Liver receptor homolog-1 explained

The liver receptor homolog-1 (LRH-1) also known as totipotency pioneer factor NR5A2 (nuclear receptor subfamily 5, group A, member 2) is a protein that in humans is encoded by the NR5A2 gene.^{[1] [2]} LRH-1 is a member of the nuclear receptor family of intracellular transcription factors.

LRH-1 plays a critical role in the regulation of development, cholesterol transport, bile acid homeostasis and steroidogenesis.^{[3] [4] [5] [6]}

LRH-1 is important for maintaining pluripotence of stem cells during embryonic development.^{[7] [6]}

Nr5a2 was recently identified at a totipotent pioneer factor. The orphan nuclear receptor Nr5a2 has been shown to be important in fertility, ovarian function,^[8] and zygotic genome activation (ZGA).^[9] Heterozygosity for Nr5a2 is associated with reduced ovarian function, specifically in the synthesis of progesterone. This impaired progesterone production was associated with infertility in female mice, as well as increased incidence of pregnancy loss. The loss of embryos around implantation associated with Nr5a2+/- mice indicated a possible interaction with genome-wide gene expression in early embryo development. Upon further investigation, Nr5a2 was found to regulate ZGA in mice embryos similar to that of Zelda in Drosophila. Nr5a2 is maternally contributed and regulates transcription activity in the early embryo by binding to distal cis-regulatory sequences and promoting chromatin accessibility. The change in chromatin conformation allows for the activation of transcription of about 72% of genes involved in ZGA.

Interactions

Liver receptor homolog-1 has been shown to interact with the small heterodimer partner.^{[10] [11]}

Further reading

• Wong M, Ramayya MS, Chrousos GP, Driggers PH, Parker KL . Cloning and sequence analysis of the human gene encoding steroidogenic factor 1 . Journal of Molecular Endocrinology . 17 . 2 . 139–147 . October 1996 . 8938589 . 10.1677/jme.0.0170139 .
• Li M, Xie YH, Kong YY, 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 . The Journal of Biological Chemistry . 273 . 44 . 29022–29031 . October 1998 . 9786908 . 10.1074/jbc.273.44.29022 . free .
• Goodwin B, Jones SA, Price RR, Watson MA, McKee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA . A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis . Molecular Cell . 6 . 3 . 517–526 . September 2000 . 11030332 . 10.1016/S1097-2765(00)00051-4 . free .
• Wang ZN, Bassett M, Rainey WE . Liver receptor homologue-1 is expressed in the adrenal and can regulate transcription of 11 beta-hydroxylase . Journal of Molecular Endocrinology . 27 . 2 . 255–258 . October 2001 . 11564608 . 10.1677/jme.0.0270255 . free .
• Zhang CK, Lin W, Cai YN, Xu PL, Dong H, Li M, Kong YY, Fu G, Xie YH, Huang GM, Wang Y . Characterization of the genomic structure and tissue-specific promoter of the human nuclear receptor NR5A2 (hB1F) gene . Gene . 273 . 2 . 239–249 . August 2001 . 11595170 . 10.1016/S0378-1119(01)00586-8 .
• Clyne CD, Speed CJ, Zhou J, Simpson ER . Liver receptor homologue-1 (LRH-1) regulates expression of aromatase in preadipocytes . The Journal of Biological Chemistry . 277 . 23 . 20591–20597 . June 2002 . 11927588 . 10.1074/jbc.M201117200 . free .
• Brendel C, Gelman L, Auwerx J . Multiprotein bridging factor-1 (MBF-1) is a cofactor for nuclear receptors that regulate lipid metabolism . Molecular Endocrinology . 16 . 6 . 1367–1377 . June 2002 . 12040021 . 10.1210/mend.16.6.0843 . free .
• Sirianni R, Seely JB, Attia G, Stocco DM, Carr BR, Pezzi V, Rainey WE . Liver receptor homologue-1 is expressed in human steroidogenic tissues and activates transcription of genes encoding steroidogenic enzymes . The Journal of Endocrinology . 174 . 3 . R13–R17 . September 2002 . 12208674 . 10.1677/joe.0.174R013 . free .
• Sablin EP, Krylova IN, Fletterick RJ, Ingraham HA . Structural basis for ligand-independent activation of the orphan nuclear receptor LRH-1 . Molecular Cell . 11 . 6 . 1575–1585 . June 2003 . 12820970 . 10.1016/S1097-2765(03)00236-3 . free .
• Privalsky ML . Activation incarnate . Developmental Cell . 5 . 1 . 1–2 . July 2003 . 12852843 . 10.1016/S1534-5807(03)00196-5 . free .
• Fayard E, Schoonjans K, Annicotte JS, Auwerx J . Liver receptor homolog 1 controls the expression of carboxyl ester lipase . The Journal of Biological Chemistry . 278 . 37 . 35725–35731 . September 2003 . 12853459 . 10.1074/jbc.M302370200 . free .
• Annicotte JS, Fayard E, Swift GH, Selander L, Edlund H, Tanaka T, Kodama T, Schoonjans K, Auwerx J . Pancreatic-duodenal homeobox 1 regulates expression of liver receptor homolog 1 during pancreas development . Molecular and Cellular Biology . 23 . 19 . 6713–6724 . October 2003 . 12972592 . 193920 . 10.1128/MCB.23.19.6713-6724.2003 .
• Peng N, Kim JW, Rainey WE, Carr BR, Attia GR . The role of the orphan nuclear receptor, liver receptor homologue-1, in the regulation of human corpus luteum 3beta-hydroxysteroid dehydrogenase type II . The Journal of Clinical Endocrinology and Metabolism . 88 . 12 . 6020–6028 . December 2003 . 14671206 . 10.1210/jc.2003-030880 .
• Cai YN, Zhou Q, Kong YY, Li M, Viollet B, Xie YH, Wang Y . LRH-1/hB1F and HNF1 synergistically up-regulate hepatitis B virus gene transcription and DNA replication . Cell Research . 13 . 6 . 451–458 . December 2003 . 14728801 . 10.1038/sj.cr.7290187 . free .
• Saxena D, Safi R, Little-Ihrig L, Zeleznik AJ . Liver receptor homolog-1 stimulates the progesterone biosynthetic pathway during follicle-stimulating hormone-induced granulosa cell differentiation . Endocrinology . 145 . 8 . 3821–3829 . August 2004 . 15117876 . 10.1210/en.2004-0423 . free .

