Alternative titles; symbols
HGNC Approved Gene Symbol: NR1H4
Cytogenetic location: 12q23.1 Genomic coordinates (GRCh38) : 12:100,473,866-100,564,414 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 12q23.1 | Cholestasis, progressive familial intrahepatic, 5 | 617049 | Autosomal recessive | 3 |
The NR1H4 gene encodes a nuclear bile acid receptor termed farnesoid X receptor (FXR) that senses bile acid levels. Elevated bile acid levels activate FXR to induce a program that represses hepatocyte bile acid biosynthesis. NR1H4 is thus a member of the nuclear receptor superfamily of ligand-activated transcription factors (summary by Gomez-Ospina et al., 2016 and Chen et al., 2012).
Nuclear hormone receptors play critical roles in many aspects of development and physiology by transducing the effects of hormones into transcriptional responses. Members of the nuclear receptor family share several structural features, including a central, highly conserved DNA-binding domain (DBD) that targets the receptor to specific DNA sequences, termed hormone response elements. The C-terminal portion of the receptor includes the ligand-binding domain (LBD), which interacts directly with the hormone and contains a hormone-dependent transcriptional activation domain. The LBD serves as a molecular switch that recruits coactivator proteins and activates the transcription of target genes when flipped into the active conformation by hormone binding (Kliewer et al., 1999).
Forman et al. (1995) isolated cDNAs encoding FXR (farnesoid X-activated receptor), a rat orphan receptor (so named because it possesses the structural features of hormone receptors but lacks a known ligand). The DBDs and LBDs of rat FXR and the insect ecdysone receptor share 81% and 34% amino acid identity, respectively. Northern blot analysis and in situ hybridization revealed that FXR expression is restricted to rat liver, gut, adrenal gland, and kidney, tissues known to have significant flux through the mevalonate pathway.
Huber et al. (2002) identified 4 Fxr splice variants in hamster. By RT-PCR, they confirmed the presence of the 4 variants in human liver and small intestine. The 2 main variants, FXR-alpha and FXR-beta, encode proteins with different N termini. Further alternative splicing generates FXR-alpha and FXR-beta transcripts with a 12-bp insertion that results in a 4-amino acid insertion near the hinge region of the proteins. The hamster and human FXR-alpha isoforms share 93% amino acid identity. Real-time PCR detected highest expression of human FXR-alpha variants in adrenal gland and liver, with lower expression in duodenum, kidney, and small intestine. FXR-beta variants were predominantly expressed in colon, duodenum, and kidney, with lower expression in liver. Expression of FXR-beta was higher in fetal colon and kidney and lower in fetal liver and small intestine compared with the corresponding adult tissues.
Bishop-Bailey et al. (2004) found that FXR was expressed in a variety of normal and pathologic human tissues. Vasculature, as well as liver, small intestine, and kidney, showed highest expression. FXR was also expressed in a number of different metastatic cancers.
Huber et al. (2002) determined that the FXR gene contains 11 exons. The 5-prime UTR contains a TATA box, and the initiation codon is within the 3-prime region of exon 3. An alternative exon 3a encodes the FXR-beta variant, which has an alternate N-terminal sequence. The 12-bp insertion found in some FXR transcripts results from alternative splicing affecting exon 5.
By genomic sequence analysis, Huber et al. (2002) mapped the NR1H4 gene to chromosome 12q23.1. By analysis of an interspecific backcross, Kozak et al. (1996) mapped the mouse Nr1h4 gene to chromosome 10 in a region showing homology of synteny with human chromosome 12q.
Forman et al. (1995) determined that FXR forms a heterodimeric complex with the retinoid X receptor (see 180245). Farnesol and related metabolites were effective activators of this complex. Farnesol metabolites are generated intracellularly and are part of the mevalonate biosynthetic pathway, which leads to the synthesis of cholesterol, bile acids, steroids, retinoids, and farnesylated proteins. Forman et al. (1995) suggested that these results provide evidence of metabolite-controlled intracellular signaling systems in higher organisms. Zavacki et al. (1997) reported that RIP14, the mouse FXR homolog, can be activated by retinoids.
