Peroxisome proliferator-activated receptor-alpha agonists repress expression of thrombin-activatable fibrinolysis inhibitor by decreasing transcript stability.

Thrombin-activatable fibrinolysis inhibitor (TAFI) (carboxypeptidase 82) is a plasma zymogen that is biosynthesised in the liver and released into the circulation. Activated TAFI is a prothrombotic factor which inhibits fibrin clot lysis. Cultured human hepatoma HepG2 cells were treated with peroxisome proliferator-activated receptor (PPAR)alpha, beta or gamma agonists, and the levels of TAFI antigen and mRNA (here, termed CPB2 mRNA) were measured. HepG2 cells treated with the PPAR alpha agonist WY14643, but not agonists for PPAR beta or PPAR gamma, decreased their release of TAFI antigen into the conditioned medium. In parallel, there were decreased levels of CPB2 mRNA and TAFI antigen in the cells. The WY14643-mediated decrease in CPB2 mRNA levels was accelerated by overexpression of PPARa and abolished by RNA interference of PPARA mRNA. CPB2 gene promoter activity was not influenced by treatment of the cells with WY14643. The half-life of the CPB2 transcript was shortened by treatment with WY14643 as compared with that of the control, and the decreased half-life of mRNA returned to control levels by treatment with a PPARa antagonist MK886 or transfection of PPARA-specific siRNA to WY14643-treated HepG2 cells. The present results suggest that PPARa agonists not only play a hypolipidaemic role, but also decrease the expression of TAFI, a prothrombotic factor, by decreasing stability of CPB2 transcripts.