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)

Hydrophobic bile acids strongly repressed transcription of the human cholesterol 7alpha-hydroxylase gene (CYP7A1) in the bile acid biosynthetic pathway in the liver. Farnesoid X receptor (FXR) repressed CYP7A1/Luc reporter activity in a transfection assay in human liver-derived HepG2 cells, but not in human embryonic kidney (HEK) 293 cells. FXR-binding activity was required for bile acid repression of CYP7A1 transcription despite the fact that FXR did not bind to the CYP7A1 promoter. FXR-induced liver-specific factors must be required for mediating bile acid repression. Bile acids and FXR repressed endogenous CYP7A1 but stimulated alpha-fetoprotein transcription factor (FTF) and small heterodimer partner (SHP) mRNA expression in HepG2 cells. Feeding of rats with chenodeoxycholic acid repressed CYP7A1, induced FTF, but had no effect on SHP mRNA expression in the liver. FTF strongly repressed CYP7A1 transcription in a dose-dependent manner, and SHP further inhibited CYP7A1 in HepG2 cells, but not in HEK 293 cells. FXR only moderately stimulated SHP transcription, whereas FTF strongly inhibited SHP transcription in HepG2 cells. Results revealed that FTF was a dominant negative factor that was induced by bile acid-activated FXR to inhibit both CYP7A1 and SHP transcription. Differential regulation of FTF and SHP expression by bile acids may explain the wide variation in CYP7A1 expression and the rate of bile acid synthesis and regulation in different species.
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PMID:Nuclear receptor-mediated repression of human cholesterol 7alpha-hydroxylase gene transcription by bile acids. 1151 59

The Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily that has been shown to play an important role in bile acid and cholesterol homeostasis. Here we identify four murine FXR transcripts, derived from a single gene, that encode four isoforms, FXRalpha1, FXRalpha2, FXRbeta1, and FXRbeta2. FXRalpha and FXRbeta differ at their amino terminus, and FXRalpha1 and FXRbeta1 have a four-amino acid residue insertion in the hinge region immediately adjacent to the DNA binding domain. Real time PCR and 5'-rapid amplification of cDNA ends followed by Southern blotting reveal that these four transcripts are expressed differentially in liver, intestine, kidney, adrenals, stomach, fat, and heart. Electrophoretic mobility shift assays demonstrate that FXRalpha2 and FXRbeta2 bind to FXR response elements with a higher affinity as compared with FXRalpha1 and FXRbeta1, suggesting that the four-amino acid insert may affect FXR function. Consistent with this idea, the results of transient transfection experiments demonstrate that the four FXR isoforms differentially transactivated a number of promoter-reporter genes; activation of an ileal bile acid-binding protein promoter-reporter gene varied 20-fold depending on the FXR isoform; the rank order of activation was FXRbeta2 > FXRalpha2 FXRalpha1 = FXRbeta1. In contrast, SHP reporter or BSEP reporter genes were activated to similar degrees by each of the FXR isoforms. Finally, NIH3T3 cells were stably infected with individual murine FXR isoforms, and the cells were treated with FXR ligands. The endogenous ileal bile acid-binding protein gene was activated by the four FXR isoforms with the same rank order as seen in transfections. This effect was gene-specific, since induction of bile salt export pump mRNA was independent of the FXR isoform. These observations suggest that there are four distinct murine FXR isoforms that differentially regulate gene expression in numerous tissues in vivo.
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PMID:Natural structural variants of the nuclear receptor farnesoid X receptor affect transcriptional activation. 1239 83

Recent studies have elucidated the mechanism and regulation of hepatic transport of bile acids and organic anions. Bile acids are taken up into hepatocytes by basolateral transporters, Na+-dependently by Na+/taurocholate cotransporting polypeptide (NTCP) and Na+-independently by organic anion transporting polypeptide (OATP) families. Organic anions are taken up into hepatocytes by OATP families. These compounds are then transported in hepatocytes bound to cytosolic binders, and subjected to transport by ATP binding cassette (ABC) transporters at the canalicular membrane. Amidated bile acids are excreted into bile by bile salt export pump (BSEP), and organic anions and bile acid sulfates and glucuronides are excreted by multidrug resistance protein 2 (MRP2). Hepatic transporters are downregulated under cholestasis in rats and humans, except for MRP3, a basolateral ABC transporter, which is upregulated and may have a role in removing bile acids and organic anions from hepatocytes to the blood under cholestatic conditions. Nuclear receptors, which bind bile acids, have been shown to regulate the expression of hepatic transporters. Farnesoid X receptor (FXR), which downregulates CYP7A1, the rate-limiting enzyme of bile acid biosynthesis, upregulates BSEP and downregulates NTCP. MRP2 is upregulated by both FXR and pregnane X receptor (PXR), which upregulates CYP3A.
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PMID:Hepatobiliary transport of bile acids and organic anions. 1248 66

Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls lipid and glucose metabolism and exerts antiinflammatory activities. PPARalpha is also reported to influence bile acid formation and bile composition. Farnesoid X receptor (FXR) is a bile acid-activated nuclear receptor that mediates the effects of bile acids on gene expression and plays a major role in bile acid and possibly also in lipid metabolism. Thus, both PPARalpha and FXR appear to act on common metabolic pathways. To determine the existence of a molecular cross-talk between these two nuclear receptors, the regulation of PPARalpha expression by bile acids was investigated. Incubation of human hepatoma HepG2 cells with the natural FXR ligand chenodeoxycholic acid (CDCA) as well as with the nonsteroidal FXR agonist GW4064 resulted in a significant induction of PPARalpha mRNA levels. In addition, hPPARalpha gene expression was up-regulated by taurocholic acid in human primary hepatocytes. Cotransfection of FXR/retinoid X receptor in the presence of CDCA led to up to a 3-fold induction of human PPARalpha promoter activity in HepG2 cells. Mutation analysis identified a FXR response element in the human PPARalpha promoter (alpha-FXR response element (alphaFXRE)] that mediates bile acid regulation of this promoter. FXR bound the alphaFXRE site as demonstrated by gel shift analysis, and CDCA specifically increased the activity of a heterologous promoter driven by four copies of the alphaFXRE. In contrast, neither the murine PPARalpha promoter, in which the alphaFXRE is not conserved, nor a mouse alphaFXRE-driven heterologous reporter, were responsive to CDCA treatment. Moreover, PPARalpha expression was not regulated in taurocholic acid-fed mice. Finally, induction of hPPARalpha mRNA levels by CDCA resulted in an enhanced induction of the expression of the PPARalpha target gene carnitine palmitoyltransferase I by PPARalpha ligands. In concert, these results demonstrate that bile acids stimulate PPARalpha expression in a species-specific manner via a FXRE located within the human PPARalpha promoter. These results provide molecular evidence for a cross-talk between the FXR and PPARalpha pathways in humans.
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PMID:Bile acids induce the expression of the human peroxisome proliferator-activated receptor alpha gene via activation of the farnesoid X receptor. 1255 53

Farnesoid X receptor (FXR) is a bile acid sensor that regulates lipid homeostasis. New structural data suggest that, unlike other nuclear receptors, FXR contains a second coactivator binding site and binds bile acids with the steroid backbone flipped head to tail, both of which have important functional ramifications.
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PMID:Nuclear receptor ligands and cofactor recruitment: is there a coactivator "on deck"? 1271 92

Farnesoid X receptor (FXR) is a bile acid-activated transcription factor that is a member of the nuclear hormone receptor superfamily. Fxr-null mice exhibit a phenotype similar to Byler disease, an inherited cholestatic liver disorder. In the liver, activation of FXR induces transcription of transporter genes involved in promoting bile acid clearance and represses genes involved in bile acid biosynthesis. We investigated whether the synthetic FXR agonist GW4064 could protect against cholestatic liver damage in rat models of extrahepatic and intrahepatic cholestasis. In the bile duct-ligation and alpha-naphthylisothiocyanate models of cholestasis, GW4064 treatment resulted in significant reductions in serum alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase, as well as other markers of liver damage. Rats that received GW4064 treatment also had decreased incidence and extent of necrosis, decreased inflammatory cell infiltration, and decreased bile duct proliferation. Analysis of gene expression in livers from GW4064-treated cholestatic rats revealed decreased expression of bile acid biosynthetic genes and increased expression of genes involved in bile acid transport, including the phospholipid flippase MDR2. The hepatoprotection seen in these animal models by the synthetic FXR agonist suggests FXR agonists may be useful in the treatment of cholestatic liver disease.
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PMID:Hepatoprotection by the farnesoid X receptor agonist GW4064 in rat models of intra- and extrahepatic cholestasis. 1523 10

Farnesoid X receptor (FXR) is a nuclear receptor for bile acids. Ligand activated-FXR regulates transcription of genes to allow feedback control of bile acid synthesis and secretion. There are five major bile acids in humans. We have previously demonstrated that lithocholate acts as an FXR antagonist, and here we show that the other four bile acids, chenodeoxycholate (CDCA), deoxycholate (DCA), cholate (CA), and ursodeoxycholate (UDCA), act as selective FXR agonists in a gene-specific fashion. In an in vitro coactivator association assay, CDCA fully activated FXR, whereas CA partially activated FXR and DCA and UDCA had negligible activities. Similar results were also obtained from a glutathione S-transferase pull-down assay in which only CDCA and the synthetic FXR agonist GW4064 significantly increased the interaction of SRC-1 with FXR. In FXR transactivation assays with a bile salt export pump (BSEP) promoter-driven luciferase construct, bile acids showed distinct abilities to activate the BSEP promoter: CDCA, DCA, CA, and UDCA increased luciferase activity by 25-, 20-, 18-, and 8-fold, respectively. Consistently, CDCA increased BSEP mRNA by 750-fold in HepG2 cells, whereas DCA, CA, and UDCA induced BSEP mRNA by 250-, 75-, and 15-fold, respectively. Despite the partial induction of BSEP mRNA, CA, DCA, and UDCA effectively repressed expression of cholesterol 7alpha-hydroxylase, another FXR target. We further showed that all four bile acids significantly increased FXR protein, suggesting the existence of an auto-regulatory loop in FXR signaling pathways. In conclusion, these results suggest that the binding of each bile acid results in a different FXR conformations, which in turn differentially regulates expression of individual FXR targets.
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PMID:The farnesoid X receptor controls gene expression in a ligand- and promoter-selective fashion. 1468 51

