The effect of plasminogen activator inhibitor-1 -675 4G/5G polymorphism on PAI-1 gene expression and adipocyte differentiation.
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.
Ozel Demiralp
Duygu
D
Proteomics Unit of Central Laboratory, Ankara University Biotechnology Institute, Tandoğan, Ankara, Turkey. ozel@medicine.ankara.edu.tr
Aktas
Huseyin
H
Akar
Nejat
N
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology*; D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002839:Chromans / Q000494:pharmacology; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D047495:PPAR gamma / Q000502:physiology; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics* / Q000502:physiology; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D045162:Thiazolidinediones / Q000494:pharmacology; D000077288:Troglitazone
D002839:Chromans; D047495:PPAR gamma; D017395:Plasminogen Activator Inhibitor 1; D045162:Thiazolidinediones; D000077288:Troglitazone; C039671:ciglitazone