Estrogen-related receptor alpha (original) (raw)

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Protein-coding gene in the species Homo sapiens

ESRRA
Available structuresPDBOrtholog search: PDBe RCSB List of PDB id codes1XB7, 2PJL, 3D24, 3K6P
Identifiers
Aliases ESRRA, ERR1, ERRa, ERRalpha, ESRL1, NR3B1, estrogen related receptor alpha
External IDs OMIM: 601998; MGI: 1346831; HomoloGene: 136738; GeneCards: ESRRA; OMA:ESRRA - orthologs
Gene location (Human)Chromosome 11 (human)Chr.Chromosome 11 (human)[1]Chromosome 11 (human)Genomic location for ESRRAGenomic location for ESRRABand11q13.1Start64,305,497 bp[1]End64,316,743 bp[1]
Gene location (Mouse)Chromosome 19 (mouse)Chr.Chromosome 19 (mouse)[2]Chromosome 19 (mouse)Genomic location for ESRRAGenomic location for ESRRABand19 A|19 5.08 cMStart6,888,345 bp[2]End6,899,208 bp[2]
RNA expression patternBgeeHuman Mouse (ortholog)Top expressed inapex of heartmucosa of transverse colongastrocnemius musclemuscle of thighright auricleleft ventricleright lobe of liverpancreatic ductal cellbody of stomachminor salivary glandsTop expressed ininterventricular septumchoroid plexus of fourth ventriclemuscle of thighRostral migratory streamgallbladderjejunumduodenumextensor digitorum longus muscledigastric muscleileumMore reference expression dataBioGPSMore reference expression data
Gene ontologyMolecular function DNA binding sequence-specific DNA binding protein domain specific binding DNA-binding transcription factor activity zinc ion binding DNA-binding transcription activator activity, RNA polymerase II-specific metal ion binding RNA polymerase II cis-regulatory region sequence-specific DNA binding steroid hormone receptor activity DNA-binding transcription repressor activity, RNA polymerase II-specific nuclear receptor activity steroid binding protein binding DNA-binding transcription factor activity, RNA polymerase II-specific Cellular component microtubule cytoskeleton nucleoplasm intercellular bridge 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 by RNA polymerase II transcription, DNA-templated positive regulation of transcription, DNA-templated cartilage development regulation of cell population proliferation regulation of osteoblast differentiation regulation of osteoclast differentiation regulation of ossification transcription initiation from RNA polymerase II promoter positive regulation of transcription by RNA polymerase II steroid hormone mediated signaling pathway intracellular receptor signaling pathway Sources:Amigo / QuickGO
OrthologsSpeciesHuman MouseEntrez210126379EnsemblENSG00000173153ENSMUSG00000024955UniProtP11474O08580RefSeq (mRNA)NM_001282450NM_001282451NM_004451NM_007953RefSeq (protein)NP_001269379NP_001269380NP_004442NP_031979Location (UCSC)Chr 11: 64.31 – 64.32 MbChr 19: 6.89 – 6.9 MbPubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[5][6] ERRα was originally cloned by DNA sequence homology to the estrogen receptor alpha (ERα, NR3A1),[6] but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERRα.[7] Currently, ERRα is considered an orphan nuclear receptor.[6][7]

Tissue distribution

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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.[8] 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.[9]

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.[10][11] 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,[12] and a possible role of ERRα in steroidogenesis with relation to SF-1 was subsequently demonstrated in adrenocortical cells.[13] 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.[13] 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.[14]

ERRα regulates genes involved in mitochondrial biogenesis,[15] gluconeogenesis,[16] oxidative phosphorylation,[17] and fatty acid metabolism,[18] and brown adipose tissue thermogenesis.[19][20] 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.[21] 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.[21] 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,[7] the lack of that nuclear receptor leading to impaired fat metabolism and absorption.[22]

Estrogen receptor alpha (ERα) and estrogen-related receptor alpha (ERRα) have been found to regulate many of the same genes.[23][24] Furthermore, ERRα appears to modulate the activity of ERα in various tissues including breast, uterus, and bone.[25]

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.[26] 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,[27] while XCT790 has been identified as a potent and selective inverse agonist of ERRα.[28] SLU-PP-332 is a potent agonist of ERRα.[29]

Cholesterol has recently been found to bind to and activate the ERRα, and may be the endogenous ligand for the receptor.[30] 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.[30] Furthermore, statin-associated myopathy and suppression of cholesterol-induced cytokine secretion by macrophages are reduced by absence or inhibition of ERRα.[30] As such, modulation of ERRα signaling is a key mediator in the actions of statins (by changes in cholesterol levels) and bisphosphonates.[30]

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000173153 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000024955 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ "Entrez Gene: ESRRA estrogen-related receptor alpha".
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  9. ^ Felizola SJ, Nakamura Y, Hui XG, Satoh F, Morimoto R, M McNamara K, et al. (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.
  10. ^ Schreiber SN, Emter R, Hock MB, Knutti D, Cardenas J, Podvinec M, et al. (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.
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This article incorporates text from the United States National Library of Medicine, which is in the public domain.