The atypical interaction of peroxisome proliferator-activated receptor alpha with liver X receptor alpha antagonizes the stimulatory effect of their respective ligands on the murine cholesterol 7alpha-hydroxylase gene promoter.
Cholesterol 7alpha-hydroxylase (cyp7a) mediates cholesterol elimination in the liver by catalyzing the first and rate-limiting step in the conversion of cholesterol into bile acids. Peroxisome proliferator-activated receptor alpha (PPARalpha; NR1C1) and liver X receptor alpha (LXRalpha; NR1H3) are two nuclear receptors that stimulate the murine Cyp7a1 gene. Here we report that co-expression of PPARalpha and LXRalpha in hepatoma cells abolishes the stimulation of Cyp7a1 gene promoter in response to their respective agonists. PPARalpha and LXRalpha form an atypical heterodimer that binds to two directly adjacent hexameric sequences localized within overlapping PPARalpha and LXRalpha response elements (termed Site I), antagonizing the interaction of PPARalpha:retinoid X receptor alpha (RXRalpha) or RXRalpha:LXRalpha with the Cyp7a1 gene promoter. Mutations within either hexameric sequences that specifically abolished LXRalpha:PPARalpha heterodimer binding to the murine Cyp7a1 Site I also relieved promoter inhibition. The LXRalpha:PPARalpha heterodimer may be important in coordinating the expression of genes that encode proteins involved in metabolism of fats and cholesterol.
Canadian Institutes of Health Research Group in Molecular and Cell Biology of Lipids and Department of Biochemistry, 328 Heritage Medical Research Centre, University of Alberta, Edmonton, Alberta, Canada.
G Franck
GF
Gbaguidi
Luis B
LB
Agellon
D000818:Animals; D001665:Binding Sites; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D019281:Dimerization; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D000071518:Liver X Receptors; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D057093:Orphan Nuclear Receptors; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D051381:Rats; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism*; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism*; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D047488:Retinoid X Receptors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation; D014212:Tretinoin / Q000031:analogs & derivatives / Q000737:chemistry / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C464754:9-cis-4-oxo-13,14-dihydro-retinoic acid; D004268:DNA-Binding Proteins; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; C000605214:Nr1h3 protein, mouse; C000605215:Nr1h3 protein, rat; D009687:Nuclear Proteins; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; D012097:Repressor Proteins; D047488:Retinoid X Receptors; D014157:Transcription Factors; D014212:Tretinoin; D002790:Cholesterol 7-alpha-Hydroxylase