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
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]
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.[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]
Metabolism
ERRα regulates genes involved in
mitochondrial biogenesis,[15]gluconeogenesis,[16]oxidative phosphorylation,[17] and
fatty acid metabolism,[18] and
brown adipose tissuethermogenesis.[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 signaling
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]
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.[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.
Cholesterol has recently been found to bind to and activate the ERRα, and may be the
endogenousligand 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
cytokinesecretion 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]