Bile acids are essential for the solubilization and transport of dietary lipids and are the major products of cholesterol catabolism. The enzymatic conversion of cholesterol to bile acids is regulated through feed-forward activation by oxysterols, a pathway mediated by the liver X receptor (see LXRA; 602423), and by feedback repression by bile acids. Parks et al. (1999) and Makishima et al. (1999) demonstrated that bile acids are the physiologic ligands for FXR. Makishima et al. (1999) found that when bound to bile acids, FXR repressed transcription of the cholesterol 7-alpha-hydroxylase gene (CYP7A1; 118455), which encodes the rate-limiting enzyme in bile acid synthesis. In addition, ligand-bound FXR activated the gene encoding intestinal bile acid-binding protein (IBABP; 600422), a candidate bile acid transporter. As Gustafsson (1999) noted, the result is a decrease in the amount of bile acid in the gut. Hence, through binding to FXR, bile acids can regulate their own synthesis and transport.
Wang et al. (1999) isolated an endogenous biliary component (chenodeoxycholic acid) that selectively activates FXR. Structure-activity analysis defined a subset of related bile acid ligands that activate FXR and promote coactivator recruitment. The authors also showed that ligand-occupied FXR inhibits transactivation from the oxysterol receptor LXRA, a positive regulator of cholesterol degradation. They suggested that FXR is the endogenous bile acid sensor and thus an important regulator of cholesterol homeostasis.
In an elegant series of experiments designed to understand the effect of retinoid X receptor (RXR; see 180245) activation on cholesterol balance, Repa et al. (2000) treated animals with the rexinoid LG268. Animals treated with rexinoid exhibited marked changes in cholesterol balance, including inhibition of cholesterol absorption and repressed bile acid synthesis. Studies with receptor-selective agonists revealed that oxysterol receptors (LXRs) and the bile acid receptor, FXR, are the RXR heterodimeric partners that mediate these effects by regulating expression of the reverse-cholesterol transporter, ABC1 (600046), and the rate-limiting enzyme of bile acid synthesis, CYP7A1, respectively. These RXR heterodimers serve as key regulators in cholesterol homeostasis by governing reverse cholesterol transport from peripheral tissues, bile acid synthesis in liver, and cholesterol absorption in intestine. Activation of RXR/LXR heterodimers inhibits cholesterol absorption by upregulation of ABC1 expression in the small intestine. Activation of RXR/FXR heterodimers represses CYP7A1 expression and bile acid production, leading to a failure to solubilize and absorb cholesterol. Studies have shown that RXR/FXR-mediated repression of CYP7A1 is dominant over RXR/LXR-mediated induction of CYP7A1, which explains why the rexinoid represses rather than activates CYP7A1 (Lu et al., 2000). Activation of the LXR signaling pathway results in the upregulation of ABC1 in peripheral cells, including macrophages, to efflux free cholesterol for transport back to the liver through high density lipoprotein, where it is converted to bile acids by the LXR-mediated increase in CYP7A1 expression. Secretion of biliary cholesterol in the presence of increased bile acid pools normally results in enhanced reabsorption of cholesterol; however, with the increased expression of ABC1 and efflux of cholesterol back into the lumen, there is a reduction in cholesterol absorption and net excretion of cholesterol and bile acid. Rexinoids therefore offer a novel class of agents for treating elevated cholesterol.
The catabolism of cholesterol into bile acids is regulated by oxysterols and bile acids, which induce or repress transcription of the pathway's rate-limiting enzyme, CYP7A1. The nuclear receptor LXRA binds oxysterols and mediates feed-forward induction. Lu et al. (2000) showed that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR; the promoter-specific activator, LRH1 (NR5A2; 604453); and the promoter-specific repressor, SHP (NR0B2; 604630). Feedback repression of CYP7A1 is accomplished by the binding of bile acids to FXR, which leads to transcription of SHP. Elevated SHP protein then inactivates LRH1 by forming a heterodimeric complex that leads to promoter-specific repression of both CYP7A1 and SHP. These results revealed an elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism.
