TRANSCRIPTIONAL ACTIVATION BY AMPHIPATHIC CARBOXYLIC PEROXISOMAL PROLIFERATORS IS INDUCED BY THE FREE ACID RATHER THAN THE ACYL-COA DERIVATIVE

Most peroxisomal proliferators consist of a carboxylic group attached to a hydrophobic backbone yielding an amphipathic carboxylate molecule . The respective CoA derivatives of peroxisomal proliferators, formed by ATP-dependent CoA thioesterification catalyzed by long-chain-acyl-C oA synthase, have been repeatedly considered as the immediate inducers of peroxisome and other genes. In this study, the putative requiremen t for prior CoA thioesterification of peroxisomal proliferators was ev aluated by analyzing the induced expression of a reporter plasmid prom oted by the peroxisomal acyl-CoA-oxidase promoter in cells transiently cotransfected with expression vectors for the peroxisome-proliferator -activated receptor and the long-chain-acyl-CoA synthase. Transcriptio nal activation of peroxisomal acyl-CoA oxidase by peroxisomal prolifer ators was inhibited in the presence of transfected functional acyl-CoA synthase. The inhibitory effect was negatively correlated with the ca pacity of the acyl-CoA synthase to catalyze CoA thioesterification of the respective proliferator. Hence, the immediate inducer is the perox isomal proliferator free acid rather than the respective CoA derivativ e or a metabolite derived from the peroxisomal-proliferator-CoA interm ediate.