Alpha-lipoic acid inhibits hepatic PAI-1 expression and fibrosis by inhibiting the TGF-beta signaling pathway.
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-beta-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-beta-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-beta-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.
Department of Internal Medicine, Keimyung University School of Medicine, Daegu 700-712, South Korea.
Ae-Kyung
AK
Min
Mi-Kyung
MK
Kim
Hye-Young
HY
Seo
Hye-Soon
HS
Kim
Byoung Kuk
BK
Jang
Jae Seok
JS
Hwang
Hueng-Sik
HS
Choi
Ki-Up
KU
Lee
Keun-Gyu
KG
Park
In-Kyu
IK
Lee
D000818:Animals; D000975:Antioxidants / Q000627:therapeutic use*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D048670:MAP Kinase Kinase 4 / Q000037:antagonists & inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis*; D015398:Signal Transduction; D051900:Smad3 Protein / Q000037:antagonists & inhibitors; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors; D008063:Thioctic Acid / Q000627:therapeutic use*; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000494:pharmacology
D000975:Antioxidants; D017395:Plasminogen Activator Inhibitor 1; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D016329:Sp1 Transcription Factor; D018808:Transcription Factor AP-1; D016212:Transforming Growth Factor beta; D008063:Thioctic Acid; D048049:Extracellular Signal-Regulated MAP Kinases; D048670:MAP Kinase Kinase 4