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]
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 tissuethermogenesis.[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 endogenousligands 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.
Cholesterol has recently been found to bind to and activate the ERRα, and may be the endogenousligand for the receptor.[25] 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.[25] Furthermore, statin-associated myopathy and suppression of cholesterol-induced cytokinesecretion by macrophages are reduced by absence or inhibition of ERRα.[25] As such, modulation of ERRα signaling is a key mediator in the actions of statins (by changes in cholesterol levels) and bisphosphonates.[25]
↑ 2.02.12.2Giguère V, Yang N, Segui P, Evans RM (January 1988). "Identification of a new class of steroid hormone receptors". Nature. 331 (6151): 91–4. doi:10.1038/331091a0. PMID3267207.
↑ 3.03.13.2Deblois G, Giguère V (August 2011). "Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease". Biochimica et Biophysica Acta. 1812 (8): 1032–40. doi:10.1016/j.bbadis.2010.12.009. PMID21172432.
↑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. PMID16923397.
↑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. PMID9178750.
↑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. PMID22079243.
↑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. PMID10412986.
↑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. PMID17259555.
↑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. PMID15337744.
