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.
Affiliated Hospital of Nantong University, Qi xiou road 19, Nantong 226001, Jiangsu, China.
Jingjing
J
Qian
Minghui
M
Niu
Xuguang
X
Zhai
Qian
Q
Zhou
Yajun
Y
Zhou
D050156:Adipogenesis / Q000187:drug effects; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D024042:Collagen Type I / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism*; D008103:Liver Cirrhosis / Q000188:drug therapy / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D020782:Matrix Metalloproteinases / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction; D053773:Transforming Growth Factor beta1 / Q000378:metabolism / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism*
D024042:Collagen Type I; D047495:PPAR gamma; D053773:Transforming Growth Factor beta1; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D020782:Matrix Metalloproteinases