TABLE 17

ERRα

Receptor nomenclature NR3B1
Receptor code 4.10.1:OR:3:B1
Other names ERR1, ESRL1
Molecular information Hs: 519aa, P11474, chr. 11q131
Rn: 421aa, Q5QJV7, chr. 1q43
Mm: 462aa, O08580, chr. 19 A2
DNA binding
   Structure Monomer, homodimer
   HRE core sequence TNA AGGTCA (ERE, SFRE)
Partners ERα (physical, functional): may play a role in the response of some genes to estrogen via heterodimerization with ERs3,4
Agonists 5,7,4′-Trihydroxyisoflavone, 7,4′-dihydroxyisoflavone, 5,7-dihydroxy-4′-methoxyisoflavone5
Antagonists XCT790 (300–500 nM), diethylstilbestrol (5–15 μM) [IC50]6,7; toxaphene, chlordane8
Coactivators PNRC2, PPARGC1A, NCOA3, NCOA2, NCOA1, PNCR9–14
Corepressors
Biologically important isoforms
Tissue distribution Developmental: nervous system, muscles, epidermis, and several endodermal derivatives, such as the epithelium of the intestine and urogenital system; adult: cerebellum, hippocampus, kidney, gut, heart, hypothalamus, liver, lung, uterus, vagina, cervix {Hs, Mm} [Northern blot, in situ hybridization, Western blot, immunohistology]1,2,4,15–18
Functional assays
Main target genes Activated: MCAD {Hs, Mm, Rn},17 osteopontin {Hs, Mm, Rn},19 lactoferrin {Hs, Mm, Rn},3 TRα {Hs, Mm, Rn},20 ApoA4 {Hs, Mm, Rn}21
Mutant phenotype Knockout mice have reduced body weight and peripheral fat deposits and are resistant to high-fat diet-induced obesity {Mm} [knockout]22
Human disease Osteoporosis: there is a statistically significant association between ERRα promoter polymorphism and lumbar spine BMD, suggesting a link between ERRα regulation and osteoporosis23; obesity: a recent study found a significant association between ERRα promoter polymorphism and elevated BMI24

  • aa, amino acids; chr., chromosome; HRE, hormone response element; PPARGC, PPAR coactivator gene; BMD, bone mineral density; BMI, body mass index; ERE, estrogen response element; SFRE, SF-1 response element; MCAD, medium-chain acyl-coenzyme A dehydrogenase

  • ↵1. Giguere, Yang N, Segui P, and Evans RM (1988) Identification of a new class of steroid hormone receptors. Nature (Lond) 331: 91-94

  • ↵2. Shigeta H, Zuo W, Yang N, DiAugustine R, and Teng CT (1997) The mouse estrogen receptor-related orphan receptor α 1: molecular cloning and estrogen responsiveness. J Mol Endocrinol 19: 299-309

  • ↵3. Yang N, Shigeta H, Shi H, and Teng CT (1996) Estrogen-related receptor, hERR1, modulates estrogen receptor-mediated response of human lactoferrin gene promoter. J Biol Chem 271: 5795-5804

  • ↵4. Johnston SD, Liu X, Zuo F, Eisenbraun TL, Wiley SR, Kraus RJ, and Mertz JE (1997) Estrogen-related receptor α 1 functionally binds as a monomer to extended half-site sequences including ones contained within estrogen-response elements. Mol Endocrinol 11: 342-352

  • ↵5. Suetsugi M, Su L, Karlsberg K, Yuan YC, and Chen S (2003) Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors. Mol Cancer Res 1: 981-991

  • ↵6. Tremblay GB, Kunath T, Bergeron D, Lapointe L, Champigny C, Bader JA, Rossant J, and Giguere V (2001) Diethylstilbestrol regulates trophoblast stem cell differentiation as a ligand of orphan nuclear receptor ERRβ. Genes Dev 15: 833-838

  • ↵7. Willy PJ, Murray IF, Qian J, Busch BB Jr, Stevens WC, Martin R, Mohan R, Zhou S, Ordentlich P, Wei P, et al. (2004) Regulation of PPARγ coactivator 1α (PGC-1α) signaling by an estrogen-related receptor α (ERRα) ligand. Proc Natl Acad Sci USA 101: 8912-8917

  • ↵8. Yang C and Chen S (1999) Two organochlorine pesticides, toxaphene and chlordane, are antagonists for estrogen-related receptor α -1 orphan receptor. Cancer Res 59: 4519-4524

