Estrogen-related receptor alpha
Encyclopedia
Estrogen-related receptor alpha (ERR-α), 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
.
encoded by this gene is a nuclear receptor
that is closely related to the estrogen receptor
. 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. A processed pseudogene
of ESRRA is located on chromosome 13q12.1.
, oxidative phosphorylation
, and fatty acid metabolism
. Furthermore ERR-α knockout mice display impaired fat metabolism and absorption.
(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.
ligand
s of ERR-α have been identified to date, hence ERR-α is classified as an 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 isoflavone
phytoestrogens genistein
and daidzein
are non-selective ERR agonists, while XCT790
has been identified as a potent and selective inverse agonist
of ERR-α.
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
that in humans is encoded by the ESRRA (EStrogen Related Receptor Alpha) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Tissue distribution
ERR-α has wide tissue distribution but it is most highly expressed in tissue that preferentially use fatty acids as energy sources such as kidney, heart, cerebellum, intestine, and skeletal muscle.Function
The proteinProtein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
encoded by this gene is a nuclear receptor
Nuclear receptor
In the field of molecular biology, nuclear receptors are a class of proteins found within cells that are responsible for sensing steroid and thyroid hormones and certain other molecules...
that is closely related to the estrogen receptor
Estrogen receptor
Estrogen receptor refers to a group of receptors that are activated by the hormone 17β-estradiol . Two types of estrogen receptor exist: ER, which is a member of the nuclear hormone family of intracellular receptors, and the estrogen G protein-coupled receptor GPR30 , which is a G protein-coupled...
. 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
Transcription Factor II B
Transcription factor II B is one of several general transcription factors that make up the RNA polymerase II preinitiation complex. It is encoded by the gene....
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
Lactoferrin
Lactoferrin , also known as lactotransferrin , is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions...
, osteopontin
Osteopontin
Osteopontin , also known as bone sialoprotein I , early T-lymphocyte activation , secreted phosphoprotein 1 , 2ar and Rickettsia resistance , is a human gene product, which is also conserved in other species...
, medium-chain acyl coenzyme A dehydrogenase (MCAD
ACADM
ACADM is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down a certain group of fats called medium-chain fatty acids. These fatty acids are found in foods such as milk and certain oils, and they are also stored in the...
) and thyroid hormone receptor
Thyroid hormone receptor
The thyroid hormone receptor is a type of nuclear receptor that is activated by binding thyroid hormone.-Function:Amongst the most important functions of thyroid hormone receptors are regulation of metabolism and heart rate...
genes. A processed pseudogene
Pseudogene
Pseudogenes are dysfunctional relatives of known genes that have lost their protein-coding ability or are otherwise no longer expressed in the cell...
of ESRRA is located on chromosome 13q12.1.
Metabolism
ERR-α regulates genes involved in mitochondrial biogenesis, gluconeogenesisGluconeogenesis
Gluconeogenesis is a metabolic pathway that results in the generation of glucose from non-carbohydrate carbon substrates such as lactate, glycerol, and glucogenic amino acids....
, oxidative phosphorylation
Oxidative phosphorylation
Oxidative phosphorylation is a metabolic pathway that uses energy released by the oxidation of nutrients to produce adenosine triphosphate . Although the many forms of life on earth use a range of different nutrients, almost all aerobic organisms carry out oxidative phosphorylation to produce ATP,...
, and fatty acid metabolism
Fatty acid metabolism
Fatty acids are an important source of energy and adenosine triphosphate for many cellular organisms. Excess fatty acids, glucose, and other nutrients can be stored efficiently as fat. Triglycerides yield more than twice as much energy for the same mass as do carbohydrates or proteins. All cell...
. Furthermore ERR-α knockout mice display impaired fat metabolism and absorption.
Estrogen signaling
Estrogen receptor alphaEstrogen receptor alpha
Estrogen receptor alpha , also known as NR3A1 , is a nuclear receptor that is activated by the sex hormone estrogen...
(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 endogenousEndogenous
Endogenous substances are those that originate from within an organism, tissue, or cell. Endogenous retroviruses are caused by ancient infections of germ cells in humans, mammals and other vertebrates...
ligand
Ligand (biochemistry)
In biochemistry and pharmacology, a ligand is a substance that forms a complex with a biomolecule to serve a biological purpose. In a narrower sense, it is a signal triggering molecule, binding to a site on a target protein.The binding occurs by intermolecular forces, such as ionic bonds, hydrogen...
s of ERR-α have been identified to date, hence ERR-α is classified as an orphan receptor
Orphan receptor
An orphan receptor is an apparent receptor that has a similar structure to other identified receptors but whose endogenous ligand has not yet been identified. If a ligand for an orphan receptor is later discovered, the receptor is referred to as an "adopted orphan".-Examples:Examples of orphan...
. 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
PPARGC1A
Peroxisome proliferator-activated receptor gamma coactivator 1-alpha is a protein that in humans is encoded by the PPARGC1A gene....
in its AF2 region which is sometimes referred to as the "protein ligand" of ERR-α.
The isoflavone
Isoflavone
Isoflavones comprise a class of organic compounds, often naturally occurring, related to the isoflavonoids. Many act as phytoestrogens in mammals...
phytoestrogens genistein
Genistein
Genistein is one of several known isoflavones. Isoflavones, such as genistein and daidzein, are found in a number of plants including lupin, fava beans, soybeans, kudzu, and psoralea being the primary food source, also in the medicinal plant, Flemingia vestita and coffee Besides functioning as...
and daidzein
Daidzein
Daidzein belongs to the group of isoflavones. Daidzein and other isoflavone compounds, such as genistein, are present in a number of plants and herbs like the Thai Kwao Krua or Pueraria mirifica, Kudzu or Pueraria lobata, and in food sources such as soybeans and soy products like tofu and textured...
are non-selective ERR agonists, while XCT790
XCT790
XCT790 is a potent and selective inverse agonist ligand of the estrogen-related receptor alpha....
has been identified as a potent and selective inverse agonist
Inverse agonist
In the field of pharmacology, an inverse agonist is an agent that binds to the same receptor as an agonist but induces a pharmacological response opposite to that agonist....
of ERR-α.