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 intracellular receptors work with other proteins to regulate the ex ...
that in humans is encoded by the ''HNF4A''
gene
In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
.
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 (genetics), transcription of genetics, genetic information from DNA to messenger RNA, by binding t ...
that binds
DNA
Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
as a
homodimer. The encoded protein controls the expression of several genes, including
hepatocyte nuclear factor 1 alpha, a transcription factor that regulates the expression of several hepatic genes. This gene plays a role in development of the
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
,
kidney
In humans, the kidneys are two reddish-brown bean-shaped blood-filtering organ (anatomy), organs that are a multilobar, multipapillary form of mammalian kidneys, usually without signs of external lobulation. They are located on the left and rig ...
, 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 tract is the largest of the body's systems, after the cardiovascular system. ...
. Alternative splicing of this gene results in multiple transcript variants.
HNF4A is required for the
PXR and
CAR
A car, or an automobile, is a motor vehicle with wheels. Most definitions of cars state that they run primarily on roads, seat one to eight people, have four wheels, and mainly transport people rather than cargo. There are around one billio ...
-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, which in humans is encoded by ''CYP3A4'' gene. It organic redox reaction, oxidizes small foreign organic molecules ( ...
.
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 cation, quaternary ammonium salt from the protoberberine group of benzylisoquinoline alkaloids, occurring naturally as a secondary metabolite in some plants including species of ''Berberis'', from which its name ...
upregulates HNF4A expression.
This gene plays a pivotal role in the expression and synthesis of
SHBG, an important
glycoprotein
Glycoproteins are proteins which contain oligosaccharide (sugar) 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 a ...
made primarily in the
liver
The liver is a major metabolic organ (anatomy), organ exclusively found in vertebrates, which performs many essential biological Function (biology), functions such as detoxification of the organism, and the Protein biosynthesis, synthesis of var ...
, which in addition to lowering insulin-resistance also reduces levels of free
Estrogen
Estrogen (also spelled oestrogen in British English; see spelling differences) is a category of sex hormone responsible for the development and regulation of the female reproductive system and secondary sex characteristics. There are three ...
as-well as prolonging the half-life of
testosterone
Testosterone is the primary male sex hormone and androgen in Male, males. In humans, testosterone plays a key role in the development of Male reproductive system, male reproductive tissues such as testicles and prostate, as well as promoting se ...
.
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 (MODY),
specifically
MODY 1. 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 (anatomy), colon or rectum (parts of the large intestine). Signs and symptoms may include Lower gastrointestinal ...
.
It has also associations with the appearance of
Fanconi syndrome phenotypes which occurs due to a missense mutation of the gene.
Interactions
Hepatocyte nuclear factor 4 alpha has been shown to
interact with:
*
Beta-catenin
Catenin beta-1, also known as β-catenin (''beta''-catenin), is a protein that in humans is encoded by the ''CTNNB1'' gene.
β-Catenin is a dual function protein, involved in regulation and coordination of cell–cell adhesion and gene transcrip ...
,
*
CREB binding protein,
*
MED1,
[
* MED14,]
See also
* Hepatocyte nuclear factor 4
* Hepatocyte nuclear factors
References
Further reading
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External links
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{{Transcription factors, g2
Intracellular receptors
Transcription factors