title: Inhibition by fibrates of plasminogen activator inhibitor type-1 expression in human adipocytes and preadipocytes.
abstract: Plasminogen activator inhibitor type-1 (PAI-1), an established marker and mediator of cardiovascular risk, is produced extensively in adipose tissue. Fibrates are hypolipidemic peroxisome proliferator activated receptor-alpha (PPARalpha) agonists. Recent laboratory and clinical observations indicate that they are also anti-atherosclerotic. Mechanisms responsible, however, remain to be fully understood. The present study was designed to elucidate modulation of PAI-1 expression in adipose cells by fibrates as a potential mechanism. Expression of PPARalpha was verified by PCR, immunohistochemistry, and Western blotting. In cultured preadipocytes and adipocytes gemfibrozil and fenofibrate significantly reduced PAI-1 protein expression by up to 55 +/- 5% and 34 +/- 4% under basal conditions and up to 56 +/- 6% and 31 +/- 6% under conditions of stimulation of the cells with 40 pM transforming growth factor (TGF)beta, respectively. Quantification of mRNA showed that the gemfibrozil-induced effect was at least in part regulated at the transcriptional level. Incubations with non-fibrate PPARalpha agonists showed similar reductions in PAI-1 expression. The decrease in PAI-1 expression induced by gemfibrozil was inhibited by MK886, a PPARalpha inhibitor. Furthermore, preadipocytes isolated from PPARalpha-deficient mice produced significantly more PAI-1 than those from wild-type mice upon stimulation with TGFbeta. Finally, fenofibrate reduced PAI-1 expression both in plasma and adipose tissue of hyperlipidemic mice. Our data support the view that PPARalpha activation down-regulates PAI-expression in adipose cells that may contribute in part to the reduction in cardiovascular mortality seen with fibrates in clinical trials.
authors.affiliation: Dept. of Cardiology and Angiology, University of Freiburg, Hugstetterstrasse 55, 79106 Freiburg, Germany. andreas.zirlik@uniklinik-freiburg.de
authors.forename: Andreas
authors.initials: A
authors.lastname: Zirlik
authors.forename: Sandra
authors.initials: S
authors.lastname: Ernst
authors.forename: Anne
authors.initials: A
authors.lastname: Leugers
authors.forename: Florian
authors.initials: F
authors.lastname: Willecke
authors.forename: Burton E
authors.initials: BE
authors.lastname: Sobel
authors.forename: Christoph
authors.initials: C
authors.lastname: Bode
authors.forename: Thomas K
authors.initials: TK
authors.lastname: Nordt
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000273:Adipose Tissue / Q000473:pathology; D000328:Adult; D000368:Aged; D000818:Animals; D002478:Cells, Cultured; D005260:Female; D011345:Fenofibrate / Q000494:pharmacology*; D015248:Gemfibrozil / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D000960:Hypolipidemic Agents; D047493:PPAR alpha; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D015248:Gemfibrozil; D011345:Fenofibrate