Goodwin et al. (2000) used a potent, nonsteroidal FXR ligand to show that FXR induces expression of SHP1, an atypical member of the nuclear receptor family that lacks a DNA-binding domain. SHP1 represses expression of CYP7A1 by inhibiting the activity of LRH1, an orphan nuclear receptor that regulates CYP7A1 expression positively. This bile acid-activated regulatory cascade provides a molecular basis for the coordinate suppression of CYP7A1 and other genes involved in bile acid biosynthesis.
Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL cholesterol levels in humans. The plant sterol guggulsterone (4,17(20)-pregnadiene-3,16-dione) is the active agent in this extract. Urizar et al. (2002) demonstrated that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor. Guggulsterone treatment decreased hepatic cholesterol in wildtype mice fed a high-cholesterol diet but was not effective in Fxr-null mice.
Huber et al. (2002) found that the transactivation and reporter activity of all 4 human FXR isoforms was increased in a transfected human hepatoma cell line following exposure to chenodeoxycholic acid, a naturally occurring bile acid. FXR-alpha was also upregulated in hepatoma cells following exposure to a nonsteroidal FXR agonist.
Using an in vitro protein binding assay, Torra et al. (2004) determined that FXR bound PPARBP (604311) in response to bile acid ligands in a dose-dependent fashion, and the potency of this interaction was associated with the ability of the ligand to activate FXR. The interaction required the activation function-2 region of the ligand-binding domain of FXR and the N-terminal LxxLL motif of PPARBP. In gel shift assays, DNA-bound FXR/RXR heterodimers recruited PPARBP. In cells overexpressing FXR/RXR, FXR-mediated transactivation was enhanced by PPARBP, and heterodimerization between FXR and RXR was required for PPARBP coactivation.
Bishop-Bailey et al. (2004) found that treatment of vascular smooth muscle cells with FXR ligands resulted in apoptosis in a manner that correlated with the ability of the ligand to activate FXR.
Huang et al. (2006) identified a role for nuclear receptor-dependent bile acid signaling in normal liver regeneration. Elevated bile acid levels accelerate regeneration, and decreased levels inhibit liver regrowth, as does the absence of the primary nuclear bile acid receptor FXR. Huang et al. (2006) proposed that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver. FXR, and possibly other nuclear receptors, may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.
In mice, Seok et al. (2014) showed that Fxr and the fasting transcriptional activator Creb (123810) coordinately regulate the hepatic autophagy gene network. Pharmacologic activation of Fxr repressed many autophagy genes even in the fasted state, and feeding-mediated inhibition of macroautophagy was attenuated in Fxr-knockout mice. From mouse liver chromatin immunoprecipitation and high-throughput sequencing data, Fxr and Creb binding peaks were detected at 178 and 112 genes, respectively, out of 230 autophagy-related genes, and 78 genes showed shared binding, mostly in their promoter regions. Creb promoted autophagic degradation of lipids, or lipophagy, under nutrient-deprived conditions, and Fxr inhibited this response. Mechanistically, Creb upregulated autophagy genes, including Atg7 (608760), Ulk1 (603168), and Tfeb (600744), by recruiting the coactivator Crtc2 (608972). After feeding or pharmacologic activation, Fxr trans-repressed these genes by disrupting the functional Creb-Crtc2 complex. Seok et al. (2014) concluded that their study identified the FXR-CREB axis as a key physiologic switch regulating autophagy, resulting in sustained nutrient regulation of autophagy during feeding/fasting cycles.
Lee et al. (2014) showed that both Ppara (170998) and Fxr regulated hepatic autophagy in mice. Pharmacologic activation of Ppara reverses the normal suppression of autophagy in the fed state, inducing lipophagy. This response is lost in Ppara-knockout mice, which are partially defective in the induction of autophagy by fasting. Pharmacologic activation of the bile acid receptor Fxr strongly suppresses the induction of autophagy in the fasting state, and this response is absent in Fxr-knockout mice, which show a partial defect in suppression of hepatic autophagy in the fed state. PPARA and FXR compete for binding to shared sites in autophagic gene promoters, with opposite transcriptional outputs. Lee et al. (2014) concluded that these results revealed complementary, interlocking mechanisms for regulation of autophagy by nutrient status.
