TY - JOUR
T1 - Activation of gene transcription by prostacyclin analogues is mediated by the peroxisome-proliferators-activated receptor (PPAR)
AU - Hertz, Rachel
AU - Berman, Ina
AU - Keppler, Dietrich
AU - Bar-Tana, Jacob
PY - 1996
Y1 - 1996
N2 - Xenobiotic amphipathic carboxylates, known collectively as hypolipidemic peroxisome proliferators (e.g., aryloxyalkanoic acids), or native long-chain fatty acids induce liver peroxisome proliferation and other biological activities. This broad spectrum of effects results from modulation of transcription of specific genes mediated by binding of peroxisome-proliferators-activated receptors (PPAR) to respective sequence-specific promoter elements (PPRE). The broad specificity and relatively low potency of reported hypolipidemic peroxisome proliferators prompted us to search for specific highly potent peroxisome proliferators. Here we report that stable prostacyclin analogues may act in such a manner. mPPARα-mediated expression of a reporter gene linked to the peroxisomal rat acyl-CoA oxidase promoter was dose-dependently induced by carbaprostacyclin and iloprost. The ED50 for carbaprostacyclin was 25 nM, and carbaprostacyclin was therefore 25-fold and 200-fold more effective than the most potent xenobiotic (5,18,11,14-eicosatetraynoic acid) and native (arachidonic acid) inducers, respectively. Induction was further increased by cotransfecting the cells with mPPARα and an expression vector for retinoic acid-X-receptor. PPAR-mediated activation of gene expression by prostacyclin analogues was specific for 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 prostacyclin analogues. Induction of gene expression by prostacyclin analogues was inhibited in cells transfected with the long-chain-acyl-CoA synthase, indicating that the acidic form of prostacyclin, rather than the respective CoA derivative or a metabolite derived thereof, serves as the activator of the PPAR/PPRE transduction pathway. Hence, PPAR-mediated modulation of gene transcription by prostacyclins may form the basis for their novel role as regulators of gene expression. Xenobiotic hypolipidemic peroxisome proliferators and native long-chain fatty acids seem to exploit the PPAR/PPRE transduction pathway used by prostacyclin.
AB - Xenobiotic amphipathic carboxylates, known collectively as hypolipidemic peroxisome proliferators (e.g., aryloxyalkanoic acids), or native long-chain fatty acids induce liver peroxisome proliferation and other biological activities. This broad spectrum of effects results from modulation of transcription of specific genes mediated by binding of peroxisome-proliferators-activated receptors (PPAR) to respective sequence-specific promoter elements (PPRE). The broad specificity and relatively low potency of reported hypolipidemic peroxisome proliferators prompted us to search for specific highly potent peroxisome proliferators. Here we report that stable prostacyclin analogues may act in such a manner. mPPARα-mediated expression of a reporter gene linked to the peroxisomal rat acyl-CoA oxidase promoter was dose-dependently induced by carbaprostacyclin and iloprost. The ED50 for carbaprostacyclin was 25 nM, and carbaprostacyclin was therefore 25-fold and 200-fold more effective than the most potent xenobiotic (5,18,11,14-eicosatetraynoic acid) and native (arachidonic acid) inducers, respectively. Induction was further increased by cotransfecting the cells with mPPARα and an expression vector for retinoic acid-X-receptor. PPAR-mediated activation of gene expression by prostacyclin analogues was specific for 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 prostacyclin analogues. Induction of gene expression by prostacyclin analogues was inhibited in cells transfected with the long-chain-acyl-CoA synthase, indicating that the acidic form of prostacyclin, rather than the respective CoA derivative or a metabolite derived thereof, serves as the activator of the PPAR/PPRE transduction pathway. Hence, PPAR-mediated modulation of gene transcription by prostacyclins may form the basis for their novel role as regulators of gene expression. Xenobiotic hypolipidemic peroxisome proliferators and native long-chain fatty acids seem to exploit the PPAR/PPRE transduction pathway used by prostacyclin.
KW - eicosanoids
KW - peroxisome proliferators
KW - peroxisome-proliferators-activated receptor
KW - prostacyclin
KW - transcription
UR - http://www.scopus.com/inward/record.url?scp=0030069325&partnerID=8YFLogxK
U2 - 10.1111/j.1432-1033.1996.00242.x
DO - 10.1111/j.1432-1033.1996.00242.x
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C2 - 8631336
AN - SCOPUS:0030069325
SN - 0014-2956
VL - 235
SP - 242
EP - 247
JO - European Journal of Biochemistry
JF - European Journal of Biochemistry
IS - 1-2
ER -