The peroxisome proliferator response element of the gene encoding the peroxisomal beta-oxidation enzyme enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase is a target for constitutive androstane receptor beta/9-cis-retinoicacid 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 d ehydrogenase (HD), contain upstream cis-acting regulatory regions termed pe roxisome proliferator response elements (PPRE), Transcription of these gene s is mediated through the binding of peroxisome proliferator-activated rece ptor 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 i s 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 t o the HD-PPRE occurred via determinants that overlap partially with those r equired for PPAR alpha/RXR alpha binding. In vivo, CAR beta/RXR alpha activ ated transcription from an HD-PPRE luciferase reporter construct, Interesti ngly, CAR beta was shown to also modulate PPAR alpha/RXR alpha-mediated tra nsactivation in a response element-specific manner. In the presence of the peroxisome proliferator, Wy-14,643, CAR beta had no effect on PPAR alpha/RX R alpha-mediated transactivation from the HD-PPRE but antagonized transacti vation from the AOx-PPRE in both the presence and the absence of proliferat or, Our results illustrate that transcription of the AOx and HD genes is di fferentially regulated by CAR beta and that the HD gene is a specific targe t for regulation by CAR beta, Overall, this study proposes a novel role for CAR beta in the regulation of peroxisomal beta-oxidation.