Hertz R, Berman I, Keppler D, Bar-Tana J
Department of Human Nutrition and Metabolism, Hebrew University, Jerusalem, Israel.
Eur J Biochem. 1996 Jan 15;235(1-2):242-7. doi: 10.1111/j.1432-1033.1996.00242.x.
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. mPPAR alpha-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 mPPAR alpha 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.
外源性两亲性羧酸盐，统称为降血脂过氧化物酶体增殖剂（如芳氧基链烷酸），或天然长链脂肪酸可诱导肝脏过氧化物酶体增殖及其他生物学活性。这种广泛的效应源于过氧化物酶体增殖物激活受体（PPAR）与各自的序列特异性启动子元件（PPRE）结合介导的特定基因转录调控。已报道的降血脂过氧化物酶体增殖剂的广泛特异性和相对较低的效力促使我们寻找特异性高效的过氧化物酶体增殖剂。在此我们报道稳定的前列环素类似物可能以这种方式发挥作用。与过氧化物酶体大鼠酰基辅酶A氧化酶启动子相连的报告基因的mPPARα介导的表达受卡前列环素和伊洛前列素剂量依赖性诱导。卡前列环素的ED50为25 nM，因此卡前列环素分别比最有效的外源性诱导剂（5,18,11,14 - 二十碳四烯酸）和天然诱导剂（花生四烯酸）有效25倍和200倍。通过用mPPARα和视黄酸X受体的表达载体共转染细胞，诱导作用进一步增强。前列环素类似物通过PPAR介导的基因表达激活对PPAR具有特异性，使用超家族的其他成员未观察到这种激活。在比前列环素类似物浓度高100倍的情况下，其他前列腺素或白三烯未诱导基因表达激活。在转染了长链酰基辅酶A合成酶的细胞中，前列环素类似物对基因表达的诱导受到抑制，这表明前列环素的酸性形式而非相应的辅酶A衍生物或其衍生的代谢物作为PPAR/PPRE转导途径的激活剂。因此，前列环素通过PPAR介导的基因转录调控可能构成其作为基因表达调节剂新作用的基础。外源性降血脂过氧化物酶体增殖剂和天然长链脂肪酸似乎利用了前列环素所使用的PPAR/PPRE转导途径。
