Estrogen-related receptor alpha explained

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.[1] [2] ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha (ERα, NR3A1),[2] but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα.[3] Currently, ERRα is considered an orphan nuclear receptor.[2] [3]

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.[4] 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.[5]

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.[6] [7] 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,[8] and a possible role of ERRα in steroidogenesis with relation to SF-1 was subsequently demonstrated in adrenocortical cells.[9] 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.[9] 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.[10]

Metabolism

ERRα regulates genes involved in mitochondrial biogenesis,[11] gluconeogenesis,[12] oxidative phosphorylation,[13] and fatty acid metabolism,[14] and brown adipose tissue thermogenesis.[15] [16] 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.[17] 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.[17] 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, the lack of that nuclear receptor leading to impaired fat metabolism and absorption.[18]

Estrogen signaling

Estrogen receptor alpha (ERα) and estrogen-related receptor alpha (ERRα) have been found to regulate many of the same genes.[19] [20] Furthermore, ERRα appears to modulate the activity of ERα in various tissues including breast, uterus, and bone.[21]

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.[22] 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,[23] while XCT790 has been identified as a potent and selective inverse agonist of ERRα.[24] SLU-PP-332 is a potent agonist of ERRα.[25]

Cholesterol has recently been found to bind to and activate the ERRα, and may be the endogenous ligand for the receptor.[26] 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. Furthermore, statin-associated myopathy and suppression of cholesterol-induced cytokine secretion by macrophages are reduced by absence or inhibition of ERRα. As such, modulation of ERRα signaling is a key mediator in the actions of statins (by changes in cholesterol levels) and bisphosphonates.

