TABLE 24

LRH-1

Receptor nomenclature NR5A2
Receptor code 4.10.1:OR:5:A2
Other names FTF, CPF, Hb1F, FTZ-F1β
Molecular information Hs: 541aa, O00482, chr. 1q321
Rn: 560aa, chr. 13q132
Mm: 560aa, P45448, chr. 1 E4
DNA binding
   Structure Monomer
   HRE core sequence YCA AGG YCR (half-site)
Partners DAX1 (physical, functional): inhibition of LRH-1-dependent transactivation3; SHP (physical, functional): inhibition of LRH-1-dependent transactivation3,4; β -catenin (physical, functional): DNA binding and increased transcriptional activity of cyclin E1 gene and cyclin D1 gene5
Agonists Phosphatidyl-(3,4,5)-inositol triphosphate, phosphatidyl-(3,4)-inositol biphosphate, phosphatidyl-(3,5)-inositol biphosphate, phosphatidyl-(4,5)-inositol biphosphate, phosphatidylethanolamine C16:1, C18:1, and C18:3, phosphatidylglycerol C16:1 and C18:16–9
Antagonists
Coactivators NCOA1, NCOA3, EP300, NCOA62, EDF18,10–12
Corepressors Prox113,14
Biologically important isoforms LRH-1v1 {Hs}: contains a larger A/B domain1,15; LRH-1v2 {Hs}: smallest isoform, contains deletions within the D and E domains caused by another alternative splicing event in exon 5, cannot activate transcription although the transcription factors have not yet been identified15,16
Tissue distribution Liver, pancreas, intestine, ovary, and preadipocyte and at lower levels in the placenta; in the adrenal gland and testis, expression is species-specific {Hs, Mm, Rn} [Northern blot, in situ hybridization, Western blot, immunohistology]1,17–25
Functional assays
Main target genes Activated: CYP11A1 {Hs},26 ApoA1 {Hs, Mm, Rn},27 cyclin E1 {Mm},5 StAR {Hs, Mm, Rn},28 ABCG5/ABCG8 {Hs}29
Mutant phenotype LRH-1–/– embryos die at embryonic days 6.5–7.5 with features typical of visceral endoderm dysfunction {Mm} [knockout]5,30,31; LRH-1+/– adult mice are hypocholesterolemic and express liver FTF at about 40% of the normal level {Mm} [knockout]5,30,31
Human disease

  • aa, amino acids; chr., chromosome; HRE, hormone response element; FTF, fetoprotein transcription factor; StAR, steroidogenic acute regulatory

  • ↵1. Galarneau L, Drouin R, and Belanger L (1998) Assignment of the fetoprotein transcription factor gene (FTF) to human chromosome band 1q32.11 by in situ hybridization. Cytogenet Cell Genet 82: 269-270

  • ↵2. Galarneau L, Pare JF, Allard D, Hamel D, Levesque L, Tugwood JD, Green S, and Belanger L (1996) The α 1-fetoprotein locus is activated by a nuclear receptor of the Drosophila FTZ-F1 family. Mol Cell Biol 16: 3853-3865

  • ↵3. Sablin EP, Krylova IN, Fletterick RJ, and Ingraham HA (2003) Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1. Mol Cell 11: 1575-1585

  • ↵4. Li Y, Choi M, Suino K, Kovach A, Daugherty J, Kliewer SA, and 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: 9505-9510

  • ↵5. Botrugno OA, Fayard E, Annicotte JS, Haby C, Brennan T, Wendling O, Tanaka T, Kodama T, Thomas W, Auwerx J, et al. (2004) Synergy between LRH-1 and β -catenin induces G1 cyclin-mediated cell proliferation. Mol Cell 15: 499-509

  • ↵6. Krylova IN, Sablin EP, Moore J, Xu RX, Waitt GM, MacKay JA, Juzumiene D, Bynum JM, Madauss K, Montana V, et al. (2005) Structural analyses reveal phosphatidyl inositols as ligands for the NR5 orphan receptors SF-1 and LRH-1. Cell 120: 343-355

  • ↵7. Li Y, Choi M, Cavey G, Daugherty J, Suino K, Kovach A, Bingham NC, Kliewer SA, and Xu HE (2005) Crystallographic identification and functional characterization of phospholipids as ligands for the orphan nuclear receptor steroidogenic factor-1. Mol Cell 17: 491-502

  • ↵8. Ortlund EA, Lee Y, Solomon IH, Hager JM, Safi R, Choi Y, Guan Z, Tripathy A, Raetz CR, McDonnell DP, et al. (2005) Modulation of human nuclear receptor LRH-1 activity by phospholipids and SHP. Nat Struct Mol Biol 12: 357-363

  • ↵9. Wang W, Zhang C, Marimuthu A, Krupka HI, Tabrizizad M, Shelloe R, Mehra U, Eng K, Nguyen H, Settachatgul C, et al. (2005) The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1. Proc Natl Acad Sci USA 102: 7505-7510

