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-CoA synthase, have been repeatedly considered as the immediate inducers of peroxisome and other genes. In this study, the putative requirement for prior CoA thioesterification of peroxisomal proliferators was evaluated by analyzing the induced expression of a reporter plasmid promoted 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. Transcriptional activation of peroxisomal acyl-CoA oxidase by peroxisomal proliferators was inhibited in the presence of transfected functional acyl-CoA synthase. The inhibitory effect was negatively correlated with the capacity of the acyl-CoA synthase to catalyze CoA thioesterification of the respective proliferator. Hence, the immediate inducer is the peroxisomal proliferator free acid rather than the respective CoA derivative or a metabolite derived from the peroxisomal-proliferator-CoA intermediate.