Alternative titles; symbols
HGNC Approved Gene Symbol: NR5A2
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38) : 1:200,027,710-200,177,415 (from NCBI)
By means of yeast 1-hybrid screening of a liver cDNA library, Li et al. (1998) cloned a cDNA encoding a novel hepatocyte transcription factor, which they called HB1F for human B1-binding factor. The deduced 495-amino acid protein, which has a molecular mass of 54 kD, belongs to the fushi tarazu factor-1 (FTZ-F1) subfamily of orphan nuclear receptors and is closely related to steroidogenic factor-1 (SF1; 184757), another member of this subfamily. HB1F contains a DNA-binding domain with 2 zinc finger motifs, an FTZ-F1 box, and a ligand-binding domain. Northern blot analysis revealed that HB1F is expressed in liver, pancreas, and lung as a 5.2-kb transcript. An additional transcript of 3.8 kb was present in hepatoma cells HepG2. The authors identified 2 HB1F isoforms which differ in their A/B region.
Cholesterol 7-alpha-hydroxylase is the first and rate-limiting enzyme in a pathway through which cholesterol is metabolized to bile acids. The gene encoding cholesterol 7-alpha-hydroxylase, CYP7A (118455), is expressed exclusively in the liver. Overexpression of CYP7A in hamsters results in reduction of serum cholesterol levels, suggesting that the enzyme plays a central role in cholesterol homeostasis. Nitta et al. (1999) reported the identification of a liver-specific transcription factor that binds to the promoter of the human CYP7A gene. They designated this factor CPF for 'CYP7A promoter-binding factor' and identified it as a human homolog of the Drosophila orphan nuclear receptor fushi tarazu F1 (Ftz-F1). Nitta et al. (1999) isolated a CPF cDNA encoding a 495-amino acid protein from a human liver cDNA library. They found evidence for 2 CPF variants derived from alternative splicing. Northern blot analysis detected enriched expression in pancreas and liver, with a low level of expression in heart and lung.
Using RT-PCR analysis, Sirianni et al. (2002) found that the expression of LRH1 was highest in human liver, lower in ovary and testis, and very low in adrenal gland and placenta.
Galarneau et al. (1998) demonstrated that the rat homolog of HB1F activates the alpha-1-fetoprotein (AFP; 104150) gene in early differentiating hepatocytes.
Li et al. (1998) showed that HB1F specifically binds and activates viral hepatitis B enhancer II, an essential element for the liver-specific regulation of hepatitis B virus gene expression.
Nitta et al. (1999) showed that mutation of the CPF binding site within the CYP7A promoter abolished liver-specific expression of the gene in transient transfection assays. Cotransfection of a CPF expression plasmid and a CYP7A reporter gene resulted in specific induction of CYP7A-directed transcription. These observations suggested that CPF is a key regulator of human CYP7A gene expression in the liver.
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 LXR-alpha (LXRA, or NR1H3; 602423) 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 (NR1H4; 603826); the promoter-specific activator, LRH1; 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.
By cotransfection in human embryonic kidney cells, Sirianni et al. (2002) showed that LRH1 could enhance reporter activity driven by the promoter region of several genes involved in steroid metabolism, including STAR (600617), CYP11A1 (118485), CYP17 (CYP17A1; 609300), HSD3B2 (613890), and CYP11B1 (610613).
Lee et al. (2011) showed that an unusual phosphatidylcholine species with 2 unsaturated 12-carbon fatty acid acyl side chains (dilauroyl phosphatidylcholine; DLPC) is an LRH1 agonist ligand in vitro. DLPC treatment induced bile acid biosynthetic enzymes in mouse liver, increased bile acid levels, and lowered hepatic triglycerides and serum glucose. DLPC treatment also decreased hepatic steatosis and improved glucose homeostasis in 2 mouse models of insulin resistance. Both the antidiabetic and lipotropic effects were lost in liver-specific Lrh1 knockouts. Lee et al. (2011) concluded that their findings identified an LRH1-dependent phosphatidylcholine signaling pathway that regulates bile acid metabolism and glucose homeostasis.
Using a global transcriptomic analysis, Cobo et al. (2018) described an epithelial cell autonomous basal preinflammatory state in the pancreas of Nr5a2 heterozygous mice that was reminiscent of the early stages of pancreatitis-induced inflammation and was conserved in histologically normal human pancreases with reduced expression of NR5A2 mRNA. In Nr5a2 heterozygous mice, Nr5a2 undergoes a marked transcriptional switch, relocating from differentiation-specific to inflammatory genes and thereby promoting gene transcription that is dependent on the AP1 transcription factor (see JUN, 165160). Pancreatic deletion of Jun rescued the preinflammatory phenotype, as well as binding of Nr5a2 to inflammatory gene promoters and the defective regenerative response to damage. Cobo et al. (2018) concluded that their findings supported the notion that, in the pancreas, the transcriptional networks involved in differentiation-specific functions also suppress inflammatory programs. Under conditions of genetic or environmental constraint, these networks can be subverted to foster inflammation.
Li et al. (1998) and Galarneau et al. (1998) independently mapped the FTF gene to human chromosome 1q32.1 by FISH.
Schoonjans et al. (2005) showed that haploinsufficiency of Lrh1 reduced intestinal tumorigenesis in 2 mouse models of intestinal tumorigenesis.
