Biology:Estrogen-related receptor alpha

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example


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,[3] 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.[26] Furthermore, statin-associated myopathy and suppression of cholesterol-induced cytokine secretion by macrophages are reduced by absence or inhibition of ERRα.[26] As such, modulation of ERRα signaling is a key mediator in the actions of statins (by changes in cholesterol levels) and bisphosphonates.[26]

See also

References

  1. ↑ "Entrez Gene: ESRRA estrogen-related receptor alpha". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=2101. 
  2. ↑ 2.0 2.1 2.2 "Identification of a new class of steroid hormone receptors". Nature 331 (6151): 91–4. January 1988. doi:10.1038/331091a0. PMID 3267207. Bibcode: 1988Natur.331...91G. 
  3. ↑ 3.0 3.1 3.2 "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. doi:10.1016/j.bbadis.2010.12.009. PMID 21172432. 
  4. ↑ "Anatomical profiling of nuclear receptor expression reveals a hierarchical transcriptional network". Cell 126 (4): 789–99. August 2006. doi:10.1016/j.cell.2006.06.049. PMID 16923397. 
  5. ↑ "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. doi:10.1016/j.mce.2012.10.020. PMID 23123734. 
  6. ↑ "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. doi:10.1073/pnas.0308686101. PMID 15087503. Bibcode: 2004PNAS..101.6472S. 
  7. ↑ "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. doi:10.1073/pnas.0607696104. PMID 17229846. Bibcode: 2007PNAS..104.1418V. 
  8. ↑ "The ERR-1 orphan receptor is a transcriptional activator expressed during bone development". Molecular Endocrinology 11 (7): 905–16. June 1997. doi:10.1210/mend.11.7.9948. PMID 9178750. 
  9. ↑ 9.0 9.1 "Transcriptional regulation of dehydroepiandrosterone sulfotransferase (SULT2A1) by estrogen-related receptor alpha". Endocrinology 146 (8): 3605–13. August 2005. doi:10.1210/en.2004-1619. PMID 15878968. 
  10. ↑ "Regulation of human CYP11B1 and CYP11B2 promoters by transposable elements and conserved cis elements". Steroids 77 (1–2): 100–9. January 2012. doi:10.1016/j.steroids.2011.10.010. PMID 22079243. 
  11. ↑ "Mechanisms controlling mitochondrial biogenesis and respiration through the thermogenic coactivator PGC-1". Cell 98 (1): 115–24. July 1999. doi:10.1016/S0092-8674(00)80611-X. PMID 10412986. 
  12. ↑ "Control of hepatic gluconeogenesis through the transcriptional coactivator PGC-1". Nature 413 (6852): 131–8. September 2001. doi:10.1038/35093050. PMID 11557972. Bibcode: 2001Natur.413..131Y. 
  13. ↑ "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. doi:10.1073/pnas.0401401101. PMID 15100410. Bibcode: 2004PNAS..101.6570M. 
  14. ↑ "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. doi:10.1128/MCB.24.20.9079-9091.2004. PMID 15456881. 
  15. ↑ "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. doi:10.1073/pnas.0607696104. PMID 17229846. Bibcode: 2007PNAS..104.1418V. 
  16. ↑ "Histone deacetylase 3 prepares brown adipose tissue for acute thermogenic challenge". Nature 546 (7659): 544–548. June 2017. doi:10.1038/nature22819. PMID 28614293. Bibcode: 2017Natur.546..544E. 
  17. ↑ 17.0 17.1 "Genomic convergence among ERRα, PROX1, and BMAL1 in the control of metabolic clock outputs". PLOS Genetics 7 (6): e1002143. June 2011. doi:10.1371/journal.pgen.1002143. PMID 21731503. 
  18. ↑ "Reduced fat mass in mice lacking orphan nuclear receptor estrogen-related receptor alpha". Molecular and Cellular Biology 23 (22): 7947–56. November 2003. doi:10.1128/MCB.23.22.7947-7956.2003. PMID 14585956. 
  19. ↑ "Transcriptional activities of the orphan nuclear receptor ERR alpha (estrogen receptor-related receptor-alpha)". Molecular Endocrinology 13 (5): 764–73. May 1999. doi:10.1210/mend.13.5.0281. PMID 10319326. 
  20. ↑ "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. doi:10.1093/emboj/18.15.4270. PMID 10428965. 
  21. ↑ "Estrogen-related receptor alpha as a therapeutic target in cancer". Endocrine-Related Cancer 13 (Suppl 1): S25–32. December 2006. doi:10.1677/erc.1.01292. PMID 17259555. 
  22. ↑ "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. doi:10.1074/jbc.M407999200. PMID 15337744. 
  23. ↑ "Flavone and isoflavone phytoestrogens are agonists of estrogen-related receptors". Molecular Cancer Research 1 (13): 981–91. November 2003. PMID 14638870. http://mcr.aacrjournals.org/cgi/pmidlookup?view=long&pmid=14638870. 
  24. ↑ "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. doi:10.1021/jm049334f. PMID 15509154. 
  25. ↑ "A Synthetic ERR Agonist Alleviates Metabolic Syndrome". The Journal of Pharmacology and Experimental Therapeutics. September 2023. doi:10.1124/jpet.123.001733. PMID 37739806. 
  26. ↑ 26.0 26.1 26.2 26.3 "Ligand Activation of ERRα by Cholesterol Mediates Statin and Bisphosphonate Effects". Cell Metabolism 23 (3): 479–91. March 2016. doi:10.1016/j.cmet.2015.12.010. PMID 26777690. 

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