Estrogen-related receptor alpha

Estrogen-related receptor alpha (ERRα), also known as NR3B1 (nuclear receptor subfamily 3, group B, member 1), is a nuclear receptor that in humans is encoded by the ESRRA (Estrogen Related Receptor Alpha) gene.[3][4] ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha (ERα, NR3A1),[4] but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα.[5] Currently, ERRα is considered an orphan nuclear receptor.[4][5]

ESRRA
Available structures PDB Human UniProt search: PDBe RCSB List of PDB id codes 1XB7, 2PJL, 3D24, 3K6P
Identifiers
Aliases	ESRRA, ERR1, ERRa, ERRalpha, ESRL1, NR3B1, estrogen related receptor alpha
External IDs	OMIM: 601998 HomoloGene: 136738 GeneCards: ESRRA
Gene location (Human) Chr. Chromosome 11 (human)[1] Band 11q13.1 Start 64,305,497 bp[1] End 64,316,743 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • DNA binding • sequence-specific DNA binding • protein domain specific binding • GO:0001131, GO:0001151, GO:0001130, GO:0001204 DNA-binding transcription factor activity • zinc ion binding • GO:0001077, GO:0001212, GO:0001213, GO:0001211, GO:0001205 DNA-binding transcription activator activity, RNA polymerase II-specific • metal ion binding • GO:0000980 RNA polymerase II cis-regulatory region sequence-specific DNA binding • steroid hormone receptor activity • GO:0001078, GO:0001214, GO:0001206 DNA-binding transcription repressor activity, RNA polymerase II-specific • GO:0038050, GO:0004886, GO:0038051 nuclear receptor activity • steroid binding • GO:0001948 protein binding • GO:0001200, GO:0001133, GO:0001201 DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component • microtubule cytoskeleton • nucleoplasm • intercellular bridge • cell nucleus • fibrillar center • cytoplasm Biological process • response to estradiol • regulation of transcription, DNA-templated • positive regulation of cellular response to insulin stimulus • mitochondrion organization • negative regulation of transcription from RNA polymerase II promoter • transcription, DNA-templated • positive regulation of transcription, DNA-templated • cartilage development • regulation of cell proliferation • regulation of osteoblast differentiation • regulation of osteoclast differentiation • regulation of ossification • transcription initiation from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • steroid hormone mediated signaling pathway • intracellular receptor signaling pathway Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	2101	n/a
Ensembl	ENSG00000173153	n/a
UniProt	P11474	n/a
RefSeq (mRNA)	NM_001282450 NM_001282451 NM_004451	n/a
RefSeq (protein)	NP_001269379 NP_001269380 NP_004442	n/a
Location (UCSC)	Chr 11: 64.31 – 64.32 Mb	n/a
PubMed search	[2]	n/a
Wikidata
View/Edit Human

Tissue distribution

ERRα has wide tissue distribution but it is most highly expressed in tissues that preferentially use fatty acids as energy sources such as kidney, heart, brown adipose tissue, cerebellum, intestine, and skeletal muscle.[6] Recently, ERRα has been detected in normal adrenal cortex tissues, in which its expression is possibly related to adrenal development, with a possible role in fetal adrenal function, in DHEAS production in adrenarche, and also in steroid production of post-adrenarche/adult life.[7]

Function

The protein encoded by this gene is a nuclear receptor that is closely related to the estrogen receptor. Results of both in vitro and in vivo studies suggest that ERRα is required for the activation of mitochondrial genes as well as increased mitochondrial biogenesis.[8][9] This protein acts as a site-specific (consensus TNAAGGTCA) transcription regulator and has been also shown to interact with estrogen and the transcription factor TFIIB by direct protein-protein contact. The binding and regulatory activities of this protein have been demonstrated in the regulation of a variety of genes including lactoferrin, osteopontin, medium-chain acyl coenzyme A dehydrogenase (MCAD) and thyroid hormone receptor genes. It was reported that ERRα can activate reporters containing steroidogenesis factor 1 (SF-1) response elements as a result of transient transfection assays,[10] and a possible role of ERRα in steroidogenesis with relation to SF-1 was subsequently demonstrated in adrenocortical cells.[11] The transcriptional activation of CYP17A1 and SULT2A1 in the adrenal has been proposed as the mechanism of action possibly accounting for the increment in DHEAS serum levels by ERRα.[11] ERRα has been suggested to act as a transcriptional activator of CYP11B1 and CYP11B2, which indicates that this nuclear receptor may be required for the production of cortisol and aldosterone in the adrenal gland.[12]

Metabolism

ERRα regulates genes involved in mitochondrial biogenesis,[13] gluconeogenesis,[14] oxidative phosphorylation,[15] and fatty acid metabolism,[16] and brown adipose tissue thermogenesis.[17][18] It was recently identified as an important regulator of the mammalian circadian clock, and its output pathways at both transcriptional and physiological levels regulated the expression of transcription factors involved in metabolic homeostasis.[19] It has been demonstrated that ERRα is required for the maintenance of diurnal cholesterol, glucose, insulin, bile acid, and trygliceride levels as well as locomotor rhythms in mice.[19] ERRα is related to mitochondrial function but studies involving ERRα knockout mice suggested that this receptor, while dispensable for basal cellular function, is definitely necessary to provide the levels of energy necessary to respond to physiological and pathological insults in diverse tissues,[5] the lack of that nuclear receptor leading to impaired fat metabolism and absorption.[20]

