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Papers In Press, published online ahead of print February 17, 2006
J. Lipid Res., doi:10.1194/jlr.M500449-JLR200
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Dept of Medicine, University of Medicine & Dentistry of New Jersey, NJ Medical School, East Orange, NJ 07018-1095
Corresponding Author: xugu{at}umdnj.edu
The transcription of CYP7A1, whose gene product is the rate limiting enzyme for bile acid biosynthesis, a major cholesterol catabolic pathway, is greatly decreased in cholesterol fed rabbits. To determine whether the molecular structure of the promoter is responsible for this down-regulation, we cloned the rabbit CYP7A1 promoter, and studied the effects of a-fetoprotein transcription factor (FTF), liver X receptor (LXRa), short heterodimer partner (SHP) and cholesterol on its transcription. A 1.1 kb 5’-flanking region of rabbit CYP7A1 (promoter) was cloned, and putative binding sites for FTF and LXR were identified. Gel shift assays demonstrated that these sites specifically bound FTF and LXRa/RXR, respectively. Adding LXRa/RXR, together with their ligands (L/R), to the promoter transfected into HepG2 cells greatly increased its activity. When the LXR binding site was mutated, baseline promoter activity was abolished and the stimulatory effect of L/R was absent. FTF did not increase the promoter activity, nor did it enhance the stimulatory effect of L/R. Mutating the FTF binding site also abolished the promoter baseline activity. Adding increasing amounts of SHP abolished the stimulatory effect of L/R and FTF enforced the effect of SHP to decrease promoter activity below baseline levels. Comparison studies showed that rabbit and rat CYP7A1 promoter respond similarly to L/R, FTF and SHP. And, cholesterol did not repress either rabbit or rat CYP7A1 promoter activity. Thus, down regulation of CYP7A1 in cholesterol-fed rabbits is due secondarily to the activation of FXR which increases SHP expression to override the positive effects of LXRa. Although FTF is a competent factor for maintaining baseline activity, it does not further enhance but may suppress CYP7A1 transcription.
Revised on February 1, 2006
Accepted on February 17, 2006
The stimulatory effect of LXR
is blocked by SHP despite the presence of a functional LXR binding site in the rabbit CYP7A1 promoter
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