Estrogen-related receptor alpha
Estrogen-related receptor alpha (ERR), 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. ERR was originally cloned by DNA sequence homology to the estrogen receptor alpha (ER, NR3A1), but subsequent ligand binding and reporter-gene transfection experiments demonstrated that estrogens did not regulate ERR. Currently, ERR is considered an orphan nuclear receptor.

# Tissue distribution
ERR 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. Recently, ERR 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.

# 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 ERR 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 lactoferrin, osteopontin, medium-chain acyl coenzyme A dehydrogenase (MCAD) and thyroid hormone receptor genes. It was reported that ERR can activate reporters containing steroidogenesis factor 1 (SF-1) response elements as a result of transient transfection assays, and a possible role of ERR in steroidogenesis with relation to SF-1 was subsequently demonstrated in adrenocortical cells. 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 ERR. ERR 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.

## Metabolism
ERR regulates genes involved in mitochondrial biogenesis, gluconeogenesis, oxidative phosphorylation, and fatty acid metabolism, and brown adipose tissue thermogenesis. 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. It has been demonstrated that ERR is required for the maintenance of diurnal cholesterol, glucose, insulin, bile acid, and trygliceride levels as well as locomotor rhythms in mice. ERR is related to mitochondrial function but studies involving ERR 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
Estrogen receptor alpha (ER) and estrogen-related receptor alpha (ERR) have been found to regulate many of the same genes. Furthermore, ERR appears to modulate the activity of ER in various tissues including breast, uterus, and bone.

# Ligands
No endogenous ligands of ERR have been identified to date, hence ERR is classified as an orphan receptor. In addition both biochemical and structural studies indicate that ERR is constitutively active in the absence of ligand. ERR does, however, interact with the  metabolic-inducible coactivator PGC1- in its AF2 region which is sometimes referred to as the "protein ligand" of ERR.
The isoflavone phytoestrogens genistein and daidzein are non-selective ERR agonists, while XCT790 has been identified as a potent and selective inverse agonist of ERR.
Cholesterol has recently been found to bind to and activate the ERR, and may be the endogenous ligand for the receptor. Moreover, the effects of cholesterol, statins, and bisphosphonates on osteoclastogenesis in bone tissue require ERR; in accordance, cholesterol-induced bone loss or bisphosphonate osteoprotection is absent in ERR knockout mice. Furthermore, statin-associated myopathy and suppression of cholesterol-induced cytokine secretion by macrophages are reduced by absence or inhibition of ERR. As such, modulation of ERR signaling is a key mediator in the actions of statins (by changes in cholesterol levels) and bisphosphonates.