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)

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 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) 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

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

Farnesoid X receptor (FXR) is a nuclear receptor involved in lipoprotein as well as glucose metabolism. Statins are widely used hypolipidemic agents with many pleiotropic actions. It is known that statins affect other nuclear hormone receptors, but no reports are available on the effect of these drugs on FXR. Employing an animal model (Syrian hamsters), we hereby present evidence to demonstrate that Simvastatin, a broadly prescribed statin, decreases the expression of FXR at both the RNA and protein levels and down-regulates its DNA-binding activity. This novel property may have important implications on the mode statins influence on lipoprotein and carbohydrate homeostasis in the organism.
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PMID:Statins and transcriptional regulation: the FXR connection. 1600 43

Bile acids are the end products of cholesterol metabolism. They are synthesized in the liver and secreted via bile into the intestine, where they aid in the absorption of fat-soluble vitamins and dietary fat. Subsequently, bile acids return to the liver to complete their enterohepatic circulation. The Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and has emerged as a key player in the control of multiple metabolic pathways. On its activation by bile acids, FXR regulates bile acid synthesis, conjugation, and transport, as well as various aspects of lipid and glucose metabolism. This review summarizes recent advances in deciphering the role of FXR in the context of hepatic lipid and glucose homeostasis and discusses the potential of FXR as a pharmacological target for therapeutic applications.
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PMID:The Farnesoid X receptor: a molecular link between bile acid and lipid and glucose metabolism. 1603 64

Farnesoid X receptor (FXR), the receptor for bile acids, including chenodeoxycholic acid (CDCA), is a member of the nuclear receptor superfamily, which also includes the receptors for retinoic acid, vitamin D (D3), thyroid hormone, thiazolidinedione and 22(R)-hydroxycholesterol. Here, we have evaluated the effects of a series of ligands and their receptors on the promoter activity induced by CDCA/FXR. The kidney cell line, CV1, was cotransfected with FXR-expression plasmid and the luciferase-based reporter gene that has a thymidine kinase promoter fused to the canonical FXR-responsive element or the natural promoter for the small heterodimer partner (SHP), bile salt export pump (BSEP), and ileum bile acid (I-BABP) gene. D3 and its receptor (VDR) inhibited the transactivation of all four reporter constructs that are enhanced by CDCA/FXR. The effect of D3 on the expression of the BSEP and SHP genes in HepG2 cells and that of the I-BABP gene in Caco-2 cells were confirmed by reverse transcription (RT)-PCR. Deletion analysis of VDR revealed that its ligand-binding domain (LBD) is responsible for the repression and the DNA-binding domain (DBD) is dispensable. Specific interaction between FXR and VDR was detected with the in vitro pull-down assay using chimeric FXR or VDR fused to glutathione-S-transferase.
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PMID:1,25-dihydroxyvitamin D3 and its receptor inhibit the chenodeoxycholic acid-dependent transactivation by farnesoid X receptor. 1652 42

Farnesoid X receptor (FXR), a bile-acid-activated member of the nuclear receptor superfamily, is essential in regulating bile-acid, cholesterol, and triglyceride homeostasis. Disruption of the FXR gene in mice results in a proatherosclerotic lipid profile with increased serum cholesterols and triglycerides. However, the role of FXR in foam-cell formation and atherosclerosis development remains unclear. The current study showed that the peritoneal macrophages isolated from FXR-null mice took up less oxidized LDL-cholesterol (oxLDL-C), which was accompanied by a marked reduction in CD36 expression in these cells. This result appears to be FXR-independent, as FXR was not detected in the peritoneal macrophages. To assess to what extent FXR modulates atherosclerosis development, FXR/ApoE double-null mice were generated. Female mice were used for atherosclerosis analysis. Compared to ApoE-null mice, the FXR/ApoE double-null mice were found to have less atherosclerotic lesion area in the aorta, despite a further increase in the serum cholesterols and triglycerides. Our results indicate that disruption of the FXR gene could attenuate atherosclerosis development, most likely resulting from reduced oxLDL-C uptake by macrophages. Our study cautions the use of serum lipid levels as a surrogate marker to determine the efficiency of FXR modulators in treating hyperlipidemia.
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PMID:Effects of FXR in foam-cell formation and atherosclerosis development. 1711 Jan 63

Farnesoid X receptor (FXR) is a metabolic nuclear receptor expressed in the liver and traditionally considered as a bile acid sensor. Yet, FXR has been recently demonstrated in other tissues and cells, such as the kidneys, the adrenals, and arterial smooth muscle cells. Immunohistochemical data reported in this study point to the expression of FXR in human breast cancer. In addition, FXR expression was also found by Western blotting and immunofluorescence microscopy in breast-cancer-derived cell lines MCF-7 (estrogen receptor [ER]-positive) and MDA-MB-231 (ER-negative). The FXR activator farnesol, a mevalonate pathway intermediate, exerts a mitogenic effect on MCF-7 cells. The growth stimulation is completely suppressed by antiestrogens. In contrast, MDA-MB-231 cells appear farnesol-insensitive, suggesting an involvement of ER in farnesol mitogenicity. In accordance with this interpretation, farnesol induces in MCF-7 cells a decrease of ER level, consistent with a phenomenon of receptor downregulation. Farnesol also increases progesterone receptor (PgR) expression in MCF-7 cells and stimulates ER-mediated gene transactivation in MVLN cells (MCF-7 cells stably transfected with an ER reporter gene). Of note, both effects of farnesol on ER expression and activity are completely suppressed by antiestrogens. In addition, farnesol-induced PgR is markedly reduced by FXR gene silencing (siRNA), demonstrating the involvement of FXR in the estrogenic effects of farnesol. Finally, coimmunoprecipitation experiments (FXR immunoprecipitation followed by Western blot analysis of ER in the immunoprecipitate) produced definite evidence that FXR interacts with ER. Altogether, these observations reveal the hitherto unreported presence of FXR in breast cancer and show that the latter receptor functionally interacts with ER. The occurrence of such a crosstalk calls for some caution regarding the pharmacological use of FXR agonists.
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PMID:Farnesol, a mevalonate pathway intermediate, stimulates MCF-7 breast cancer cell growth through farnesoid-X-receptor-mediated estrogen receptor activation. 1733 35

Farnesoid X receptor (FXR) is a member of the nuclear receptor family and is known to play important roles in bile acid homeostasis, and lipid and glucose metabolism. In this study, to elucidate the systemic physiological functions of FXR, comprehensive immunohistochemical analysis of cell/subcellular localization of FXR and its heterodimer partner, retinoid X receptor (RXR)-alpha, in adult mice tissues was performed using tissue microarray (TMA)-based immunohistochemistry. FXR immunolabeling was observed in the enterohepatic system--including absorptive epithelium in the intestines, hepatocytes and gall bladder epithelium, several epithelial lineage cells including the basal cells of stratified epithelium in the tongue, esophagus, forestomach--skin, corneal epithelium and ciliary body epithelium in the eye and adrenocortical cells--including glandular cells in the zona reticularis/fasciculata. In these FXP-positive cells, FXR was preferentially localized to the nucleus. RXR-alpha was ubiquitously distributed in the nucleus of most cell types, including FXR-positive cell types in the examined tissues. These data suggest that FXR might have various physiological roles, not only in bile acid homeostasis, and lipid and glucose metabolism, but also in the epithelial cell barrier, visual and urinary function through multiple organ systems.
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PMID:Immunolocalization of farnesoid X receptor (FXR) in mouse tissues using tissue microarray. 1796 22


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