Alvarez et al. (2004) investigated the possibility of hepatic downregulation of FXR in PFIC1 (211600). They identified compound heterozygosity for missense and nonsense mutations in the ATP8B1 gene (602397.0012-602397.0013) in 3 Spanish Gypsy sibs with PFIC1, born of consanguineous parents. Expression of 2 main FXR isoforms was specifically decreased in the liver of 1 of the sibs compared to patients with other forms of liver disease and a normal control. A consistent and concomitant reduction in mRNA levels of FXR targets, such as ABCB11 (603201) and SHP1 (NR0B2; 604630) was also found. Gene-profiling experiments identified 163 transcripts whose expression changed significantly in PFIC1-disease liver, including downregulation of several genes involved in synthesis, conjugation, and transport of bile acids. A cluster of genes involved in lipid metabolism was also differentially expressed. Alvarez et al. (2004) suggested that hepatic downregulation of FXR contributes to the severe cholestasis of PFIC1.
Progressive Familial Intrahepatic Cholestasis 5
In 4 patients from 2 unrelated families with neonatal-onset progressive familial intrahepatic cholestasis-5 (PFIC5; 617049), Gomez-Ospina et al. (2016) identified biallelic loss of function mutations in the NR1H4 gene (603826.0001-603826.0003). The mutations, which were found by whole-exome sequencing and SNP array analysis, segregated with the disorder in the families. All patients also presented with severe vitamin K-independent coagulopathy early in the course of their disease. In a human liver cell line, FXR agonists induced mRNA expression of 3 fibrinogen genes (FGA, 134820; FGB, 134830; FGG, 134850), and caused increased expression of genes encoding several coagulation factors. These responses were decreased by FXR knockdown. Overall, the findings demonstrated a pivotal role for FXR in bile acid homeostasis and liver protection from bile acid-induced liver toxicity.
Sinal et al. (2000) generated mice lacking Fxr, also called Bar. These mice developed normally and were outwardly identical to wildtype littermates. Fxr-null mice were distinguished from wildtype mice by elevated serum bile acid, cholesterol, and triglycerides; increased hepatic cholesterol and triglycerides; and a proatherogenic serum lipoprotein profile. Fxr-null mice also had reduced bile acid pools and reduced fecal bile acid excretion due to decreased expression of the major hepatic canalicular bile acid transport protein (BSEP; 603201). Bile acid repression and induction of cholesterol 7-alpha-hydroxylase and IBABP, respectively, did not occur in Fxr-null mice, establishing the regulatory role of FXR for the expression of these genes in vivo. These data demonstrated that FXR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile acid sensor.
Using Fxr -/- mice that were fasted for 48 hours, Cariou et al. (2005) found that Fxr modulated the kinetics of alterations of glucose homeostasis during fasting. Fxr -/- mice displayed an early, accelerated hypoglycemia response with lower basal hepatic glucose production and reduced liver glycogen content. Hepatic Pepck (PCK1; 614168) gene expression was transiently lower in Fxr -/- mice after 6 hours of fasting and was decreased in Fxr -/- hepatocytes. Cariou et al. (2005) concluded that FXR plays a role in control of fuel availability during fasting.
In both diabetic db/db and wildtype mice, Zhang et al. (2006) found that activation of Fxr by a synthetic agonist or by hepatic overexpression of constitutively active Fxr significantly lowered blood glucose levels. Fxr-null mice exhibited glucose intolerance and insulin insensitivity. When Fxr was activated in db/db mice, Zhang et al. (2006) observed repression of hepatic gluconeogenic genes and increased hepatic glycogen synthesis and glycogen content by a mechanism that involved enhanced insulin sensitivity.
Ma et al. (2006) generated Fxr-null mice, which developed severe fatty liver and elevated circulating free fatty acids associated with elevated serum glucose and impaired glucose and insulin tolerance. Insulin resistance was confirmed by hyperinsulinemic euglycemic clamp, which showed attenuated inhibition of hepatic glucose production by insulin and reduced peripheral glucose disposal. In Fxr -/- skeletal muscle and liver, multiple steps in the insulin signaling pathway were markedly blunted. In both Fxr-null and Shp-null mice, there was no repression of gluconeogenic genes or decrease in serum glucose in response to bile acid, demonstrating that the previously described FXR-SHP nuclear receptor cascade (see Lu et al., 2000) also targets glucose metabolism.
