Forkhead transcription factor FoxO1 inhibits insulin- and transforming growth factor-beta-stimulated plasminogen activator inhibitor-1 expression.
Biochem Biophys Res Commun
; 386(4): 757-61, 2009 Sep 04.
Article
em En
| MEDLINE
| ID: mdl-19563779
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)-beta-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-beta/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-beta-induced PAI-1 expression.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fator de Crescimento Transformador beta
/
Inibidor 1 de Ativador de Plasminogênio
/
Fatores de Transcrição Forkhead
/
Hiperinsulinismo
/
Insulina
Tipo de estudo:
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2009
Tipo de documento:
Article
País de afiliação:
Coréia do Sul