The stimulatory effect of LXRα is blocked by SHP despite the presence of a LXRα binding site in the rabbit CYP7A1 promoter

The transcription of the cholesterol 7a-hydroxy- lase gene (CYP7A1) is greatly decreased in cholesterol-fed rabbits. To determine whether the molecular structure of the promoter is responsible for this downregulation, we cloned the rabbit CYP7A1 promoter, identified the binding sites for a-fetoprotein transcription factor (FTF) and liver X receptor (LXRa), and studied the effects of FTF, LXRa, and SHP on its transcription. Adding LXRa/retinoid X receptor together with their ligands (L/R) to the promoter/ reporter construct transfected into HepG2 cells greatly in- creased its activity. FTF did not increase promoter activity, nor did it enhance the stimulatory effect of L/R. Mutating the FTF binding site abolished the promoter baseline activ- ity. Increasing amounts of SHP abolished the effect of L/R, and FTF enhanced the ability of SHP to decrease promoter activity below baseline levels. Thus, downregulation of CYP7A1 in cholesterol-fed rabbits is attributable secondarily to the activation of farnesoid X receptor, which increases SHP expression to override the positive effects of LXRa. Al- though FTF is a competent factor for maintaining baseline activity, it does not further enhance and may suppress CYP7A1 transcription.—Shang, Q., L. Pan, M. Saumoy, J. Y. L. Chiang, G. S. Tint, G. Salen, and G. Xu. The stimulatory effect of LXRa is blocked by SHP despite the presence of a LXRa binding site in the rabbit CYP7A1 promoter. J. Lipid Res. 2006. 47: 997-1004.