ACTIVATION OF GENE-TRANSCRIPTION BY PROSTACYCLIN ANALOGS IS MEDIATED BY THE PEROXISOME-PROLIFERATORS-ACTIVATED RECEPTOR (PPAR)

Xenobiotic amphipathic carboxylates, known collectively as hypolipidem ic peroxisome proliferators (e.g., aryloxyalkanoic acids), or native l ong-chain fatty acids induce liver peroxisome proliferation and other biological activities. This broad spectrum of effects results from mod ulation of transcription of specific genes mediated by binding of pero xisome-proliferators-activated receptors (PPAR) to respective sequence -specific promoter elements (PPRE). The broad specificity and relative ly low potency of reported hypolipidemic peroxisome proliferators prom pted us to search for specific highly potent peroxisome proliferators. Here we report that stable prostacyclin analogues may act in such a m anner. mPPAR alpha-mediated expression of a reporter gene linked to th e peroxisomal rat acyl-CoA oxidase promoter was dose-dependently induc ed by carbaprostacyclin and iloprost. The ED,, for carbaprostacyclin w as 25 nM, and carbaprostacyclin was therefore 25-fold and 200-fold mor e effective than the most potent xenobiotic (5,18,11,14-eicosatetrayno ic acid) and native (arachidonic acid) inducers, respectively. Inducti on was further increased by cotransfecting the cells with mPPAR alpha and an expression vector for retinoic acid-X-receptor. PPAR-mediated a ctivation of gene expression by prostacyclin analogues was specific fo r PPAR and was not observed using other members of the superfamily. No activation of gene expression was induced by other prostaglandins or leukotrienes at concentrations 100-fold higher than those of the prost acyclin analogues. Induction of gene expression by prostacyclin analog ues was inhibited in cells transfected with the long-chain-acyl-CoA sy nthase, indicating that the acidic form of prostacyclin, rather than t he respective CoA derivative or a metabolite derived thereof, serves a s the activator of the PPAR/PPRE transduction pathway. Hence, PPAR-med iated modulation of gene transcription by prostacyclins may form the b asis for their novel role as regulators of gene expression. Xenobiotic hypolipidemic peroxisome proliferators and native long-chain fatty ac ids seem to exploit the PPAR/PPRE transduction pathway used by prostac yclin.