Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:B6ZGS9 (Farnesoid X receptor)
 212 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nuclear receptors are ligand-dependent transcription factors that recently have been shown to play important roles in the metabolism of cholesterol and bile acids. Cholesterol homeostasis is maintained by de novo synthesis, absorption from diet, catabolism to bile acids and other steroids, and excretion into bile. Dysregulation of this mechanism leads to atherosclerosis and its life-threatening coronary and cerebrovascular sequelae. Conversion of cholesterol to bile acids in the liver is positively regulated by liver X receptor (LXR) alpha, a nuclear receptor for oxysterols. LXRalpha and LXRbeta, a second oxysterol receptor, regulate intestinal absorption and biliary excretion of cholesterol by inducing target gene expression. LXRs stimulate reverse cholesterol transport from peripheral tissues and exhibit antiatherogenic activity. Farnesoid X receptor (FXR), a bile acid receptor, represses bile acid synthesis and import in hepatocytes, stimulates bile acid export from cells, and protects hepatocytes from bile acid toxicity. Pregnane X receptor (PXR) and vitamin D receptor (VDR) respond to secondary bile acids and induce their catabolism. Thus, nuclear receptors play important roles in regulation of cholesterol and bile acid metabolism.
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PMID:Nuclear receptors as targets for drug development: regulation of cholesterol and bile acid metabolism by nuclear receptors. 1572 1

As previously reported by us, mice with targeted disruption of the CYP8B1 gene (CYP8B1-/-) fail to produce cholic acid (CA), upregulate their bile acid synthesis, reduce the absorption of dietary cholesterol and, after cholesterol feeding, accumulate less liver cholesterol than wild-type (CYP8B1+/+) mice. In the present study, cholesterol-enriched diet (0.5%) or administration of a synthetic liver X receptor (LXR) agonist strongly upregulated CYP7A1 expression in CYP8B1-/- mice, compared to CYP8B1+/+ mice. Cholesterol-fed CYP8B1-/- mice also showed a significant rise in HDL cholesterol and increased levels of liver ABCA1 mRNA. A combined CA (0.25%)/cholesterol (0.5%) diet enhanced absorption of intestinal cholesterol in both groups of mice, increased their liver cholesterol content, and reduced their expression of CYP7A1 mRNA. The ABCG5/G8 liver mRNA was increased in both groups of mice, but cholesterol crystals were only observed in bile from the CYP8B1+/+ mice. The results demonstrate the cholesterol-sparing effects of CA: enhanced absorption and reduced conversion into bile acids. Farnesoid X receptor (FXR)-mediated suppression of CYP7A1 in mice seems to be a predominant mechanism for regulation of bile acid synthesis under normal conditions and, as confirmed, able to override LXR-mediated mechanisms. Interaction between FXR- and LXR-mediated stimuli might also regulate expression of liver ABCG5/G8.
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PMID:Studies on LXR- and FXR-mediated effects on cholesterol homeostasis in normal and cholic acid-depleted mice. 1626 96