Duggavathi et al. (2008) stated that Lrh1 deletion in mice is embryonic lethal. They found that targeted deletion of Lrh1 in granulosa cells caused sterility due to anovulation. Preovulatory stimuli failed to elicit cumulus expansion, luteinization, and follicular rupture. Multiple defects led to increased intrafollicular estradiol levels in the absence of Lrh1, which caused dysfunction of prostaglandin and hyaluronic acid cascades and interrupted cumulus expansion. Lack of Lrh1 also interfered with progesterone synthesis and compromised the expression of extracellular matrix proteases essential for ovulation. Duggavathi et al. (2008) concluded that LRH1 regulates multiple mechanisms essential for the maturation of ovarian follicles and for ovulation.
Using mouse models with conditional deletion of Nr5a2 and/or Esrrb (602167), Festuccia et al. (2024) demonstrated that maternally expressed Nr5a2 and Esrrb were dispensable for embryogenesis and were not decisive maternal regulators of zygotic genome activation (ZGA). Gene expression analysis suggested that zygotically and maternally expressed Nr5a2 began contributing to the regulation of gene expression immediately after the initiation of zygotic transcription, but that the role of Nr5a2 during ZGA was minor. Nr5a2 predominantly acted as a master regulator at the 8-cell stage, controlling expression of lineage-specifying transcription factors and genes involved in mitosis, telomere maintenance, and DNA repair, thereby coordinating proliferation, genome stability, and lineage specification to ensure correct morula development.
Cobo, I., Martinelli, P., Flandez, M., Bakiri, L., Zhang, M., Carrillo-de-Santa-Pau, E., Jia, J., Sanchez-Arevalo Lobo, V. J., Megias, D., Felipe, I., Del Pozo, N., Millan, I., and 11 others. Transcriptional regulation by NR5A2 links differentiation and inflammation in the pancreas. Nature 554: 533-537, 2018. [PubMed: 29443959] [Full Text: https://doi.org/10.1038/nature25751]
Duggavathi, R., Volle, D. H., Mataki, C., Antal, M. C., Messaddeq, N., Auwerx, J., Murphy, B. D., Schoonjans, K. Liver receptor homolog 1 is essential for ovulation. Genes Dev. 22: 1871-1876, 2008. [PubMed: 18628394] [Full Text: https://doi.org/10.1101/gad.472008]
Festuccia, N., Vandormael-Pournin, S., Chervova, A., Geiselmann, A., Langa-Vives, F., Coux, R. X., Gonzalez, I., Collet, G. G., Cohen-Tannoudji, M., Navarro, P. Nr5a2 is dispensable for zygotic genome activation but essential for morula development. Science 386: eadg7325, 2024. [PubMed: 39361745] [Full Text: https://doi.org/10.1126/science.adg7325]
Galarneau, L., Drouin, R., Belanger, L. Assignment of the fetoprotein transcription factor gene (FTF) to human chromosome band 1q32.11 by in situ hybridization. Cytogenet. Cell Genet. 82: 269-270, 1998. [PubMed: 9858833] [Full Text: https://doi.org/10.1159/000015116]
Goodwin, B., Jones, S. A., Price, R. R., Watson, M. A., McKee, D. D., Moore, L. B., Galardi, C., Wilson, J. G., Lewis, M. C., Roth, M. E., Maloney, P. R., Willson, T. M., Kliewer, S. A. A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Molec. Cell 6: 517-526, 2000. [PubMed: 11030332] [Full Text: https://doi.org/10.1016/s1097-2765(00)00051-4]
Lee, J. M., Lee, Y. K., Mamrosh, J. L., Busby, S. A., Griffin, P. R., Pathak, M. C., Ortlund, E. A., Moore, D. D. A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature 474: 506-510, 2011. [PubMed: 21614002] [Full Text: https://doi.org/10.1038/nature10111]
Li, M., Xie, Y.-H., Kong,Y.-Y., Wu, X., Zhu, L., Wang, Y. Cloning and characterization of a novel human hepatocyte transcription factor, hB1F, which binds and activates enhancer II of hepatitis B virus. J. Biol. Chem. 273: 29022-29031, 1998. [PubMed: 9786908] [Full Text: https://doi.org/10.1074/jbc.273.44.29022]
Lu, T. T., Makishima, M., Repa, J. J., Schoonjans, K., Kerr, T. A., Auwerx, J., Mangelsdorf, D. J. Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Molec. Cell 6: 507-515, 2000. [PubMed: 11030331] [Full Text: https://doi.org/10.1016/s1097-2765(00)00050-2]
Nitta, M., Ku, S., Brown, C., Okamoto, A. Y., Shan, B. CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7-alpha-hydroxylase gene. Proc. Nat. Acad. Sci. 96: 6660-6665, 1999. [PubMed: 10359768] [Full Text: https://doi.org/10.1073/pnas.96.12.6660]
Schoonjans, K., Dubuquoy, L., Mebis, J., Fayard, E., Wendling, O., Haby, C., Geboes, K., Auwerx, J. Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation. Proc. Nat. Acad. Sci. 102: 2058-2062, 2005. [PubMed: 15684064] [Full Text: https://doi.org/10.1073/pnas.0409756102]
Sirianni, R., Seely, J. B., Attia, G., Stocco, D. M., Carr, B. R., Pezzi, V., Rainey, W. E. Liver receptor homologue-1 is expressed in human steroidogenic tissues and activates transcription of genes encoding steroidogenic enzymes. J. Endocr. 174: R13-R17, 2002. Note: Electronic Article. [PubMed: 12208674] [Full Text: https://doi.org/10.1677/joe.0.174r013]