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Target not currently curated in GtoImmuPdb
Target id: 633
Nomenclature: Liver receptor homolog-1
Systematic Nomenclature: NR5A2
Gene and Protein Information  |
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| Species | AA | Chromosomal Location | Gene Symbol | Gene Name | Reference |
| Human | 541 | 1q32.1 | NR5A2 | nuclear receptor subfamily 5 group A member 2 | 8 |
| Mouse | 560 | 1 E4 | Nr5a2 | nuclear receptor subfamily 5, group A, member 2 | 20 |
| Rat | 560 | 13q13 | Nr5a2 | nuclear receptor subfamily 5, group A, member 2 | 9 |
| Previous and Unofficial Names |
| B1F2 | FTZ-F1 | hB1F-2 | α1-fetoprotein transcription factor | B1-binding factor | hepatocytic transcription factor | LRH-1 | FTF | FTZ-F1 beta2 protein | liver receptor homolog 1 | FTZ-F1β | nuclear receptor subfamily 5 |
| Database Links |
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| Alphafold | O00482 (Hs), P45448 (Mm), Q9QWM1 (Rn) |
| CATH/Gene3D | 3.30.50.10 |
| ChEMBL Target | CHEMBL3544 (Hs) |
| Ensembl Gene | ENSG00000116833 (Hs), ENSMUSG00000026398 (Mm), ENSRNOG00000000653 (Rn) |
| Entrez Gene | 2494 (Hs), 26424 (Mm), 60349 (Rn) |
| Human Protein Atlas | ENSG00000116833 (Hs) |
| KEGG Gene | hsa:2494 (Hs), mmu:26424 (Mm), rno:60349 (Rn) |
| OMIM | 604453 (Hs) |
| Pharos | O00482 (Hs) |
| RefSeq Nucleotide | NM_003822 (Hs), NM_030676 (Mm), NM_001159769 (Mm), NM_021742 (Rn) |
| RefSeq Protein | NP_003813 (Hs), NP_995582 (Hs), NP_109601 (Mm), NP_068510 (Rn) |
| UniProtKB | O00482 (Hs), P45448 (Mm), Q9QWM1 (Rn) |
| Wikipedia | NR5A2 (Hs) |
| Selected 3D Structures |
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| Natural/Endogenous Ligands |
| Comments: Orphan |
Download all structure-activity data for this target as a CSV file 
| Agonists |
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| Key to terms and symbols | View all chemical structures | Click column headers to sort | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Immuno Process Associations | ||
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| DNA Binding |
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| DNA Binding Comments | |||||||
| In the NR5A subfamily, specificity of DNA binding is dictated by the Ftz-F1 box, which is a stretch of 26 amino acids at the C terminus of the DBD. | |||||||
| Co-binding Partners |
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| Name | Interaction | Effect | Reference |
| DAX1 | Physical, Functional | Inhibition of LRH-1 dependent transactivation. | 24 |
| SHP | Physical, Functional | Inhibition of LRH-1 dependent transactivation. | 15,24 |
| Beta catenin | Physical, Functional | DNA binding and LRH-1 interacts with the armadillo repeats of beta-catenin. Beta catenin:LRH-1 complex formation enhance LRH-1 dependent transcriptional activation of the Cyclin E1 gene and beta catenin dependent activation of the Cyclin D1 gene. | 2 |
| Main Co-regulators |
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| Name | Activity | Specific | Ligand dependent | AF-2 dependent | Comments | References |
| NCOA1 | Co-activator | No | No | Yes | 32 | |
| NCOA3 | Co-activator | No | No | Yes | 19 | |
| EP300 | Co-activator | No | No | Yes | 30 | |
| EID1 | Co-activator | No | No | No | MBF-1 interacts with the Ftz-F1 box of LRH-1 and not with the AF-2. MBF-1 does not possess any of the classical histone modifying activities such as histone acetyl- or methyl transferase activities, linked to chromatin remodeling, but interacts in vitro with the transcription factor IID complex | 3 |
| PROX1 | Co-repressor | No | No | No | Prox1 interacts with both the ligand binding domain (LBD) and the DNA binding domain (DBD) of hLRH-1. Gel shift assays reveal that Prox1 impairs the binding of hLRH-1 to the promoter of human cyp7a1 gene | 22,28 |
| SNW1 | Co-activator | No | No | No | NCOA62 interacts and selectively activates LRH-1 in cell transfections assays. The SNW domain is required. (personal expert communication) | |
| Main Target Genes |
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| Name | Species | Effect | Technique | Comments | References |
| CYP11A1 | Human | Activated | Transient transfection, EMSA | 11 | |
| APOA1 | Human | Activated | ChIP, Transient transfection, EMSA, Other | Activation of Apolipoprotein A-1 was shown in all species examined | 5 |
