Estrogen-related receptor alpha

Estrogen-related receptor alpha (ERR-α), also known as NR3B1 (nuclear receptor subfamily 3, group B, member 1), is a is_associated_with::nuclear receptor that in humans is encoded by the ESRRA (Estrogen Related Receptor Alpha) is_associated_with::gene. ERR-α was originally cloned by DNA sequence homology to the is_associated_with::estrogen receptor alpha (ER-α, is_associated_with::NR3A1), but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERR-α. Currently, ERRα is considered an orphan nuclear receptor.

Tissue distribution
ERR-α has wide tissue distribution but it is most highly expressed in tissues that preferentially use fatty acids as energy sources such as is_associated_with::kidney, is_associated_with::heart, is_associated_with::cerebellum, is_associated_with::intestine, and is_associated_with::skeletal muscle. Recently, ERR-α has been detected in normal is_associated_with::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 is_associated_with::adrenarche, and also in steroid production of post-adrenarche/adult life.

Function
The is_associated_with::protein encoded by this gene is a is_associated_with::nuclear receptor that is closely related to the is_associated_with::estrogen receptor. Results of both in vitro and in vivo studies suggest that ERR-α is required for the activation of mitochondrial genes as well as increased mitochondrial biogenesis. 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 is_associated_with::lactoferrin, is_associated_with::osteopontin, medium-chain acyl coenzyme A dehydrogenase (MCAD) and is_associated_with::thyroid hormone receptor genes. It was reported that ERR-α can activate reporters containing steroidogenesis factor 1 (SF-1) response elements as a result of transient transfection assays, and a possible role of ERR-α in steroidogenesis with relation to SF-1 was subsequently demonstrated in adrenocortical cells. The transcriptional activation of is_associated_with::CYP17A1 and is_associated_with::SULT2A1 in the adrenal has been proposed as the mechanism of action possibly accounting for the increment in DHEAS serum levels by ERR-α. ERR-α has been suggested to act as a transcriptional activator of is_associated_with::CYP11B1 and CYP11B2, which indicates that this nuclear receptor may be required for the production of is_associated_with::cortisol and is_associated_with::aldosterone in the is_associated_with::adrenal gland.

Metabolism
ERR-α regulates genes involved in is_associated_with::mitochondrial biogenesis, is_associated_with::gluconeogenesis, is_associated_with::oxidative phosphorylation, and is_associated_with::fatty acid metabolism. It was recently identified as an important regulator of the mammalian is_associated_with::circadian clock, and its output pathways at both transcriptional and physiological levels regulated the expression of transcription factors involved in metabolic is_associated_with::homeostasis. It has been demonstrated that ERRα is required for the maintenance of diurnal is_associated_with::cholesterol, is_associated_with::glucose, is_associated_with::insulin, is_associated_with::bile acid, and trygliceride levels as well as locomotor rhythms in mice. ERRα is related to mitochondrial function but studies involving ERR-α is_associated_with::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, the lack of that nuclear receptor leading to impaired fat metabolism and absorption.

Estrogen signaling
is_associated_with::Estrogen receptor alpha (ER-α) and estrogen related receptor alpha (ERR-α) have been found to regulate many of the same genes. Furthermore ERR-α appears to modulate the activity of ER-α in various tissues including breast, uterus, and bone.

Ligands
No is_associated_with::endogenous ligands of ERR-α have been identified to date, hence ERR-α is classified as an is_associated_with::orphan receptor. In addition both biochemical and structural studies indicate that ERR-α is constitutively active in the absence of ligand. ERR-α does, however, interact with the metabolic-inducible coactivator PGC1-α in its AF2 region which is sometimes referred to as the "protein ligand" of ERR-α.

The is_associated_with::isoflavone is_associated_with::phytoestrogens is_associated_with::genistein and is_associated_with::daidzein are non-selective ERR agonists, while is_associated_with::XCT790 has been identified as a potent and selective is_associated_with::inverse agonist of ERR-α.