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Alpha-lipoic acid inhibits hepatic PAI-1 expression and fibrosis by inhibiting the TGF-β signaling pathway

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Author(s)
Ae-Kyung MinMi-Kyung KimHye-Young SeoHye-Soon KimByoung Kuk JangJae Seok HwangHueng-Sik ChoiKi-Up LeeKeun-Gyu ParkIn-Kyu Lee
Publication Year
2010
Abstract
Accumulating evidence suggests that plasminogen activator inhibitor (PAI)-1 plays an important role in the development of hepatic fibrosis via its involvement in extracellular matrix remodeling. We previously reported that alpha-lipoic acid (ALA), a naturally occurring thiol antioxidant, prevents hepatic steatosis by inhibiting the expression of sterol regulatory element binding protein-1c. The aim of the present study was to determine whether ALA prevents hepatic PAI-1 expression and fibrosis through the inhibition of multiple TGF-β-mediated molecular mediators. We investigated whether ALA inhibited the development of hepatic fibrosis in mice following bile duct ligation (BDL), an established animal model of liver fibrosis. We found that ALA markedly inhibited BDL-induced hepatic fibrosis and PAI-1 expression. We also found that ALA attenuated TGF-β-stimulated PAI-1 mRNA expression, and inhibited PAI-1 promoter activity in liver cells; this effect was mediated by Smads and the JNK and ERK pathways. The results of the present study indicate that ALA inhibits hepatic PAI-1 expression through inhibition of TGF-β-mediated molecular mediators, including Smad3, AP1, and Sp1, and prevents the development of BDL-induced hepatic fibrosis. These findings suggest that ALA may have a clinical application in preventing the development and progression of hepatic fibrosis.

Keywords
Alpha-lipoic acid;
Plasminogen activator inhibitor-1;
Transforming growth factor-β;
Hepatic fibrosis
Department
Dept. of Internal Medicine (내과학)
Publisher
School of Medicine
Citation
Biochemical and Biophysical Research Communications, Vol.393(3) : 536-541, 2010
Type
Article
ISSN
0006-291X
DOI
10.1016/j.bbrc.2010.02.050
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/35195
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