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)

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

The Farnesoid X receptor (FXR) has recently become a potential therapeutical target. The recruitment of coactivator protein (specified by LXXLL sequence) is the initial step in transcriptional activation of nuclear receptors (NRs). In this paper, the process of recognition of the LXXLL motif by the ligand binding domain (LBD) of FXR is observed in a 25 ns molecular dynamics simulation. The hydrophobic and hydrogen bonding interactions between the LBD and the coactivator are fully analyzed. This observation provides justification for the 'on deck' model proposed by Nettles and Greene. At last, insight to the protein-polypeptide interactions and protein conformational changes are discussed.
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PMID:Recognition of LXXLL by ligand binding domain of the Farnesoid X receptor in molecular dynamics simulation. 1712 2

Farnesoid X receptor (FXR, NR1H4) is a member of the nuclear hormone receptor superfamily, which plays an essential role in regulating bile acid, lipid, and glucose homeostasis. Both male and female FXR(-/-) mice spontaneously developed liver tumors; however, no other tumors were developed after 15 months of age. In contrast, no liver tumors were observed in wild-type mice of the same age. Histologic analyses confirm that tumors were hepatocellular adenoma and carcinoma. Although there was no obvious tumor at ages 9 to 12 months, FXR(-/-) livers displayed prominent liver injury and inflammation. Strong labeling of apoptotic hepatocytes and liver damage-induced compensatory regeneration were observed. Deregulation of genes involved in bile acid homeostasis in FXR(-/-) mice was consistent with abnormal levels of bile acids presented in serum and liver. Genes involved in inflammation and cell cycle were up-regulated in aging FXR(-/-) mice but not in wild-type controls. Increasing the bile acid levels by feeding mice with a 0.2% cholic acid diet strongly promoted N-nitrosodiethylamine-initiated liver tumorigenesis, whereas lowering bile acid pool in FXR(-/-) mice by a 2% cholestyramine feeding significantly reduced the malignant lesions. Our results suggest an intriguing link between metabolic regulation and hepatocarcinogenesis.
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PMID:Spontaneous development of liver tumors in the absence of the bile acid receptor farnesoid X receptor. 1762 66

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

Maintenance of normal lipid levels has implicated the involvement of genes induced by liver X receptor alpha (LXRalpha) and Farnesoid X receptor (FXR). This study was designed to evaluate the hypolipidemic effects of n-butanol extract (NE3) of Panax notoginseng (Burk.) F.H. Chen root on lipid homeostasis and investigate the possible mechanisms in animal experiments. In the transactivation assays, NE3 was identified as a dual FXR/LXRalpha agonist. Subsequently, Sprague-Dawley male rats on a high-fat/high-cholesterol diet were treated orally with NE3 or vehicle alone. As expected, the concentrations of serum TC, TG and LDL-C in rats treated with various concentrations of NE3 showed significant (P<0.01) and dose-dependent decrease, respectively, accompanied with a significant (P<0.01) and dose-dependent decrease in the concentration of hepatic TC and TG. Express-level analysis indicated that both LXRalpha target genes including ABCA1, ABCG5, ABCG8 and FXR target genes including ApoCII and SHP were significantly induced by NE3 (P<0.01). Interestingly, LDLR mRNA level was significantly higher by NE3 (P<0.01), accompanied with the significantly decreased expression levels of CYP7A1, ApoCIII and SREBP1c genes (P<0.01). Based on these results, it can be concluded that NE3 as a dual FXR/LXRalpha agonist largely prevented the accumulation of abnormal lipid in the hyperlipidemic rats.
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PMID:Hypolipidemic effects and mechanisms of Panax notoginseng on lipid profile in hyperlipidemic rats. 1768 43

Farnesoid X receptor (FXR), a bile acid receptor, belongs to nuclear hormone receptor super-family. FXR regulates expression of a diversity of target genes controlling bile acid homeostasis and lipid and carbohydrate metabolism. Studies on FXR will help to clarify its potential as a pharmacological target for therapeutic applications in many metabolic diseases.
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PMID:[Farnesoid X receptor (FXR): a novel regulative factor involved in metabolism]. 1788 78

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

Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, has been shown to be important in controlling numerous metabolic pathways; these include roles in maintaining bile acid, lipid and glucose homeostasis, in preventing intestinal bacterial infection and gallstone formation and in modulating liver regeneration and tumorigenesis. The accumulating data suggest that FXR may be a pharmaceutical target for the treatment of certain metabolic diseases.
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PMID:FXR signaling in metabolic disease. 1802 84

Nuclear receptors function as ligand-inducible transcription factors that regulate various physiological functions such as development, reproduction, and metabolism. Dysregulation of the metabolism of cholesterol, triglyceride, and glucose leads to the metabolic syndrome including type 2 diabetes mellitus, obesity, dyslipidemia, and atherosclerosis. Studies of nuclear receptors promise to provide discoveries of therapeutic agents against the metabolic syndrome. Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and is activated by bile acids. FXR regulates the metabolism of not only bile acid but also cholesterol, lipoprotein, triglyceride, and glucose, and is considered a potential therapeutic target for the metabolic syndrome because of these functions. Nuclear receptors have two regions for transactivation, a constitutive activation function (AF-1) and a ligand-dependent activation function (AF-2). AF-1 and AF-2 seem to require interactions with coactivators for the activation function and both work synergistically to give full transactivation of nuclear receptors. However, coactivators for AF-1 activity are poorly understood, whereas coactivators required for AF-2 activity have been well studied. To understand the molecular mechanism of AF-1 in FXR, we isolated proteins associated with AF-1 by GST pull-down assay using the N-terminal region of FXR and nuclear extracts from HeLa cells. This review focuses on the roles of FXR and our new findings regarding FXR-associated factors.
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PMID:[Functional analysis of nuclear receptor FXR controlling metabolism of cholesterol]. 1831 Oct 53

Alagille syndrome (AGS) is a rare hereditary disorder exhibiting fluctuating cholestasis and dyslipidemia. Farnesoid X receptor (FXR) and liver X receptor (LXR) are hepatic nuclear receptors that regulate bile acid and lipoprotein metabolism. To investigate whether cholestasis is related to dyslipidemia and hepatic nuclear receptor expression in AGS patients, we determined the blood levels of total bile acid (TBA) and lipoprotein parameters, and examined hepatic nuclear receptor expression in three AGS children and their three incomplete AGS parents repeatedly over several years. In the AGS children, TBA level showed significant positive correlations with low-density lipoprotein-cholesterol, apolipoprotein E (apoE)-rich high-density lipoprotein-cholesterol (HDL-C), apoA-I, apoE, and cholesteryl ester transfer protein (CETP) concentrations, but negative correlation with apoE-poor HDL-C concentration. Western blot analysis of liver biopsy specimens revealed that FXR and LXR expression increased in parallel with TBA level. CETP- and ATP-binding cassette transporter A1 expression also increased with TBA level, while scavenger receptor class B type-I expression showed the opposite response. However, apoA-I expression was similar to the control level at any TBA level. In the incomplete AGS parents, TBA and lipoprotein parameters showed little fluctuation. In summary, cholestasis is closely related to dyslipidemia and hepatic nuclear receptor expression in AGS patients.
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PMID:Fluctuation of lipoprotein metabolism linked with bile acid-activated liver nuclear receptors in Alagille syndrome. 1843 Apr 27


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