The stimulatory effect of LXR alpha is blocked by SHP despite the presence of a LXR alpha binding site in the rabbit CYP7A1 promoter
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
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.
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
Journal Article
<a href="http://doi.org/10.1194/jlr.M500449-JLR200" target="_blank" rel="noreferrer noopener">10.1194/jlr.M500449-JLR200</a>
On the mechanism of bile acid inhibition of rat sterol 12 alpha-hydroxylase gene (CYP8B1) transcription: roles of alpha-fetoprotein transcription factor and hepatocyte nuclear factor 4 alpha
activation; bile acid synthesise; Biochemistry & Molecular Biology; Biophysics; biosynthesis; Cell Biology; cholesterol 7-alpha-hydroxylase gene; Cyp7a1; cytochrome P450; expression; feedback-regulation; gene regulation; liver microsomal metabolism; nuclear receptor; promoter; receptor; repression
The sterol 12alpha-hydroxylase (CYP8B1) is a key enzyme of the bile acid biosynthetic pathway. It regulates the composition of bile acids in bile, i.e. ratio between cholic acid (CA) and chenodeoxycholic acid (CDCA). In similarity with cholesterol 7alpha-hydroxylase (CYP7A1), this enzyme is subjected to a negative feedback regulation by bile acids, It has been recently reported that bile acid-activated famesoid X receptor (FXR) induces the small heterodimer partner (SHP) that interacts with alpha-fetoprotein transcription factor (FTF) and down-regulates CYP7A1 transcription. We studied whether the same mechanism also regulated rat CYP8B1 gene transcription. Feeding rats with CDCA caused a 40-50% decrease of CYP8B1 and hepatocyte nuclear factor 4alpha (HNF4alpha) mRNA expression levels. This was associated with an increase in FTF mRNA expression, but SHP mRNA expression was not altered. Electrophoretic mobility shift assay (EMSA) and transient transfection assay of promoter/reporter genes coupled to mutagenesis analysis identified a putative bile acid response element (BARE) that has an HNF4alpha binding site embedded in two overlapping FTF binding sites. Mutation of the HNF4alpha binding site markedly reduced basal promoter activity and its repression by bile acids. Cotransfection with FTF strongly repressed CYP8B1 transcription. Interestingly, HNF4alpha could overcome the inhibitory effects of FTF and bile acids. We conclude that FTF and HNF4alpha not only play critical roles on CYP8B1 gene transcription, but also mediate bile acid feedback inhibition. This study reveals a novel mechanism by which bile acids inhibit rat CYP8B1 gene transcription by inducing FTF and inhibiting HNF4alpha expression. (C) 2002 Elsevier Science B.V. All rights reserved.
Yang Y Z; Zhang M; Eggertsen G; Chiang J Y L
Biochimica Et Biophysica Acta-Molecular and Cell Biology of Lipids
2002
2002-06
Journal Article
<a href="http://doi.org/10.1016/s1388-1981(02)00186-5" target="_blank" rel="noreferrer noopener">10.1016/s1388-1981(02)00186-5</a>
Bile Synthesis In Rat Models Of Inflammatory Bowel Diseases
acid synthesis; acute-phase response; acute-phase response; bile synthesis; cholesterol 7-alpha hydroxylase; cholesterol 7-alpha-hydroxylase gene; colitis; crohns-disease; experimental; General & Internal Medicine; inflammatory bowel disease; intestinal inflammation; messenger-rna; nitric-oxide; Research & Experimental Medicine; sulfonic-acid; ulcerative-colitis
Dikopoulos N; Schmid R M; Bachem M; Buttenschoen K; Adler G; Chiang J Y L; Weidenbach H
European Journal of Clinical Investigation
2007
2007-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1111/j.1365-2362.2007.01779.x" target="_blank" rel="noreferrer noopener">10.1111/j.1365-2362.2007.01779.x</a>