our results demonstrated that TGF-β1 evidently inhibited PPARγ expression and activity in cultured HSCs, which were mediated through β-catenin pathway. TGF-β1 promoted β-catenin expression and also increased the stability of β-catenin protein through ERK1/2/glycogen synthase kinase-3β (GSK-3β) axis in cultured HSCs. Moreover, TGF-β1 inhibition of PPARγ expression by β-catenin pathway caused the increase in alpha1(1) collagen and tissue inhibitor of matrix metalloproteinase expression. These results indicated for the first time that TGF-β1 could down-regulate PPARγ expression through β-catenin pathway and subsequently contributed to the increase in alpha1(1) collagen level in cultured HSCs.

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