In a mouse model of obstructive cholestasis caused by bile duct ligation, Stedman et al. (2006) found that Fxr-null mice were more protected from liver injury compared to wildtype mice and Pxr (NR1I2; 603065)-null mice. Fxr-null mice had decreased bile infarcts in the liver and decreased serum bilirubin and bile acid concentrations compared to the other genotypes. Fxr-null mice showed increased expression of several bile acid transporters, particularly Mrp4 (ABCC4; 605250), suggesting an increased capacity to export bile acids out of the hepatocyte, thereby reducing hepatotoxicity. Fxr-null mice demonstrated a biphasic lipid profile after bile duct ligation, with an increase in HDL cholesterol and hypertriglyceridemia by day 6. The findings implicated Fxr in cholestasis modulation and triglyceride regulation.
Bariatric surgical procedures, such as vertical sleeve gastrectomy (VSG), are an effective therapy for the treatment of obesity, and are associated with considerable improvements in comorbidities, including type-2 diabetes. Substantial changes in circulating total bile acids occur after VSG. Moreover, bile acids regulate metabolism by binding to the nuclear receptor FXR (NR1H4). Ryan et al. (2014) therefore examined the results of VSG applied to mice with diet-induced obesity and targeted genetic disruption of Fxr. Ryan et al. (2014) demonstrated that the therapeutic value of VSG does not result from mechanical restriction imposed by a smaller stomach; rather, VSG is associated with increased circulating bile acids and associated changes to gut microbial communities. Moreover, in the absence of Fxr, the ability of VSG to reduce body weight and improve glucose tolerance is substantially reduced. Ryan et al. (2014) concluded that these results point to bile acids and FXR signaling as an important molecular underpinning for the beneficial effects of this weight-loss surgery.
In 2 sibs, born of consanguineous parents, with progressive familial intrahepatic cholestasis-5 (PFIC5; 617049), Gomez-Ospina et al. (2016) identified a homozygous c.526C-T transition (c.526C-T, NM_005123) in the NR1H4 gene, resulting in an arg176-to-ter (R176X) substitution predicted to result in the loss of both the DNA binding and hormone receptor domain, consistent with a loss of function. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient liver samples showed complete absence of NR1H4 and BSEP (ABCB11; 603201), although mutations were not found in the ABCB11 gene. Gomez-Ospina et al. (2016) noted that Chen et al. (2012) had identified a heterozygous R176X mutation, resulting from a c.874C-T transition, in a Chinese infant with cholestasis, cirrhosis, and increased GGT. That patient was 1 of 78 children who were screened for mutations in the NR1H4 gene. Familial segregation studies were not performed in the Chinese infant. However, the heterozygous parents in the family reported by Gomez-Ospina et al. (2016) had normal liver biochemistry and the mother did not have symptoms of cholestasis during any of her 3 pregnancies, suggesting that heterozygosity for R176X is not sufficient to cause infantile cholestasis. Gomez-Ospina et al. (2016) suggested that the patient reported by Chen et al. (2012) may have had a deleterious mutation in another gene.
In 2 sibs with progressive familial intrahepatic cholestasis-5 (PFIC5; 617049), Gomez-Ospina et al. (2016) identified compound heterozygous mutations in the NR1H4 gene: an in-frame 3-bp insertion (c.419_420insAAA, NM_005123), resulting in an insertion of a residue (Tyr139_Asn140insLys), which was inherited from the asymptomatic mother, and an intragenic 31.7-kb deletion (603826.0003) on the paternal allele. The deletion spanned the first 2 coding exons and was predicted to result in a complete loss of protein expression. The insertion mutation is located in the first zinc-binding module close to the DNA-recognition helix, and in vitro studies showed that the mutant protein had no detectable binding to a consensus FXR/RXR-binding site. The mutation also abolished transcriptional activity on a synthetic promoter. These findings were consistent with a loss of function.
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