Estrogen-related receptor alpha (ERRα), also known asNR3B1 (nuclear receptor subfamily 3, group B, member 1), is anuclear receptor that in humans is encoded by theESRRA (Estrogen Related Receptor Alpha)gene.[5][6] ERRα was originally cloned by DNA sequence homology to theestrogen 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]
ERRα has wide tissue distribution but it is most highly expressed in tissues that preferentially use fatty acids as energy sources such askidney,heart,brown adipose tissue,cerebellum,intestine, andskeletal muscle.[8] Recently, ERRα has been detected in normaladrenal cortex tissues, in which its expression is possibly related to adrenal development, with a possible role in fetal adrenal function, inDHEAS production inadrenarche, and also insteroid production of post-adrenarche/adult life.[9]
Theprotein encoded by this gene is anuclear receptor that is closely related to theestrogen receptor. Results of bothin vitro andin 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 factorTFIIB by direct protein-protein contact. The binding and regulatory activities of this protein have been demonstrated in the regulation of a variety of genes includinglactoferrin,osteopontin, medium-chain acyl coenzyme A dehydrogenase (MCAD) andthyroid 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 inadrenocortical cells.[13] The transcriptional activation ofCYP17A1 andSULT2A1 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 ofCYP11B1 andCYP11B2, which indicates that this nuclear receptor may be required for the production ofcortisol andaldosterone in theadrenal gland.[14]
ERRα regulates genes involved inmitochondrial biogenesis,[15]gluconeogenesis,[16]oxidative phosphorylation,[17] andfatty acid metabolism,[18] andbrown adipose tissuethermogenesis.[19][20] It was recently identified as an important regulator of the mammaliancircadian clock, and its output pathways at both transcriptional and physiological levels regulated the expression of transcription factors involved in metabolichomeostasis.[21] It has been demonstrated that ERRα is required for the maintenance of diurnalcholesterol,glucose,insulin,bile acid, and trygliceride levels as well as locomotor rhythms in mice.[21] ERRα is related to mitochondrial function but studies involving ERRαknockout 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]
Noendogenousligands of ERRα have been identified to date, hence ERRα is classified as anorphan 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 coactivatorPGC1-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 theendogenousligand for thereceptor.[30] Moreover, the effects of cholesterol,statins, andbisphosphonates onosteoclastogenesis in bone tissue require ERRα; in accordance, cholesterol-inducedbone loss or bisphosphonateosteoprotection is absent in ERRαknockout mice.[30] Furthermore, statin-associatedmyopathy and suppression of cholesterol-inducedcytokinesecretion bymacrophages 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]
^Busch BB, Stevens WC, Martin R, Ordentlich P, Zhou S, Sapp DW, et al. (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.PMID15509154.
