title: Peroxisome proliferator-activated receptor-alpha agonists repress expression of thrombin-activatable fibrinolysis inhibitor by decreasing transcript stability.
abstract: Thrombin-activatable fibrinolysis inhibitor (TAFI) (carboxypeptidase B2) 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)α, β or γ agonists, and the levels of TAFI antigen and mRNA (here, termed CPB2 mRNA) were measured. HepG2 cells treated with the PPARα agonist WY14643, but not agonists for PPARβ or PPARγ, 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 PPARα and abolished by RNA interference of  PPAR A 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 PPARα antagonist MK886 or transfection of  PPAR A-specific siRNA to WY14643-treated HepG2 cells. The present results suggest that PPARα agonists not only play a hypolipidaemic role, but also decrease the expression of TAFI, a prothrombotic factor, by decreasing stability of  CPB2  transcripts.
authors.affiliation: Laboratory of Molecular and Cellular Pathophysiology, Showa Pharmaceutical University, Machida, Tokyo, Japan.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Masuda
authors.forename: Dan
authors.initials: D
authors.lastname: Saotome
authors.forename: Kimihiko
authors.initials: K
authors.lastname: Takada
authors.forename: Katsuyoshi
authors.initials: K
authors.lastname: Sugimoto
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Sasaki
authors.forename: Hidemi
authors.initials: H
authors.lastname: Ishii
mesh_terms: D043424:Carboxypeptidase B / Q000235:genetics / Q000378:metabolism; D025901:Carboxypeptidase B2 / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000235:genetics; D045744:Cell Line, Tumor; D005342:Fibrinolysis / Q000187:drug effects*; D005786:Gene Expression Regulation; D056945:Hep G2 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047493:PPAR alpha / Q000819:agonists* / Q000235:genetics; D047495:PPAR gamma / Q000819:agonists; D048068:PPAR-beta / Q000819:agonists; D011743:Pyrimidines / Q000494:pharmacology; D012322:RNA Precursors / Q000235:genetics; D020871:RNA Stability; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D014158:Transcription, Genetic; D002722:Chlorobenzenes
chemical_list: D043424:Carboxypeptidase B; D025901:Carboxypeptidase B2; D007211:Indoles; D047493:PPAR alpha; D047495:PPAR gamma; D048068:PPAR-beta; D011743:Pyrimidines; D012322:RNA Precursors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C060893:MK-886; D002722:Chlorobenzenes; C006253:pirinixic acid