Disease relevance of NR1H4

• Cerebrotendinous xanthomatosis (CTX), sterol 27-hydroxylase (CYP27A1) deficiency, is associated with markedly reduced chenodeoxycholic acid (CDCA), the most powerful activating ligand for farnesoid X receptor (FXR) [1].
• Our findings show for the first time that FXR is expressed in breast cancer tissue and has multiple properties that could be used for the treatment of breast cancer [2].
• CONCLUSIONS: These data suggest that UGT2B4 gene induction by bile acids contributes to a feed-forward reduction of bile acid toxicity and a decrease of the activity of these biological FXR activators [3].
• METHODS: Human hepatocytes or hepatoblastoma HepG2 cells were treated with chenodeoxycholic acid or the synthetic FXR agonist GW4064, and the levels of UGT2B4 messenger RNA, protein, and activity were determined by using real-time polymerase chain reaction, Western blot, and glucuronidation assays [3].
• Because FXR agonists lower triglyceride levels, our results suggest a novel role for RXR-mediated antagonism of FXR activity in the development of hypertriglyceridemia observed with RXR agonists in rodents and humans [4].

High impact information on NR1H4

• Bile acids activate the farnesoid X receptor (FXR) to inhibit transcription of the gene for cholesterol 7alpha-hydroxylase, and stimulate excretion and transport of bile acids [5].
• Therefore, FXR and LXR play critical roles in coordinate control of bile acid, cholesterol, and triglyceride metabolism to maintain lipid homeostasis [5].
• As ligands, these bile acids and their conjugates modulated interaction of FXR with a peptide derived from steroid receptor coactivator 1 [6].
• Physiological concentrations of free and conjugated chenodeoxycholic acid, lithocholic acid, and deoxycholic acid activated the farnesoid X receptor (FXR; NR1H4), an orphan nuclear receptor [6].
• When bound to bile acids, FXR repressed transcription of the gene encoding cholesterol 7alpha-hydroxylase, which is the rate-limiting enzyme in bile acid synthesis, and activated the gene encoding intestinal bile acid-binding protein, which is a candidate bile acid transporter [7].

Chemical compound and disease context of NR1H4

• CONCLUSION: These findings suggest that PGC-1 can play a role in the prevention of cholesterol gallstone disease in humans; this might take place via interaction with the bile acid receptor FXR, whose protective role in cholelithiasis has been suggested by recent evidence in animal models and other coactivators [8].
• FXR also targets sodium taurocholate cotransport peptide and bile salt export pump (protein) genes to limit bile salt uptake and enhance export, respectively, which prevents bile salt toxicity [9].
• Expression of the ASCT2 transporter in HepG2 hepatoma cells is stimulated by glutamine by a pathway involving the promoter element AGGTGAATGACTT which binds FXR/RXR dimers [10].
• Here, we investigated whether FXR ligands regulate PPARgamma expression in HSCs and models of liver fibrosis induced in rats by porcine serum and carbon tetrachloride administration and bile duct ligation [11].
• In conclusion, HRR can further risk stratify patients who undergo dobutamine stress echocardiography and provides independent and incremental prognostic value over standard cardiovascular risk factors and also independent of echocardiographic myocardial ischemia and left ventricular dysfunction and is superior to 85% MPHR [12].

Biological context of NR1H4

• In conclusion, FXR agonists may increase gallbladder fluid secretion through transcriptional activation of VPAC1, which may contribute to the regulation of bile secretion by bile salts and to a protective effect of FXR pharmacological agonists in gallstone disease [13].
• Analysis of the VPAC1 gene revealed the presence of potential FXR response element sequences, and both FXR and RXRalpha expressions were detected in gallbladder epithelial cells [13].
• Chenodeoxycholate activated endogenous FXR in gallbladder epithelial cells, as ascertained by electromobility shift assay and upregulation of the FXR target gene, small heterodimer partner [13].
• Luciferase reporter gene assays showed that the ABCB11 promoter is positively controlled by FXR, RXRalpha, and bile salts in a concentration-dependent manner [14].
• Reducing endogenous FXR levels using RNA interference fully repressed the bile salt-induced ABCB11 expression [14].

Anatomical context of NR1H4

• Expression of the farnesoid X receptor (FXR; NR1H4) is limited to the liver, intestine, kidney, and adrenal gland [15].
• VPAC1 expression is regulated by FXR agonists in the human gallbladder epithelium [13].
• Treatment of human hepatocytes with either naturally occurring (chenodeoxycholic acid) or synthetic (GW4064) FXR ligands resulted in both induction of SDC1 mRNA and enhanced binding, internalization, and degradation of low density lipoprotein [16].
• OBJECTIVES: To determine the role of PPARs, farnesoid X receptor (FXR) and other orphan nuclear hormone receptors in sebaceous gland function in vitro by investigating the biochemical effects of appropriate ligands, and by establishing the RNA and protein expression patterns of a number of nuclear receptors in sebaceous glands ex vivo [17].
• FXR cis-element binding and FXR protein were reduced primarily in nuclear but not cytoplasmic extracts from familial intrahepatic cholestasis-1-negative Caco-2 cells [18].