| Ccne1 | Mouse | Activated | 2 | ||
| STAR | Human | Activated | Transient transfection, EMSA | shown in all species | 12 |
| ABCG5 | Human | Activated | Transient transfection, EMSA, Other | LRH-1 activates the ABCG5/ABCG8 intergenic promoter | 7 |
| ABCG8 | Human | Activated | Transient transfection, EMSA, Other | LRH-1 activates the ABCG5/ABCG8 intergenic promoter | 7 |
| Tissue Distribution
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| Physiological Consequences of Altering Gene Expression
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| Phenotypes, Alleles and Disease Models
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Mouse data from MGI | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Biologically Significant Variants
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| General Comments |
| Reported to be stimulated by dilauroylphosphatidylcholine [13,23]. |
1. Boerboom D, Pilon N, Behdjani R, Silversides DW, Sirois J. (2000) Expression and regulation of transcripts encoding two members of the NR5A nuclear receptor subfamily of orphan nuclear receptors, steroidogenic factor-1 and NR5A2, in equine ovarian cells during the ovulatory process. Endocrinology, 141 (12): 4647-56. [PMID:11108279]
2. Botrugno OA, Fayard E, Annicotte JS, Haby C, Brennan T, Wendling O, Tanaka T, Kodama T, Thomas W, Auwerx J, Schoonjans K. (2004) Synergy between LRH-1 and beta-catenin induces G1 cyclin-mediated cell proliferation. Mol Cell, 15 (4): 499-509. [PMID:15327767]
3. Brendel C, Gelman L, Auwerx J. (2002) Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism. Mol Endocrinol, 16 (6): 1367-77. [PMID:12040021]
4. Clyne CD, Speed CJ, Zhou J, Simpson ER. (2002) Liver receptor homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. J Biol Chem, 277 (23): 20591-7. [PMID:11927588]
5. Delerive P, Galardi CM, Bisi JE, Nicodeme E, Goodwin B. (2004) Identification of liver receptor homolog-1 as a novel regulator of apolipoprotein AI gene transcription. Mol Endocrinol, 18 (10): 2378-87. [PMID:15218078]
6. Fahmi AI, Patel M, Stevens EB, Fowden AL, John JE, Lee K, Pinnock R, Morgan K, Jackson AP, Vandenberg JI. (2001) The sodium channel beta-subunit SCN3b modulates the kinetics of SCN5a and is expressed heterogeneously in sheep heart. J Physiol (Lond.), 537 (Pt 3): 693-700. [PMID:11744748]
7. Freeman LA, Kennedy A, Wu J, Bark S, Remaley AT, Santamarina-Fojo S, Brewer HB. (2004) The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter. J Lipid Res, 45 (7): 1197-206. [PMID:15121760]
8. Galarneau L, Drouin R, Bélanger L. (1998) Assignment of the fetoprotein transcription factor gene (FTF) to human chromosome band 1q32.11 by in situ hybridization. Cytogenet Cell Genet, 82 (3-4): 269-70. [PMID:9858833]
9. Galarneau L, Paré JF, Allard D, Hamel D, Levesque L, Tugwood JD, Green S, Bélanger L. (1996) The alpha1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family. Mol Cell Biol, 16 (7): 3853-65. [PMID:8668203]
10. Hinshelwood MM, Repa JJ, Shelton JM, Richardson JA, Mangelsdorf DJ, Mendelson CR. (2003) Expression of LRH-1 and SF-1 in the mouse ovary: localization in different cell types correlates with differing function. Mol Cell Endocrinol, 207 (1-2): 39-45. [PMID:12972182]
11. Kim JW, Havelock JC, Carr BR, Attia GR. (2005) The orphan nuclear receptor, liver receptor homolog-1, regulates cholesterol side-chain cleavage cytochrome p450 enzyme in human granulosa cells. J Clin Endocrinol Metab, 90 (3): 1678-85. [PMID:15613430]
12. Kim JW, Peng N, Rainey WE, Carr BR, Attia GR. (2004) Liver receptor homolog-1 regulates the expression of steroidogenic acute regulatory protein in human granulosa cells. J Clin Endocrinol Metab, 89 (6): 3042-7. [PMID:15181096]
13. Lee JM, Lee YK, Mamrosh JL, Busby SA, Griffin PR, Pathak MC, Ortlund EA, Moore DD. (2011) A nuclear-receptor-dependent phosphatidylcholine pathway with antidiabetic effects. Nature, 474 (7352): 506-10. [PMID:21614002]
14. Li M, Xie YH, Kong YY, Wu X, Zhu L, Wang Y. (1998) 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 (44): 29022-31. [PMID:9786908]
15. Li Y, Choi M, Suino K, Kovach A, Daugherty J, Kliewer SA, Xu HE. (2005) Structural and biochemical basis for selective repression of the orphan nuclear receptor liver receptor homolog 1 by small heterodimer partner. Proc Natl Acad Sci USA, 102 (27): 9505-10. [PMID:15976031]
