Orphan nuclear hormone receptor RevErbα modulates expression from the promoter of the hydratase-dehydrogenase gene by inhibiting peroxisome proliferator-activated receptor α-dependent transactivation

Peroxisome proliferator-activated receptor alpha (PPAR alpha) heterodimerizes with the 9-cis-retinoic acid receptor (RXR alpha) to bind to peroxisome proliferator-response elements (PPRE) present in the upstream regions of a number of genes involved in metabolic homeostasis. Among these genes are those encoding fatty acyl-CoA oxidase (AOx) and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase (HD), the first two enzymes of the peroxisomal beta-oxidation pathway. Here we demonstrate that the orphan nuclear hormone receptor, RevErb alpha, modulates PPAR alpha/RXR alpha-dependent transactivation in a response element specific manner. In vitro binding analysis showed that RevErb alpha bound the HD-PPRE but not the AOx-PPRE. Determinants within the HD-PPRE required for RevErb alpha binding were distinct from those required for PPAR alpha/RXR alpha binding. In transient transfections, RevErb alpha antagonized transactivation by PPAR alpha/RXR alpha from an HD-PPRE luciferase reporter construct, whereas no effects were observed with an AOx-PPRE reporter construct. These data identify the HD gene as a target for RevErb alpha and illustrate cross-talk between the RevErb alpha and PPAR alpha signaling pathways on the HD-PPRE. Our results suggest a novel role for RevErb alpha in regulating peroxisomal beta-oxidation.