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Forkhead transcription factor FoxO1 inhibits insulin- and transforming growth factor-β-stimulated plasminogen activator inhibitor-1 expression

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Author(s)
김미경김혜순조호찬박근규
Alternative Author(s)
Kim, Mi KyungKim, Hye SoonCho, Ho ChanPark, Keun Gyu
Publication Year
2009
Abstract
Elevated levels of plasminogen activator inhibitor-1 (PAI-1) are considered a risk factor for chronic liver disease in patients with hyperinsulinemia. Insulin increases the expression of PAI-1, and inactivates the forkhead box-containing protein FoxO1. We were interested in whether the inactivation of FoxO1 is involved in the activation of PAI-1 expression under conditions of insulin stimulation. Here, we examined whether adenoviral-mediated expression of a constitutively active form of FoxO1 (Ad-CA-FoxO1) inhibited insulin-stimulated PAI-1 expression in human HepG2 hepatocellular liver carcinoma cells and mouse AML12 hepatocytes. Treatment of cells with insulin increased PAI-1 gene expression, and this effect was abolished by Ad-CA-FoxO1. Insulin also increased the transforming growth factor (TGF)-β-induced expression of PAI-1 mRNA, and Ad-CA-FoxO1 inhibited this effect. Transient transfection assays using a reporter gene under the control of the PAI-1 promoter revealed that CA-FoxO1 inhibits Smad3-stimulated PAI-1 promoter activity. Taken together, our results indicate that FoxO1 inhibits PAI-1 expression through the inhibition of TGF-β/Smad-mediated signaling pathways. Our data also suggest that in the hyperinsulinemic state, FoxO1 is inactivated by increased levels of insulin, and does not function as an inhibitor of TGF-β-induced PAI-1 expression.

Keywords
Plasminogen activator inhibitor-1;
Transforming growth factor β;
Forkhead box-containing protein FoxO1;
Hyperinsulinemia;
Liver fibrosis
Department
Dept. of Internal Medicine (내과학)
Institute for Medical Science (의과학연구소)
Publisher
School of Medicine
Citation
Biochemical and Biophysical Research Communications, Vol.386(4) : 757-761, 2009
Type
Article
ISSN
0006-291X
DOI
10.1016/j.bbrc.2009.06.124
URI
http://kumel.medlib.dsmc.or.kr/handle/2015.oak/35197
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