Estrogen signaling

Estrogen receptor alpha (ERα) and estrogen-related receptor alpha (ERRα) have been found to regulate many of the same genes.[21][22] Furthermore, ERRα appears to modulate the activity of ERα in various tissues including breast, uterus, and bone.[23]

Ligands

No endogenous ligands of ERRα have been identified to date, hence ERRα is classified as an orphan receptor. In addition both biochemical and structural studies indicate that ERRα is constitutively active in the absence of ligand.[24] ERRα does, however, interact with the metabolic-inducible coactivator PGC1-α in its AF2 region which is sometimes referred to as the "protein ligand" of ERRα.

The isoflavone phytoestrogens genistein and daidzein are non-selective ERR agonists,[25] while XCT790 has been identified as a potent and selective inverse agonist of ERRα.[26]

Cholesterol has recently been found to bind to and activate the ERRα, and may be the endogenous ligand for the receptor.[27] Moreover, the effects of cholesterol, statins, and bisphosphonates on osteoclastogenesis in bone tissue require ERRα; in accordance, cholesterol-induced bone loss or bisphosphonate osteoprotection is absent in ERRα knockout mice.[27] Furthermore, statin-associated myopathy and suppression of cholesterol-induced cytokine secretion by macrophages are reduced by absence or inhibition of ERRα.[27] As such, modulation of ERRα signaling is a key mediator in the actions of statins (by changes in cholesterol levels) and bisphosphonates.[27]

