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

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

Shang Q; Pan L X; Saumoy M; Chiang J Y L; Tint G S; Salen G; Xu G R

Journal of Lipid Research

2006

2006-05

The transcription of the cholesterol 7 alpha-hydroxylase 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 (LXR alpha), and studied the effects of FTF, LXR alpha, and SHP on its transcription. Adding LXR alpha/retinoid X receptor together with their ligands (L/R) to the promoter/reporter construct transfected into HepG2 cells greatly increased 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 activity. 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 LXR alpha. Although FFF is a competent factor for maintaining baseline activity, it does not further enhance and may suppress CYP7A1 transcription.

alpha-fetoprotein transcription; bile-acid biosynthesis; Biochemistry & Molecular Biology; cholesterol 7 alpha-hydroxylase; cholesterol 7-alpha-hydroxylase gene; dietary-cholesterol; dietary-cholesterol; factor; farnesoid X receptor; farnesoid X receptor; inhibition; liver X receptor; messenger-rna levels; nuclear receptor; orphan; rat; SHP; taurocholate; transcription

Journal Article

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