The murine and human cholesterol 7α-hydroxylase gene promoters are differentially responsive to regulation by fatty acids mediated via peroxisome proliferator-activated receptor α

We determined if fatty acids can regulate the murine Cyp7a1 and human CYP7A1 gene promoters via peroxisome proliferator-activated receptor alpha (PPAR alpha)/9-cis-retinoic acid receptor alpha (RXR alpha). In transfected cells, the murine Cyp7a1 gene promoter displayed markedly lower basal activity, but greater sensitivity to fatty acid-or WY 14,643-activated PPAR alpha/RXR alpha when compared with the human CYP7A1 gene promoter. PPAR alpha/RXR alpha can bind to a site (Site II) located within the region at nucleotides - 158 to -132 of both promoters. Mutagenesis of the human CYP7A1 Site II element abolished the response to activated PPAR alpha/RXR alpha. The murine Cyp7a1 gene promoter contains an additional PPAR/alpha RXR alpha-binding site (Site I) located within nucleotides -72 to -57. Replacement of a single residue in human CYP7A1 Site I with that found in the murine Cyp7a1 Site I sequence enabled PPAR alpha/RXR alpha binding, and this mutation resulted in reduced basal activity, but substantially improved the response to activated PPAR alpha/RXR alpha in transfected cells. We conclude that fatty acids can regulate the cyp7a gene promoter via PPAR alpha/RXR alpha. The differential response of the murine Cyp7a1 and human CYP7A1 gene promoters to PPAR alpha activators is attributable to the additional PPAR alpha/RXR alpha-binding site in the murine Cyp7a1 gene promoter.