Orphan nuclear hormone receptor RevErbalpha modulates expression from the promoter of the hydratase-dehydrogenase gene by inhibiting peroxisome proliferator-activated receptor alpha-dependent transactivation.
Peroxisome proliferator-activated receptor alpha (PPARalpha) heterodimerizes with the 9-cis-retinoic acid receptor (RXRalpha) 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, RevErbalpha, modulates PPARalpha/RXRalpha- dependent transactivation in a response element-specific manner. In vitro binding analysis showed that RevErbalpha bound the HD-PPRE but not the AOx-PPRE. Determinants within the HD-PPRE required for RevErbalpha binding were distinct from those required for PPARalpha/RXRalpha binding. In transient transfections, RevErbalpha antagonized transactivation by PPARalpha/RXRalpha 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 RevErbalpha and illustrate cross-talk between the RevErbalpha and PPARalpha signaling pathways on the HD-PPRE. Our results suggest a novel role for RevErbalpha in regulating peroxisomal beta-oxidation.
Kassam
A
A
Department of Cell Biology, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
Capone
J P
JP
Rachubinski
R A
RA
D015094:3-Hydroxyacyl CoA Dehydrogenases / Q000096:biosynthesis / Q000235:genetics*; D042962:Acyl-CoA Oxidase; D000818:Animals; D004268:DNA-Binding Proteins; D004746:Enoyl-CoA Hydratase / Q000096:biosynthesis / Q000235:genetics*; D017930:Genes, Reporter; D006801:Humans; D007535:Isomerases; D008156:Luciferases / Q000096:biosynthesis / Q000235:genetics; D008830:Microbodies / Q000378:metabolism; D009097:Multienzyme Complexes / Q000096:biosynthesis / Q000235:genetics*; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000235:genetics; D063994:Peroxisomal Bifunctional Enzyme; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D020239:Receptor Cross-Talk; D018160:Receptors, Cytoplasmic and Nuclear / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; D009097:Multienzyme Complexes; C064353:NR1D1 protein, human; C498263:Nr1d1 protein, rat; D056953:Nuclear Receptor Subfamily 1, Group D, Member 1; D011506:Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D010088:Oxidoreductases; D015094:3-Hydroxyacyl CoA Dehydrogenases; D008156:Luciferases; D042962:Acyl-CoA Oxidase; C576253:EHHADH protein, human; D004746:Enoyl-CoA Hydratase; D063994:Peroxisomal Bifunctional Enzyme; D007535:Isomerases