Associations of NR1H4 with chemical compounds

• Examples of some natural product ligands for NHRs include genestein (estrogen receptors NR3A1 and NR3A2), guggulsterone (farnesoid X receptor NR1H4), and St [19].
• The farnesoid X receptor (FXR) functions as a heterodimer with the retinoid X receptor alpha (RXRalpha) and can be activated by the bile salt chenodeoxycholic acid (CDCA) [14].
• In these cells, the FXR pharmacological agonist GW4064 upregulated VPAC1 expression in a dose-dependent manner, and this effect was antagonized by the RXRalpha ligand, 9-cis retinoic acid [13].
• Despite the partial induction of BSEP mRNA, CA, DCA, and UDCA effectively repressed expression of cholesterol 7alpha-hydroxylase, another FXR target [20].
• In an in vitro coactivator association assay, CDCA fully activated FXR, whereas CA partially activated FXR and DCA and UDCA had negligible activities [20].

Physical interactions of NR1H4

• Two functional FXR binding motifs were identified in the OSTalpha gene and one in the OSTbeta gene [21].
• In conclusion, the genes encoding the human OSTalpha/OSTbeta complex are induced by bile acids and FXR [21].
• Retinoid X receptor activation abolished the induction of UGT2B4 expression and inhibited binding of FXR to the B4-BARE, suggesting that retinoid X receptor modulates FXR target gene activation [3].
• In this study we demonstrate that DRIP205 binds FXR in a ligand-dependent manner in vitro and in vivo [22].
• These results show that the stimulation of ASCT2 expression in response to glutamine in part involves binding of FXR/RXR to the ASCT2 promoter [23].

Regulatory relationships of NR1H4

• Thus, current studies demonstrate that hepatic SDC1 is induced in an FXR isoform-specific manner [16].
• Although multidrug resistance transporters were regulated and are known FXR target genes, GW4064 had no effect on the cell death induced by the anticancer drug paclitaxel [2].
• FXR induces the UGT2B4 enzyme in hepatocytes: a potential mechanism of negative feedback control of FXR activity [3].
• The goal of this study is to elucidate the mechanism of CYP7A1 transcription by bile acid-activated farnesoid X receptor (FXR) in its native promoter and cellular context and to identify FXR response elements in the gene [24].
• In this study we show that the human kininogen gene is strongly up-regulated by agonists of the farnesoid X receptor (FXR), a nuclear receptor for bile acids [25].

Other interactions of NR1H4

• Because VPAC1 expression was previously shown to be regulated by nuclear receptors, we tested the hypothesis that it may be regulated by the farnesoid X receptor (FXR) [13].
• The methyl transferase PRMT1 functions as co-activator of farnesoid X receptor (FXR)/9-cis retinoid X receptor and regulates transcription of FXR responsive genes [26].
• The nuclear receptor for bile acids, FXR, transactivates human organic solute transporter-alpha and -beta genes [21].
• The rank order and absolute potency was conserved (CDCA IC(50) = 8.7 microM, DCA IC(50) = 27.2 microM, UDCA and CA inactive) consistent with bile acid repression of CYP7A1 being mediated by FXR [27].
• We demonstrate that the farnesoid X receptor (FXR; NR1H4), which regulates a variety of genes involved in lipoprotein metabolism, also regulates the expression of PDK4 [28].

Analytical, diagnostic and therapeutic context of NR1H4

• A mammalian two-hybrid assay was utilized to assess the ability of FXR to recruit SRC-1 in a ligand-dependent manner [27].
• Furthermore, we show by chromatin immunoprecipitation that the ligand-dependent activation of the human BSEP locus is associated with a simultaneous increase of FXR and CARM1 occupation [29].
• 5'-Deletion, mutagenesis, and gel shift analysis identified a heretofore unknown element at positions -103/-84 consisting of an inverted repeat of two consensus receptor-binding hexads separated by 8 nucleotides (IR8), which was required for the response to bile acid-activated FXR [30].
• Northern blot analysis confirmed the up-regulation of kininogen expression by FXR agonists [25].
• AlphaA-crystallin was identified in a microarray screen as one of the most highly induced genes after treatment of HepG2 cells with the synthetic FXR ligand GW4064 [31].

References