See also

• Estrogen-related receptor

References

1. GRCh38: Ensembl release 89: ENSG00000173153 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Entrez Gene: ESRRA estrogen-related receptor alpha".
4. Giguère V, Yang N, Segui P, Evans RM (January 1988). "Identification of a new class of steroid hormone receptors". Nature. 331 (6151): 91–4. Bibcode:1988Natur.331...91G. doi:10.1038/331091a0. PMID 3267207. S2CID 4275394.
5. Deblois G, Giguère V (August 2011). "Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease". Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1812 (8): 1032–40. doi:10.1016/j.bbadis.2010.12.009. PMID 21172432.
6. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ (August 2006). "Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network". Cell. 126 (4): 789–99. doi:10.1016/j.cell.2006.06.049. PMC 6211849. PMID 16923397.
7. Felizola SJ, Nakamura Y, Hui XG, Satoh F, Morimoto R, M McNamara K, Midorikawa S, Suzuki S, Rainey WE, Sasano H (January 2013). "Estrogen-related receptor α in normal adrenal cortex and adrenocortical tumors: involvement in development and oncogenesis". Molecular and Cellular Endocrinology. 365 (2): 207–11. doi:10.1016/j.mce.2012.10.020. PMC 4097865. PMID 23123734.
8. Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M, Oakeley EJ, Kralli A (April 2004). "The estrogen-related receptor alpha (ERRalpha) functions in PPARgamma coactivator 1alpha (PGC-1alpha)-induced mitochondrial biogenesis". Proceedings of the National Academy of Sciences of the United States of America. 101 (17): 6472–7. Bibcode:2004PNAS..101.6472S. doi:10.1073/pnas.0308686101. PMC 404069. PMID 15087503.
9. Villena JA, Hock MB, Chang WY, Barcas JE, Giguère V, Kralli A (January 2007). "Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis". Proceedings of the National Academy of Sciences of the United States of America. 104 (4): 1418–23. Bibcode:2007PNAS..104.1418V. doi:10.1073/pnas.0607696104. PMC 1783094. PMID 17229846.
10. Bonnelye E, Vanacker JM, Dittmar T, Begue A, Desbiens X, Denhardt DT, Aubin JE, Laudet V, Fournier B (June 1997). "The ERR-1 orphan receptor is a transcriptional activator expressed during bone development". Molecular Endocrinology. 11 (7): 905–16. doi:10.1210/MEND.11.7.9948. PMID 9178750.
11. Seely J, Amigh KS, Suzuki T, Mayhew B, Sasano H, Giguere V, Laganière J, Carr BR, Rainey WE (August 2005). "Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha". Endocrinology. 146 (8): 3605–13. doi:10.1210/en.2004-1619. PMID 15878968.
12. Cheng LC, Pai TW, Li LA (January 2012). "Regulation of human CYP11B1 and CYP11B2 promoters by transposable elements and conserved cis elements". Steroids. 77 (1–2): 100–9. doi:10.1016/j.steroids.2011.10.010. PMID 22079243. S2CID 140208125.
13. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM (July 1999). "Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1". Cell. 98 (1): 115–24. doi:10.1016/S0092-8674(00)80611-X. PMID 10412986. S2CID 16143809.
14. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM (September 2001). "Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1". Nature. 413 (6852): 131–8. Bibcode:2001Natur.413..131Y. doi:10.1038/35093050. PMID 11557972. S2CID 11184579.
15. Mootha VK, Handschin C, Arlow D, Xie X, St Pierre J, Sihag S, Yang W, Altshuler D, Puigserver P, Patterson N, Willy PJ, Schulman IG, Heyman RA, Lander ES, Spiegelman BM (April 2004). "Erralpha and Gabpa/b specify PGC-1alpha-dependent oxidative phosphorylation gene expression that is altered in diabetic muscle". Proceedings of the National Academy of Sciences of the United States of America. 101 (17): 6570–5. Bibcode:2004PNAS..101.6570M. doi:10.1073/pnas.0401401101. PMC 404086. PMID 15100410.
16. Huss JM, Torra IP, Staels B, Giguère V, Kelly DP (October 2004). "Estrogen-related receptor alpha directs peroxisome proliferator-activated receptor alpha signaling in the transcriptional control of energy metabolism in cardiac and skeletal muscle". Molecular and Cellular Biology. 24 (20): 9079–91. doi:10.1128/MCB.24.20.9079-9091.2004. PMC 517878. PMID 15456881.
17. Villena JA, Hock MB, Chang WY, Barcas JE, Giguère V, Kralli A (January 2007). "Orphan nuclear receptor estrogen-related receptor alpha is essential for adaptive thermogenesis". Proceedings of the National Academy of Sciences of the United States of America. 104 (4): 1418–23. Bibcode:2007PNAS..104.1418V. doi:10.1073/pnas.0607696104. PMC 1783094. PMID 17229846.
18. Emmett MJ, Lim HW, Jager J, Richter HJ, Adlanmerini M, Peed LC, Briggs ER, Steger DJ, Ma T, Sims CA, Baur JA, Pei L, Won KJ, Seale P, Gerhart-Hines Z, Lazar MA (June 2017). "Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge". Nature. 546 (7659): 544–548. Bibcode:2017Natur.546..544E. doi:10.1038/nature22819. PMC 5826652. PMID 28614293.
19. Dufour CR, Levasseur MP, Pham NH, Eichner LJ, Wilson BJ, Charest-Marcotte A, Duguay D, Poirier-Héon JF, Cermakian N, Giguère V (June 2011). Mangelsdorf DJ (ed.). "Genomic convergence among ERRα, PROX1, and BMAL1 in the control of metabolic clock outputs". PLOS Genetics. 7 (6): e1002143. doi:10.1371/journal.pgen.1002143. PMC 3121748. PMID 21731503.
20. Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguère V (November 2003). "Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha". Molecular and Cellular Biology. 23 (22): 7947–56. doi:10.1128/MCB.23.22.7947-7956.2003. PMC 262360. PMID 14585956.
21. Vanacker JM, Bonnelye E, Chopin-Delannoy S, Delmarre C, Cavaillès V, Laudet V (May 1999). "Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha)". Molecular Endocrinology. 13 (5): 764–73. CiteSeerX 10.1.1.321.1698. doi:10.1210/me.13.5.764. PMID 10319326.
22. Vanacker JM, Pettersson K, Gustafsson JA, Laudet V (August 1999). "Transcriptional targets shared by estrogen receptor- related receptors (ERRs) and estrogen receptor (ER) alpha, but not by ERbeta". The EMBO Journal. 18 (15): 4270–9. doi:10.1093/emboj/18.15.4270. PMC 1171503. PMID 10428965.
23. Stein RA, McDonnell DP (December 2006). "Estrogen-related receptor alpha as a therapeutic target in cancer". Endocrine-Related Cancer. 13 Suppl 1: S25–32. doi:10.1677/erc.1.01292. PMID 17259555.
24. Kallen J, Schlaeppi JM, Bitsch F, Filipuzzi I, Schilb A, Riou V, Graham A, Strauss A, Geiser M, Fournier B (November 2004). "Evidence for ligand-independent transcriptional activation of the human estrogen-related receptor alpha (ERRalpha): crystal structure of ERRalpha ligand binding domain in complex with peroxisome proliferator-activated receptor coactivator-1alpha". The Journal of Biological Chemistry. 279 (47): 49330–7. doi:10.1074/jbc.M407999200. PMID 15337744.
25. Suetsugi M, Su L, Karlsberg K, Yuan YC, Chen S (November 2003). "Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors". Molecular Cancer Research. 1 (13): 981–91. PMID 14638870.
26. Busch BB, Stevens WC, Martin R, Ordentlich P, Zhou S, Sapp DW, Horlick RA, Mohan R (November 2004). "Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha". Journal of Medicinal Chemistry. 47 (23): 5593–6. doi:10.1021/jm049334f. PMID 15509154.
27. Wei W, Schwaid AG, Wang X, Wang X, Chen S, Chu Q, Saghatelian A, Wan Y (March 2016). "Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects". Cell Metabolism. 23 (3): 479–91. doi:10.1016/j.cmet.2015.12.010. PMC 4785078. PMID 26777690.

External links

• FactorBook ERRA
• Overview of all the structural information available in the PDB for UniProt: P11474 (Steroid hormone receptor ERR1) at the PDBe-KB.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.