  • ↵9. Zhou D and Chen S (2001) PNRC2 is a 16 kDa coactivator that interacts with nuclear receptors through an SH3-binding motif. Nucleic Acids Res 29: 3939-3948

  • ↵10. Ichida M, Nemoto S, and Finkel T (2002) Identification of a specific molecular repressor of the peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α). J Biol Chem 277: 50991-50995

  • ↵11. Schreiber SN, Knutti D, Brogli K, Uhlmann T, and Kralli A (2003) The transcriptional coactivator PGC-1 regulates the expression and activity of the orphan nuclear receptor estrogen-related receptor α (ERRα). J Biol Chem 278: 9013-9018

  • ↵12. Huss JM, Kopp RP, and Kelly DP (2002) Peroxisome proliferator-activated receptor coactivator-1α (PGC-1α) coactivates the cardiac-enriched nuclear receptors estrogen-related receptor-α and -γ : identification of novel leucine-rich interaction motif within PGC-1α. J Biol Chem 277: 40265-40274

  • ↵13. Xie W, Hong H, Yang NN, Lin RJ, Simon CM, Stallcup MR, and Evans RM (1999) Constitutive activation of transcription and binding of coactivator by estrogen-related receptors 1 and 2. Mol Endocrinol 13: 2151-2162

  • ↵14. Zhou D, Quach KM, Yang C, Lee SY, Pohajdak B, and Chen S (2000) PNRC: a proline-rich nuclear receptor coregulatory protein that modulates transcriptional activation of multiple nuclear receptors including orphan receptors SF1 (steroidogenic factor 1) and ERRα 1 (estrogen related receptor α -1). Mol Endocrinol 14: 986-998

  • ↵15. Bonnelye E, Vanacker JM, Dittmar T, Begue A, Desbiens X, Denhardt DT, Aubin JE, Laudet V, and Fournier B (1997) The ERR-1 orphan receptor is a transcriptional activator expressed during bone development. Mol Endocrinol 11: 905-916

  • ↵16. Bonnelye E, Vanacker JM, Spruyt N, Alric S, Fournier B, Desbiens X, and Laudet V (1997) Expression of the estrogen-related receptor 1 (ERR-1) orphan receptor during mouse development. Mech Dev 65: 71-85

  • ↵17. Sladek R, Bader JA, and Giguere V (1997) The orphan nuclear receptor estrogen-related receptor α is a transcriptional regulator of the human medium-chain acyl coenzyme A dehydrogenase gene. Mol Cell Biol 17: 5400-5409

  • ↵18. Horard B, Rayet B, Triqueneaux G, Laudet V, Delaunay F, and Vanacker JM (2004) Expression of the orphan nuclear receptor ERRα is under circadian regulation in estrogen-responsive tissues. J Mol Endocrinol 33: 87-97

  • ↵19. Vanacker JM, Delmarre C, Guo X, and Laudet V (1998) Activation of the osteopontin promoter by the orphan nuclear receptor estrogen receptor related α. Cell Growth Differ 9: 1007-1014

  • ↵20. Vanacker JM, Bonnelye E, Delmarre C, and Laudet V (1998) Activation of the thyroid hormone receptor α gene promoter by the orphan nuclear receptor ERR α. Oncogene 17: 2429-2435

  • ↵21. Carrier JC, Deblois G, Champigny C, Levy E, and Giguere V (2004) Estrogen-related receptor α (ERRα) is a transcriptional regulator of apolipoprotein A-IV and controls lipid handling in the intestine. J Biol Chem 279: 52052-52058

  • ↵22. Luo J, Sladek R, Carrier J, Bader JA, Richard D, and Giguere V (2003) Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor α. Mol Cell Biol 23: 7947-7956

  • ↵23. Laflamme N, Giroux S, Loredo-Osti JC, Elfassihi L, Dodin S, Blanchet C, Morgan K, Giguere V, and Rousseau F (2005) A frequent regulatory variant of the estrogen-related receptor α gene associated with BMD in French-Canadian premenopausal women. J Bone Miner Res 20: 938-944

  • ↵24. Kamei Y, Lwin H, Saito K, Yokoyama T, Yoshiike N, Ezaki O, and Tanaka H (2005) The 2.3 genotype of ESRRA23 of the ERR α gene is associated with a higher BMI than the 2.2 genotype. Obes Res 13: 1843-1844