The Peroxisome Proliferator Response Element of the Gene Encoding the Peroxisomal β-Oxidation Enzyme Enoyl-CoA Hydratase/3-Hydroxyacyl-CoA Dehydrogenase Is a Target for Constitutive Androstane Receptor β/9-cis-Retinoic Acid Receptor-mediated Transactivation

Abstract

The genes encoding the first two enzymes of the peroxisomal beta-oxidation pathway, acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), contain upstream cis-acting regulatory regions termed peroxisome proliferator response elements (PPRE). Transcription of these genes is mediated through the binding of peroxisome proliferator-activated receptor alpha (PPARalpha), which binds to a PPRE as a heterodimer with the 9-cis-retinoic acid receptor (RXRalpha). Here we demonstrate that the HD-PPRE is also a target for the constitutive androstane receptor beta (CARbeta). In vitro binding analysis showed that CARbeta bound the HD-PPRE, but not the AOx-PPRE, as a heterodimer with RXRalpha. Binding of CARbeta/RXRalpha to the HD-PPRE occurred via determinants that overlap partially with those required for PPARalpha/RXRalpha binding. In vivo, CARbeta/RXRalpha activated transcription from an HD-PPRE luciferase reporter construct. Interestingly, CARbeta was shown to also modulate PPARalpha/RXRalpha-mediated transactivation in a response element-specific manner. In the presence of the peroxisome proliferator, Wy-14,643, CARbeta had no effect on PPARalpha/RXRalpha-mediated transactivation from the HD-PPRE but antagonized transactivation from the AOx-PPRE in both the presence and the absence of proliferator. Our results illustrate that transcription of the AOx and HD genes is differentially regulated by CARbeta and that the HD gene is a specific target for regulation by CARbeta. Overall, this study proposes a novel role for CARbeta in the regulation of peroxisomal beta-oxidation.