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

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 or (PPAR alpha), which binds to a PPRE as a heterodimer with the 9-cis-retinoic acid receptor (RXR alpha). Here we demonstrate that the HD-PPRE is also a target for the constitutive androstane receptor beta (CAR beta) In vitro binding analysis showed that CAR beta bound the HD-PPRE, but not the AOx-PPRE, as a heterodimer with RXR alpha, Binding of CAR beta/RXR alpha to the HD-PPRE occurred via determinants that overlap partially with those required for PPAR alpha/RXR alpha binding. In vivo, CAR beta/RXR alpha activated transcription from an HD-PPRE luciferase reporter construct, Interestingly, CAR beta was shown to also modulate PPAR alpha/RXR alpha-mediated transactivation in a response element-specific manner. In the presence of the peroxisome proliferator, Wy-14,643, CAR beta had no effect on PPAR alpha/RXR alpha-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 CAR beta and that the HD gene is a specific target for regulation by CAR beta, Overall, this study proposes a novel role for CAR beta in the regulation of peroxisomal beta-oxidation.