Notes and References

1. Bernier D, Thomassin H, Allard D, Guertin M, Hamel D, Blaquière M, Beauchemin M, LaRue H, Estable-Puig M, Bélanger L . Functional analysis of developmentally regulated chromatin-hypersensitive domains carrying the alpha 1-fetoprotein gene promoter and the albumin/alpha 1-fetoprotein intergenic enhancer . Molecular and Cellular Biology . 13 . 3 . 1619–1633 . March 1993 . 7680097 . 359474 . 10.1128/mcb.13.3.1619 .
2. Galarneau L, Drouin R, Bélanger L . Assignment of the fetoprotein transcription factor gene (FTF) to human chromosome band 1q32.11 by in situ hybridization . Cytogenetics and Cell Genetics . 82 . 3–4 . 269–270 . 1998 . 9858833 . 10.1159/000015116 . 46813832 .
3. Fayard E, Auwerx J, Schoonjans K . LRH-1: an orphan nuclear receptor involved in development, metabolism and steroidogenesis . Trends in Cell Biology . 14 . 5 . 250–260 . May 2004 . 15130581 . 10.1016/j.tcb.2004.03.008 .
4. Luo Y, Liang CP, Tall AR . The orphan nuclear receptor LRH-1 potentiates the sterol-mediated induction of the human CETP gene by liver X receptor . The Journal of Biological Chemistry . 276 . 27 . 24767–24773 . July 2001 . 11331284 . 10.1074/jbc.M100912200 . free .
5. Nitta M, Ku S, Brown C, Okamoto AY, Shan B . CPF: an orphan nuclear receptor that regulates liver-specific expression of the human cholesterol 7alpha-hydroxylase gene . Proceedings of the National Academy of Sciences of the United States of America . 96 . 12 . 6660–6665 . June 1999 . 10359768 . 21971 . 10.1073/pnas.96.12.6660 . free . 1999PNAS...96.6660N .
6. Gassler J, Kobayashi W, Gáspár I, Ruangroengkulrith S, Mohanan A, Gómez Hernández L, Kravchenko P, Kümmecke M, Lalic A, Rifel N, Ashburn RJ, Zaczek M, Vallot A, Cuenca Rico L, Ladstätter S, Tachibana K . Zygotic genome activation by the totipotency pioneer factor Nr5a2 . Science . 378 . 6626 . 1305–1315 . December 2022 . 36423263 . 10.1126/science.abn7478 . 248923539 . 2022Sci...378.1305G .
7. Gu P, Goodwin B, Chung AC, Xu X, Wheeler DA, Price RR, Galardi C, Peng L, Latour AM, Koller BH, Gossen J, Kliewer SA, Cooney AJ . Orphan nuclear receptor LRH-1 is required to maintain Oct4 expression at the epiblast stage of embryonic development . Molecular and Cellular Biology . 25 . 9 . 3492–3505 . May 2005 . 15831456 . 1084298 . 10.1128/MCB.25.9.3492-3505.2005 .
8. Labelle-Dumais C, Paré JF, Bélanger L, Farookhi R, Dufort D . Impaired progesterone production in Nr5a2+/- mice leads to a reduction in female reproductive function . Biology of Reproduction . 77 . 2 . 217–225 . August 2007 . 17409375 . 10.1095/biolreprod.106.059121 .
9. Gassler J, Kobayashi W, Gáspár I, Ruangroengkulrith S, Mohanan A, Gómez Hernández L, Kravchenko P, Kümmecke M, Lalic A, Rifel N, Ashburn RJ, Zaczek M, Vallot A, Cuenca Rico L, Ladstätter S, Tachibana K . Zygotic genome activation by the totipotency pioneer factor Nr5a2 . Science . 378 . 6626 . 1305–1315 . December 2022 . 36423263 . 10.1126/science.abn7478 . 248923539 . 2022Sci...378.1305G .
10. Brendel C, Schoonjans K, Botrugno OA, Treuter E, Auwerx J . The small heterodimer partner interacts with the liver X receptor alpha and represses its transcriptional activity . Molecular Endocrinology . 16 . 9 . 2065–2076 . September 2002 . 12198243 . 10.1210/me.2001-0194 . free .
11. Lee YK, Moore DD . Dual mechanisms for repression of the monomeric orphan receptor liver receptor homologous protein-1 by the orphan small heterodimer partner . The Journal of Biological Chemistry . 277 . 4 . 2463–2467 . January 2002 . 11668176 . 10.1074/jbc.M105161200 . free .