Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 (nuclear receptor subfamily 2, group A, member 1) is a

nuclear receptor In the field of molecular biology, nuclear receptors are a class of proteins responsible for sensing steroids, thyroid hormones, vitamins, and certain other molecules. These receptors work with other proteins to regulate the expression of speci ...

that in humans is encoded by the ''HNF4A'' gene.

Function

HNF-4α is a nuclear

transcription factor In molecular biology, a transcription factor (TF) (or sequence-specific DNA-binding factor) is a protein that controls the rate of transcription of genetic information from DNA to messenger RNA, by binding to a specific DNA sequence. The fu ...

that binds DNA as a homodimer. The encoded protein controls the expression of several genes, including hepatocyte nuclear factor 1 alpha, a transcription factor which regulates the expression of several hepatic genes. This gene plays a role in development of the

liver The liver is a major Organ (anatomy), organ only found in vertebrates which performs many essential biological functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of proteins and biochemicals necessary for ...

kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...

, and

intestines The gastrointestinal tract (GI tract, digestive tract, alimentary canal) is the tract or passageway of the digestive system that leads from the mouth to the anus. The GI tract contains all the major organs of the digestive system, in humans ...

. Alternative splicing of this gene results in multiple transcript variants. HNF4A is required for the PXR and

CAR A car or automobile is a motor vehicle with wheels. Most definitions of ''cars'' say that they run primarily on roads, seat one to eight people, have four wheels, and mainly transport people instead of goods. The year 1886 is regarded as ...

-mediated transcriptional activation of

CYP3A4 Cytochrome P450 3A4 (abbreviated CYP3A4) () is an important enzyme in the body, mainly found in the liver and in the intestine. It oxidizes small foreign organic molecules (xenobiotics), such as toxins or drugs, so that they can be removed from t ...

. Genetic mutations in the ''HNF4A'' gene can influence the activity of HNF4α's downstream proteins such as CYP2D6, ''in vitro'' and ''in vivo''. The alkaloid

berberine Berberine is a quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids found in such plants as ''Berberis vulgaris'' (barberry), '' Berberis aristata'' (tree turmeric), '' Mahonia aquifolium'' (Oregon grape), '' Hyd ...

upregulates the expression of HNF4A. This gene also plays a pivotal role in the expression and synthesis of

SHBG Sex hormone-binding globulin (SHBG) or sex steroid-binding globulin (SSBG) is a glycoprotein that binds to androgens and estrogens. When produced by the Sertoli cells in the seminiferous tubules of the testis, it has also been called androgen ...

, an important

glycoprotein Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycos ...

made primarily in the

, which in addition to lowering insulin-resistance also serves in reducing levels of free

Estrogen Estrogen or oestrogen is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three major endogenous estrogens that have estrogenic hormonal acti ...

as-well as prolonging the half-life of

Testosterone Testosterone is the primary sex hormone and anabolic steroid in males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testes and prostate, as well as promoting secondar ...

. Function of HNF4A gene can be effectively examined by siRNA knockdown based on an independent validation.

Clinical significance

Mutations in the HNF4A gene are associated with a form of diabetes called

maturity onset diabetes of the young Maturity-onset diabetes of the young (MODY) refers to any of several hereditary forms of diabetes mellitus caused by mutations in an autosomal dominant gene disrupting insulin production. MODY is often referred to as monogenic diabetes to disting ...

(MODY), specifically

MODY 1 MODY 1 is a form of maturity onset diabetes of the young. MODY 1 is due to a loss-of-function mutation in the ''HNF4A'' (''MODY1'') gene on chromosome 12. This gene codes for hepatocyte nuclear factor 4-alpha (HNF4-α) protein also known as trans ...

. At least 56 disease-causing mutations in this gene have been discovered. Increased amplification of hepatocyte nuclear factor 4 alpha has been observed in

colorectal cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...

. It has also associations with the appearance of

Fanconi syndrome Fanconi syndrome or Fanconi's syndrome (, ) is a syndrome of inadequate reabsorption in the proximal renal tubules of the kidney. The syndrome can be caused by various underlying congenital or acquired diseases, by toxicity (for example, from toxi ...

phenotypes which occurs due to a missense mutation of the gene.

Interactions

Hepatocyte nuclear factor 4 alpha has been shown to

interact Advocates for Informed Choice, dba interACT or interACT Advocates for Intersex Youth, is a 501(c)(3) nonprofit organization using innovative strategies to advocate for the legal and human rights of children with intersex traits. The organizati ...

with: *

Beta-catenin Catenin beta-1, also known as beta-catenin (β-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene. Beta-catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcripti ...

, *

CREB binding protein Cyclic adenosine monophosphate Response Element Binding protein Binding Protein (CREB-binding protein), also known as CREBBP or CBP or KAT3A, is a coactivator encoded by the ''CREBBP'' gene in humans, located on chromosome 16p13.3. CBP has intrin ...

, *

MED1 Mediator of RNA polymerase II transcription subunit 1 also known as DRIP205 or Trap220 is a subunit of the Mediator complex and is a protein that in humans is encoded by the ''MED1'' gene. MED1 functions as a nuclear receptor coactivator. Func ...

, *

MED14 Mediator of RNA polymerase II transcription subunit 14 is an enzyme that in humans is encoded by the ''MED14'' gene. The activation of gene transcription is a multistep process that is triggered by factors that recognize transcriptional enhancer ...

, *

Small heterodimer partner The small heterodimer partner (SHP) also known as NR0B2 (nuclear receptor subfamily 0, group B, member 2) is a protein that in humans is encoded by the ''NR0B2'' gene. SHP is a member of the nuclear receptor family of intracellular transcription ...

Testicular receptor 4 Testicular receptor 4 also known as NR2C2 (nuclear receptor subfamily 2, group C, member 2) is a protein that in humans is encoded by the ''NR2C2'' gene. The testicular receptor 4 is a member of the nuclear receptor family of transcription factor ...

References

External links

* {{Transcription factors, g2 Intracellular receptors Transcription factors

Function

Clinical significance

Interactions

See also

References

Further reading

External links