PPARγ activation induces acute PAI-1 gene expression in the liver but not in adipose tissues of diabetic model mice

Thromb Res. 2011 Nov;128(5):e81-5. doi: 10.1016/j.thromres.2011.06.020. Epub 2011 Jul 14.


Insulin resistance in patients with type II diabetes has recently been treated with thiazolidinediones, a class of peroxisome proliferator-activated receptor γ (PPARγ) agonists. However, these compounds are possibly associated with a significant increase in the risk of cardiovascular events. We examined the effect of the PPARγ agonist rosiglitazone on the expression of plasminogen activator inhibitor-1 (PAI-1) that is the primary inhibitor of fibrinolysis in the liver of diabetic mice and cultured mouse and human hepatocytes. Concentrations of plasma PAI-1 and levels of its mRNA expression in the liver were significantly elevated in accordance with hepatic PPARγ1 and PPARγ2 mRNA accumulation in genetically diabetic db/db mice. An intraperitoneal injection of rosiglitazone significantly increased plasma PAI-1 concentrations in parallel with hepatic, but not with adipose mRNA levels in db/db mice, and did not affect these parameters in wild-type mice. Rosiglitazone as well as the PPARα agonist bezafibrate significantly induced PAI-1 mRNA expression in cultured mouse hepatocytes. Furthermore, both rosiglitazone and pioglitazone significantly induced, whereas bezafibrate did not affect PAI-1 mRNA expression in the human liver carcinoma cell line HepG2. The transient induction of PAI-1 gene expression mediated by PPARγ in the fatty liver might be involved in the increased risk of cardiovascular events associated with thiazolidinediones in diabetic patients through decreasing fibrinolytic activity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue / metabolism*
  • Animals
  • Cardiovascular Diseases / chemically induced
  • Cell Line
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / metabolism*
  • Humans
  • Hypoglycemic Agents
  • Liver / cytology
  • Liver / metabolism*
  • Mice
  • PPAR gamma / agonists
  • PPAR gamma / metabolism*
  • Plasminogen Activator Inhibitor 1 / biosynthesis
  • Plasminogen Activator Inhibitor 1 / genetics*
  • RNA, Messenger / analysis
  • Rosiglitazone
  • Thiazolidinediones / administration & dosage
  • Thiazolidinediones / pharmacology
  • Transcriptional Activation*


  • Hypoglycemic Agents
  • PPAR gamma
  • Plasminogen Activator Inhibitor 1
  • RNA, Messenger
  • Thiazolidinediones
  • Rosiglitazone