16. Liu DL, Liu WZ, Li QL, Wang HM, Qian D, Treuter E, Zhu C. (2003) Expression and functional analysis of liver receptor homologue 1 as a potential steroidogenic factor in rat ovary. Biol Reprod, 69 (2): 508-17. [PMID:12672674]
17. Mays SG, Flynn AR, Cornelison JL, Okafor CD, Wang H, Wang G, Huang X, Donaldson HN, Millings EJ, Polavarapu R et al.. (2019) Development of the First Low Nanomolar Liver Receptor Homolog-1 Agonist through Structure-guided Design. J Med Chem, 62 (24): 11022-11034. [PMID:31419141]
18. Nitta M, Ku S, Brown C, Okamoto AY, Shan B. (1999) CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7alpha-hydroxylase gene. Proc Natl Acad Sci USA, 96 (12): 6660-5. [PMID:10359768]
19. Ortlund EA, Lee Y, Solomon IH, Hager JM, Safi R, Choi Y, Guan Z, Tripathy A, Raetz CR, McDonnell DP, Moore DD, Redinbo MR. (2005) Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nat Struct Mol Biol, 12 (4): 357-63. [PMID:15723037]
20. Pare JF, Roy S, Galarneau L, Belanger L. (2001) The mouse fetoprotein transcription factor (FTF) gene promoter is regulated by three GATA elements with tandem E box and Nkx motifs, and FTF in turn activates the Hnf3beta, Hnf4alpha, and Hnf1alpha gene promoters. J Biol Chem, 276 (16): 13136-44. [PMID:11145965]
21. Paré JF, Malenfant D, Courtemanche C, Jacob-Wagner M, Roy S, Allard D, Bélanger L. (2004) The fetoprotein transcription factor (FTF) gene is essential to embryogenesis and cholesterol homeostasis and is regulated by a DR4 element. J Biol Chem, 279 (20): 21206-16. [PMID:15014077]
22. Qin J, Gao DM, Jiang QF, Zhou Q, Kong YY, Wang Y, Xie YH. (2004) Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-alpha-hydroxylase gene. Mol Endocrinol, 18 (10): 2424-39. [PMID:15205472]
23. Sablin EP, Blind RD, Krylova IN, Ingraham JG, Cai F, Williams JD, Fletterick RJ, Ingraham HA. (2009) Structure of SF-1 bound by different phospholipids: evidence for regulatory ligands. Mol Endocrinol, 23 (1): 25-34. [PMID:18988706]
24. Sablin EP, Krylova IN, Fletterick RJ, Ingraham HA. (2003) Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. Mol Cell, 11 (6): 1575-85. [PMID:12820970]
25. Schoonjans K, Annicotte JS, Huby T, Botrugno OA, Fayard E, Ueda Y, Chapman J, Auwerx J. (2002) Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I. EMBO Rep, 3 (12): 1181-7. [PMID:12446566]
26. Schoonjans K, Dubuquoy L, Mebis J, Fayard E, Wendling O, Haby C, Geboes K, Auwerx J. (2005) Liver receptor homolog 1 contributes to intestinal tumor formation through effects on cell cycle and inflammation. Proc Natl Acad Sci USA, 102 (6): 2058-62. [PMID:15684064]
27. Sirianni R, Seely JB, Attia G, Stocco DM, Carr BR, Pezzi V, Rainey WE. (2002) Liver receptor homologue-1 is expressed in human steroidogenic tissues and activates transcription of genes encoding steroidogenic enzymes. J Endocrinol, 174 (3): R13-7. [PMID:12208674]
28. Steffensen KR, Holter E, Båvner A, Nilsson M, Pelto-Huikko M, Tomarev S, Treuter E. (2004) Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue. EMBO Rep, 5 (6): 613-9. [PMID:15143342]
29. Wang ZN, Bassett M, Rainey WE. (2001) Liver receptor homologue-1 is expressed in the adrenal and can regulate transcription of 11 beta-hydroxylase. J Mol Endocrinol, 27 (2): 255-8. [PMID:11564608]
30. Weck J, Mayo KE. (2006) Switching of NR5A proteins associated with the inhibin alpha-subunit gene promoter after activation of the gene in granulosa cells. Mol Endocrinol, 20 (5): 1090-103. [PMID:16423880]
31. Whitby RJ, Stec J, Blind RD, Dixon S, Leesnitzer LM, Orband-Miller LA, Williams SP, Willson TM, Xu R, Zuercher WJ et al.. (2011) Small molecule agonists of the orphan nuclear receptors steroidogenic factor-1 (SF-1, NR5A1) and liver receptor homologue-1 (LRH-1, NR5A2). J Med Chem, 54 (7): 2266-81. [PMID:21391689]
32. Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K et al.. (2004) Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell, 116 (6): 883-95. [PMID:15035989]
33. Zhang CK, Lin W, Cai YN, Xu PL, Dong H, Li M, Kong YY, Fu G, Xie YH, Huang GM, Wang Y. (2001) Characterization of the genomic structure and tissue-specific promoter of the human nuclear receptor NR5A2 (hB1F) gene. Gene, 273 (2): 239-49. [PMID:11595170]
5A. Fushi tarazu F1-like receptors: Liver receptor homolog-1. Last modified on 10/09/2019. Accessed on 06/12/2024. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=633.
