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