The effect of plasminogen activator inhibitor-1-675 4G/5G polymorphism on PAI-1 gene expression and adipocyte differentiation


Demiralp D. O., Aktas H., Akar N.

CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS, vol.14, no.4, pp.438-446, 2008 (SCI-Expanded) identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 14 Issue: 4
  • Publication Date: 2008
  • Doi Number: 10.1177/1076029607305081
  • Journal Name: CLINICAL AND APPLIED THROMBOSIS-HEMOSTASIS
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Page Numbers: pp.438-446
  • Keywords: plasminogen activator-1, human umbilical cord vein endothelial cells, troglitazone, ciglitazone, BINDING PROTEIN-DELTA, NECROSIS-FACTOR-ALPHA, INSULIN SENSITIVITY, PPAR-GAMMA, ADIPOSE-TISSUE, C/EBP-ALPHA, ADIPOGENESIS, RESISTANCE, CHILDREN, OBESITY
  • Dokuz Eylül University Affiliated: No

Abstract

Obesity is a complex, multifactorial chronic disease frequently associated with cardiovascular risks, hypertriglyceridemia, low high-density lipoprotein-cholesterol, high blood pressure, and the insulin resistance that appears to be central to the pathogenesis of Type II diabetes. Plasminogen activator inhibitor-1 expression induced in differentiating adipose tissue, but its role in adipogenesis and obesity is poorly understood. Circulating, plasminogen activator inhibitor-1 levels are elevated at an early stage of impaired glucose tolerance, resulting in diabetes and metabolic syndrome. plasminogen activator inhibitor-1 levels are also significantly elevated in the plasma of obese individuals and in adipose tissues of obese mice and humans. Some investigators proposed that the -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter caused overexpression of this gene and predisposed carriers to obesity. In this study, we investigated the role of -675 4G/5G polymorphism in plasminogen activator inhibitor-1 promoter in the expression of this gene and the contribution of plasminogen activator inhibitor-1 to adipogenesis. Using a dual-luciferase promoter assay, we determined that the -675 4G/5G polymorphism contributes significantly to overexpression of plasminogen activator inhibitor-1 in the course of adipogenesis. The antidiabetic agents troglitazone and ciglitazone inhibited reporter gene expression driven by wild-type and -675 4G/5G mutant promoter, as well as the expression of endogenous plasminogen activator inhibitor-1, indicating that suppression of plasminogen activator inhibitor-1 expression may contribute to antidiabetic effects of these agents. The results indicate that absence of plasminogen activator inhibitor-1 in adipocytes may protect the cells against insulin resistance by promoting glucose uptake and adipocyte differentiation via a decrease in the peroxisome proliferator activated receptor-gamma expression that modulates the adipocyte differentiation.