THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR REGULATES MITOCHONDRIAL FATTY-ACID OXIDATIVE ENZYME GENE-EXPRESSION

Medium-chain acyl-CoA dehydrogenase (MCAD) catalyzes a pivotal reactio n in mitochondrial fatty acid (FA) beta-oxidation. To examine the pote ntial 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 palmi toyltransferase I inhibitors to mice or rats resulted in tissue-limite d increases in steady-state MCAD mRNA levels. HepG2 cell cotransfectio n experiments with MCAD promoter reporter plasmids demonstrated that t his was a transcriptional effect mediated by the peroxisome proliferat or-activated receptor (PPAR). The activity mapped to a nuclear recepto r response element that functioned in a heterologous promoter context and specifically bound immunoreactive PPAR in rat hepatic nuclear extr acts, confirming an in vivo interaction. PPAR-mediated transactivation s of this promoter and element were also induced by exogenously added FA and fibric acid derivatives. Induction of PPAR transactivation by p erturbation of this discrete metabolic step is unusual and indicates t hat intracellular FA metabolites that accumulate during such inhibitio n can regulate MCAD expression and are likely candidates for PPAR liga nd(s). These results dictate an expanded role for the PPAR in the regu lation of FA metabolism.