  • ↵10. Xu PL, Liu YQ, Shan SF, Kong YY, Zhou Q, Li M, Ding JP, Xie YH, and Wang Y (2004) Molecular mechanism for the potentiation of the transcriptional activity of human liver receptor homolog 1 by steroid receptor coactivator-1. Mol Endocrinol 18: 1887-1905

  • ↵11. Weck J and Mayo KE (2006) Switching of NR5A proteins associated with the inhibin α -subunit gene promoter following activation of the gene in granulosa cells. Mol Endocrinol 20: 1090-1103

  • ↵12. Brendel C, Gelman L, and Auwerx J (2002) Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism. Mol Endocrinol 16: 1367-1377

  • ↵13. Qin J, Gao DM, Jiang QF, Zhou Q, Kong YY, Wang Y, and Xie YH (2004) Prospero-related homeobox (Prox1) is a corepressor of human liver receptor homolog-1 and suppresses the transcription of the cholesterol 7-α -hydroxylase gene. Mol Endocrinol 18: 2424-2439

  • ↵14. Steffensen KR, Holter E, Bavner A, Nilsson M, Pelto-Huikko M, Tomarev S, and Treuter E (2004) Functional conservation of interactions between a homeodomain cofactor and a mammalian FTZ-F1 homologue. EMBO Rep 5: 613-619

  • ↵15. Nitta M, Ku S, Brown C, Okamoto AY, and Shan B (1999) CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7α -hydroxylase gene. Proc Natl Acad Sci USA 96: 6660-6665

  • ↵16. Zhang CK, Lin W, Cai YN, Xu PL, Dong H, Li M, Kong YY, Fu G, Xie YH, Huang GH, et al. (2001) Characterization of the genomic structure and tissue-specific promoter of the human nuclear receptor NR5A2 (hB1F) gene. Gene 273: 239-249

  • ↵17. Boerboom D, Pilon N, Behdjani R, Silversides DW, and 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: 4647-4656

  • ↵18. Li M, Xie YH, Kong YY, Wu X, Zhu L, and 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: 29022-29031

  • ↵19. Wang ZN, Bassett M, and Rainey WE (2001) Liver receptor homologue-1 is expressed in the adrenal and can regulate transcription of 11β -hydroxylase. J Mol Endocrinol 27: 255-258

  • ↵20. Schoonjans K, Annicotte JS, Huby T, Botrugno OA, Fayard E, Ueda Y, Chapman J, and Auwerx J (2002) Liver receptor homolog 1 controls the expression of the scavenger receptor class B type I. EMBO Rep 3: 1181-1187

  • ↵21. Hinshelwood MM, Repa JJ, Shelton JM, Richardson JA, Mangelsdorf DJ, and 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: 39-45

  • ↵22. Liu DL, Liu WZ, Li QL, Wang HM, Qian D, Treuter E, and Zhu C (2003) Expression and functional analysis of liver receptor homologue 1 as a potential steroidogenic factor in rat ovary. Biol Reprod 69: 508-517

  • ↵23. Falender AE, Lanz R, Malenfant D, Belanger and Richards JS (2003) Differential expression of steroidogenic factor-1 and FTF/LRH-1 in the rodent ovary. Endocrinology 144: 3598-3610

  • ↵24. Sirianni R, Seely JB, Attia G, Stocco DM, Carr BR, Pezzi V, and Rainey WE (2002) Liver receptor homologue-1 is expressed in human steroidogenic tissues and activates transcription of genes encoding steroidogenic enzymes. J Endocrinol 174: R13-17

  • ↵25. Clyne CD, Speed CJ, Zhou J, and Simpson ER (2002) Liver receptor homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes. J Biol Chem 277: 20591-20597

  • ↵26. Kim JW, Havelock JC, Carr BR, and 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: 1678-1685

  • ↵27. Delerive P, Galardi CM, Bisi JE, Nicodeme E, and Goodwin B (2004) Identification of liver receptor homolog-1 as a novel regulator of apolipoprotein AI gene transcription. Mol Endocrinol 18: 2378-2387

  • ↵28. Kim JW, Peng N, Rainey WE, Carr BR, and Attia GR (2004) Liver receptor homolog-1 regulates the expression of steroidogenic acute regulatory protein in human granulosa cells. J Clin Endocrinol Metab 89: 3042-3047

  • ↵29. Freeman LA, Kennedy A, Wu J, Bark S, Remaley AT, Santamarina-Fojo S, and Brewer Jr HB (2004) The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter. J Lipid Res 45: 1197-1206

  • ↵30. Pare JF, Malenfant D, Courtemanche C, Jacob-Wagner M, Roy S, Allard D, and Belanger 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: 21206-21216

  • ↵31. Schoonjans K, Dubuquoy L, Mebis J, Fayard E, Wendling O, Haby C, Geboes K, and 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: 2058-2062