See also

Notes and References

  1. Web site: Entrez Gene: ESRRA estrogen-related receptor alpha.
  2. Giguère V, Yang N, Segui P, Evans RM . Identification of a new class of steroid hormone receptors . Nature . 331 . 6151 . 91–4 . January 1988 . 3267207 . 10.1038/331091a0 . 1988Natur.331...91G . 4275394 .
  3. Deblois G, Giguère V . 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 . August 2011 . 21172432 . 10.1016/j.bbadis.2010.12.009 . free .
  4. Bookout AL, Jeong Y, Downes M, Yu RT, Evans RM, Mangelsdorf DJ . Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network . Cell . 126 . 4 . 789–99 . August 2006 . 16923397 . 6211849 . 10.1016/j.cell.2006.06.049 .
  5. Felizola SJ, Nakamura Y, Hui XG, Satoh F, Morimoto R, M McNamara K, Midorikawa S, Suzuki S, Rainey WE, Sasano H . Estrogen-related receptor α in normal adrenal cortex and adrenocortical tumors: involvement in development and oncogenesis . Molecular and Cellular Endocrinology . 365 . 2 . 207–11 . January 2013 . 23123734 . 4097865 . 10.1016/j.mce.2012.10.020 .
  6. Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M, Oakeley EJ, Kralli A . 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 . April 2004 . 15087503 . 404069 . 10.1073/pnas.0308686101 . 2004PNAS..101.6472S . free .
  7. Villena JA, Hock MB, Chang WY, Barcas JE, Giguère V, Kralli A . 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 . January 2007 . 17229846 . 1783094 . 10.1073/pnas.0607696104 . 2007PNAS..104.1418V . free .
  8. Bonnelye E, Vanacker JM, Dittmar T, Begue A, Desbiens X, Denhardt DT, Aubin JE, Laudet V, Fournier B . The ERR-1 orphan receptor is a transcriptional activator expressed during bone development . Molecular Endocrinology . 11 . 7 . 905–16 . June 1997 . 9178750 . 10.1210/mend.11.7.9948 . free .
  9. Seely J, Amigh KS, Suzuki T, Mayhew B, Sasano H, Giguere V, Laganière J, Carr BR, Rainey WE . Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha . Endocrinology . 146 . 8 . 3605–13 . August 2005 . 15878968 . 10.1210/en.2004-1619 . free .
  10. Cheng LC, Pai TW, Li LA . Regulation of human CYP11B1 and CYP11B2 promoters by transposable elements and conserved cis elements . Steroids . 77 . 1–2 . 100–9 . January 2012 . 22079243 . 10.1016/j.steroids.2011.10.010 . 140208125 .
  11. Wu Z, Puigserver P, Andersson U, Zhang C, Adelmant G, Mootha V, Troy A, Cinti S, Lowell B, Scarpulla RC, Spiegelman BM . Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1 . Cell . 98 . 1 . 115–24 . July 1999 . 10412986 . 10.1016/S0092-8674(00)80611-X . 16143809 . free .
  12. Yoon JC, Puigserver P, Chen G, Donovan J, Wu Z, Rhee J, Adelmant G, Stafford J, Kahn CR, Granner DK, Newgard CB, Spiegelman BM . Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1 . Nature . 413 . 6852 . 131–8 . September 2001 . 11557972 . 10.1038/35093050 . 2001Natur.413..131Y . 11184579 .
  13. 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 . 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 . April 2004 . 15100410 . 404086 . 10.1073/pnas.0401401101 . 2004PNAS..101.6570M . free .
  14. Huss JM, Torra IP, Staels B, Giguère V, Kelly DP . 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 . October 2004 . 15456881 . 517878 . 10.1128/MCB.24.20.9079-9091.2004 .
  15. Villena JA, Hock MB, Chang WY, Barcas JE, Giguère V, Kralli A . 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 . January 2007 . 17229846 . 10.1073/pnas.0607696104 . 1783094 . 2007PNAS..104.1418V . free .
  16. 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 . Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge . Nature . 546 . 7659 . 544–548 . June 2017 . 10.1038/nature22819 . 28614293 . 5826652. 2017Natur.546..544E .
  17. Dufour CR, Levasseur MP, Pham NH, Eichner LJ, Wilson BJ, Charest-Marcotte A, Duguay D, Poirier-Héon JF, Cermakian N, Giguère V . Genomic convergence among ERRα, PROX1, and BMAL1 in the control of metabolic clock outputs . PLOS Genetics . 7 . 6 . e1002143 . June 2011 . 21731503 . 3121748 . 10.1371/journal.pgen.1002143 . Mangelsdorf DJ . free .
  18. Luo J, Sladek R, Carrier J, Bader JA, Richard D, Giguère V . Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha . Molecular and Cellular Biology . 23 . 22 . 7947–56 . November 2003 . 14585956 . 262360 . 10.1128/MCB.23.22.7947-7956.2003 .
  19. Vanacker JM, Bonnelye E, Chopin-Delannoy S, Delmarre C, Cavaillès V, Laudet V . Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha) . Molecular Endocrinology . 13 . 5 . 764–73 . May 1999 . 10.1210/mend.13.5.0281 . 10319326 . 10.1.1.321.1698 .
  20. Vanacker JM, Pettersson K, Gustafsson JA, Laudet V . 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 . August 1999 . 10428965 . 1171503 . 10.1093/emboj/18.15.4270 .
  21. Stein RA, McDonnell DP . Estrogen-related receptor alpha as a therapeutic target in cancer . Endocrine-Related Cancer . 13 . S25–32 . December 2006 . Suppl 1 . 17259555 . 10.1677/erc.1.01292 . free .
  22. Kallen J, Schlaeppi JM, Bitsch F, Filipuzzi I, Schilb A, Riou V, Graham A, Strauss A, Geiser M, Fournier B . 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 . November 2004 . 15337744 . 10.1074/jbc.M407999200 . free .
  23. Suetsugi M, Su L, Karlsberg K, Yuan YC, Chen S . Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors . Molecular Cancer Research . 1 . 13 . 981–91 . November 2003 . 14638870 .
  24. Busch BB, Stevens WC, Martin R, Ordentlich P, Zhou S, Sapp DW, Horlick RA, Mohan R . Identification of a selective inverse agonist for the orphan nuclear receptor estrogen-related receptor alpha . Journal of Medicinal Chemistry . 47 . 23 . 5593–6 . November 2004 . 15509154 . 10.1021/jm049334f .
  25. Billon C, Schoepke E, Avdagic A, Chatterjee A, Butler AA, Elgendy B, Walker JK, Burris TP . A Synthetic ERR Agonist Alleviates Metabolic Syndrome . The Journal of Pharmacology and Experimental Therapeutics . 388. 2. September 2023 . 232–240 . 37739806 . 10.1124/jpet.123.001733 . free . 10801787 . February 1, 2025 .
  26. Wei W, Schwaid AG, Wang X, Wang X, Chen S, Chu Q, Saghatelian A, Wan Y . Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects . Cell Metabolism . 23 . 3 . 479–91 . March 2016 . 26777690 . 10.1016/j.cmet.2015.12.010 . 4785078.

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