Farnesoid X receptor (FXR) was identified as a bile acid receptor for regulation of bile acid biosynthesis and cholesterol metabolism. FXR became a potential therapeutic target for lowering serum cholesterol and certain cardiovascular and liver diseases. In this review, the discovery of FXR, its roles in regulating bile acid and cholesterol metabolism and its application in cardiovascular disease will be summarized.
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PMID:[On the bile acid receptor FXR]. 1499 12

Farnesoid X receptor (FXR) is a bile acid sensor that regulates the expression of a number of genes the products of which control bile acid and cholesterol homeostasis; however, the role of DRIP205 in FXR-mediated gene regulation remains unexplored. In this study we demonstrate that DRIP205 binds FXR in a ligand-dependent manner in vitro and in vivo. Glutathione S-transferase pull-down assays showed that DRIP205 binds FXR in response to bile acid ligands in a dose-dependent fashion and that the potency of this interaction is associated with the ability of the ligand to activate FXR. In addition, the FXR-DRIP205 interaction required the presence of an intact LXXLL nuclear receptor box 1 (N-terminal) motif of DRIP205. In gel shift assays FXR was also able to recruit DRIP205 in the context of a DNA-bound FXR/RXR (retinoid X receptor) heterodimer. In transient transfection assays, DRIP205 efficiently enhanced a bile acid-activated FXRE-driven reporter gene in a dose-dependent manner in cells overexpressing FXR/RXR, demonstrating that DRIP205 enhances FXR-mediated transactivation. By contrast, an FXRW469A mutant in the activation function 2 domain that does not bind to DRIP205 was unable to activate ligand-stimulated FXR transcription, indicating that DRIP205 is recruited to activation function 2 of FXR. Requirement for the FXR/RXR heterodimer in the DRIP205-FXR interaction was evaluated using an RXR heterodimerization-deficient FXR mutant (FXRL433R). FXRL433R was not able to bind to DRIP205 and failed to enhance an FXRE-driven reporter gene. In addition, DRIP205 was unable to induce FXR-mediated transactivation in the absence of RXR overexpression, indicating that FXR heterodimerization with RXR is required for coactivation by DRIP205. Finally, in HepG2 cells, overexpression or reduction of DRIP205 levels modulated the induction of endogenous FXR target gene mRNA expression by ligand. Together, these results demonstrate that DRIP205 acts as a bona fide coactivator of FXR and underscore the importance of DRIP205 in modulating the bile acid response of FXR target genes.
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PMID:Identification of DRIP205 as a coactivator for the Farnesoid X receptor. 1518 81

Farnesoid X receptor (FXR) is a transcription factor that controls bile acid homeostasis. The phenotype of Fxr null mice is characterized by hypercholanaemia, impaired secretion of bile acids and failure to thrive. Human disorders with these characteristics include FIC1 disease (caused by mutations in ATP8B1, which encodes a putative aminophospholipid translocase, FIC1, whose function in bile handling is unknown) and bile salt export pump (BSEP) disease (caused by mutation in ABCB11, which encodes BSEP, the primary canalicular bile salt export pump). We investigated the possibility of hepatic down-regulation of FXR in FIC1 disease and BSEP disease. Three siblings with this phenotype, born to consanguine parents, were initially studied. The children were demonstrated to be compound heterozygotes for missense and nonsense mutations in ATP8B1. Expression of specific genes in liver was analysed, comparing one of these siblings with a child homozygous for missense mutation in ABCB11, as well as with a child having idiopathic cholestatic liver disease, a child with extrahepatic biliary atresia and a normal organ donor. The expression of two main FXR isoforms was specifically decreased in the liver of the FIC1 disease patient. A consistent and concomitant reduction in messenger RNA levels of FXR targets, such as BSEP and small heterodimer partner, was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in FIC1-disease liver. Of note was that several genes involved in synthesis, conjugation and transport of bile acids were down-regulated. A cluster of genes involved in lipid metabolism was also differentially expressed. Our findings suggest that hepatic down-regulation of FXR contributes to the severe cholestasis of FIC1 disease.
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PMID:Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1. 1531 49


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