Gulick T, Cresci S, Caira T, Moore D D, Kelly D P
Department of Molecular Biology, Massachusetts General Hospital, Boston.
Proc Natl Acad Sci U S A. 1994 Nov 8;91(23):11012-6. doi: 10.1073/pnas.91.23.11012.
Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes a pivotal reaction in mitochondrial fatty acid (FA) beta-oxidation. To examine the potential role of FAs and their metabolites in the regulation of MCAD gene expression, we measured MCAD mRNA levels in animals fed inhibitors of mitochondrial long-chain FA import. Administration of carnitine palmitoyltransferase I inhibitors to mice or rats resulted in tissue-limited increases in steady-state MCAD mRNA levels. HepG2 cell cotransfection experiments with MCAD promoter reporter plasmids demonstrated that this was a transcriptional effect mediated by the peroxisome proliferator-activated receptor (PPAR). The activity mapped to a nuclear receptor response element that functioned in a heterologous promoter context and specifically bound immunoreactive PPAR in rat hepatic nuclear extracts, confirming an in vivo interaction. PPAR-mediated transactions of this promoter and element were also induced by exogenously added FA and fibric acid derivatives. Induction of PPAR transactivation by perturbation of this discrete metabolic step is unusual and indicates that intracellular FA metabolites that accumulate during such inhibition can regulate MCAD expression and are likely candidates for PPAR ligand(s). These results dictate an expanded role for the PPAR in the regulation of FA metabolism.
中链酰基辅酶A脱氢酶（MCAD）催化线粒体脂肪酸（FA）β-氧化中的关键反应。为了研究脂肪酸及其代谢产物在MCAD基因表达调控中的潜在作用，我们测定了喂食线粒体长链脂肪酸导入抑制剂的动物体内MCAD mRNA水平。给小鼠或大鼠施用肉碱棕榈酰转移酶I抑制剂会导致稳态MCAD mRNA水平在组织中有局限性的升高。用MCAD启动子报告质粒进行的HepG2细胞共转染实验表明，这是一种由过氧化物酶体增殖物激活受体（PPAR）介导的转录效应。该活性定位于一个核受体反应元件，该元件在异源启动子环境中起作用，并能特异性结合大鼠肝核提取物中的免疫反应性PPAR，证实了体内的相互作用。外源性添加的脂肪酸和贝特类衍生物也能诱导该启动子和元件的PPAR介导的作用。通过干扰这一特定代谢步骤来诱导PPAR反式激活是不寻常的，这表明在这种抑制过程中积累的细胞内脂肪酸代谢产物可以调节MCAD表达，并且很可能是PPAR配体的候选物。这些结果表明PPAR在脂肪酸代谢调控中具有更广泛的作用。
