Hepatocyte nuclear factors (HNFs) are a group of phylogenetically unrelated

transcription factors 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 func ...

that regulate the

transcription Transcription refers to the process of converting sounds (voice, music etc.) into letters or musical notes, or producing a copy of something in another medium, including: Genetics * Transcription (biology), the copying of DNA into RNA, the fir ...

of a diverse group of

genes In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

into

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

s. These proteins include

blood clotting Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism o ...

factors and in addition,

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...

s and transporters involved with

glucose Glucose is a simple sugar with the molecular formula . Glucose is overall the most abundant monosaccharide, a subcategory of carbohydrates. Glucose is mainly made by plants and most algae during photosynthesis from water and carbon dioxide, using ...

cholesterol Cholesterol is any of a class of certain organic molecules called lipids. It is a sterol (or modified steroid), a type of lipid. Cholesterol is biosynthesized by all animal cells and is an essential structural component of animal cell mem ...

, and

fatty acid In chemistry, particularly in biochemistry, a fatty acid is a carboxylic acid with an aliphatic chain, which is either saturated or unsaturated. Most naturally occurring fatty acids have an unbranched chain of an even number of carbon atoms, fr ...

transport and

metabolism Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

Function

As the name suggests, hepatocyte nuclear factors are expressed predominantly in 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 ...

. However HNFs are also expressed and play important roles in a number of other tissues so that the name ''hepatocyte nuclear factor'' is somewhat misleading. Nevertheless, the liver is the only tissue in which a significant number of different HNFs are expressed at the same time. In addition, there are a number of genes which contain multiple promoter and enhancer regions each

regulated Regulation is the management of complex systems according to a set of rules and trends. In systems theory, these types of rules exist in various fields of biology and society, but the term has slightly different meanings according to context. Fo ...

by a different HNF. Furthermore, efficient expression of these genes require synergistic activation by multiple HNFs. Hence hepatocyte nuclear factors function to ensure liver specific expression of certain genes. As is the case with many transcription factors, HNFs regulate the expression of a wide variety of target genes and therefore functions. These functions (and especially functions involving the liver) include

development Development or developing may refer to: Arts *Development hell, when a project is stuck in development *Filmmaking, development phase, including finance and budgeting *Development (music), the process thematic material is reshaped * Photograph ...

and

metabolic Metabolism (, from el, μεταβολή ''metabolē'', "change") is the set of life-sustaining chemical reactions in organisms. The three main functions of metabolism are: the conversion of the energy in food to energy available to run cell ...

homeostasis In biology, homeostasis (British English, British also homoeostasis) Help:IPA/English, (/hɒmɪə(ʊ)ˈsteɪsɪs/) is the state of steady internal, physics, physical, and chemistry, chemical conditions maintained by organism, living systems. Thi ...

of the organism. For example, HNFs influence expression of the

insulin Insulin (, from Latin ''insula'', 'island') is a peptide hormone produced by beta cells of the pancreatic islets encoded in humans by the ''INS'' gene. It is considered to be the main anabolic hormone of the body. It regulates the metabolism o ...

gene as well as genes involved in glucose transport and metabolism. In embryo development, HNF4α is thought to have an important role in the development of the

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 ...

Disease implication

Variants of the genes can cause several relatively rare forms of

MODY 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 ...

, an inherited, early onset form of diabetes. Mutations in the HNF4α, HNF1α, or HNF1β genes are linked to

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 transc ...

MODY 3 MODY 3 (also HNF1A-MODY) is a form of maturity-onset diabetes of the young. It is caused by mutations of the HNF1-alpha gene, a homeobox gene on human chromosome 12. This is the most common type of MODY in populations with European ancestry, acco ...

, and MODY 5 respectively. Mutations in HNF genes are also associated with a number of others diseases including hepatic

adenomas An adenoma is a benign tumor of epithelial tissue with glandular origin, glandular characteristics, or both. Adenomas can grow from many glandular organs, including the adrenal glands, pituitary gland, thyroid, prostate, and others. Some adenom ...

and renal

cysts A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that have grouped together to form a sac (like the manner in which water molecules group together to form a bubble) ...

Members

The following is a list of human hepatocyte nuclear factors (see also boxes to the right for additional information about these proteins):

HNF1

Members of the HNF1 subfamily contain a POU-homeodomain and bind to DNA as homodimers. * HNF1α/TCF1/MODY3 (related disease:

) * HNF1β/TCF2/MODY5 (related disease: MODY 5)

HNF3

The HNF3 subfamily members contain a winged helix DNA-binding domain and bind to DNA as monomers. * HNF3α/

FOXA1 Forkhead box protein A1 (FOXA1), also known as hepatocyte nuclear factor 3-alpha (HNF-3A), is a protein that in humans is encoded by the ''FOXA1'' gene. Function FOXA1 is a member of the forkhead class of DNA-binding proteins. These hepatocy ...

(

forkhead box FOX (forkhead box) proteins are a family of transcription factors that play important roles in regulating the expression of genes involved in cell growth, proliferation, differentiation, and longevity. Many FOX proteins are important to embryon ...

A1) * HNF3β/

FOXA2 Forkhead box protein A2 (FOXA2), also known as hepatocyte nuclear factor 3-beta (HNF-3B), is a transcription factor that plays an important role during development, in mature tissues and, when dysregulated or mutated, also in cancer. Structure ...

(forkhead box A2) * HNF3γ/

FOXA3 Hepatocyte nuclear factor 3-gamma (HNF-3G), also known as forkhead box protein A3 (FOXA3) or transcription factor 3G (TCF-3G) is a protein that in humans is encoded by the ''FOXA3'' gene. Function HNF-3G is a member of the forkhead class of DN ...

(forkhead box A3)

HNF4 HNF4 (Hepatocyte Nuclear Factor 4) is a nuclear receptor protein mostly expressed in the liver, gut, kidney, and pancreatic beta cells that is critical for liver development. In humans, there are two isoforms of HNF4, HNF4α and HNF4γ, enco ...

Members of the HNF4 subfamily are

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 ...

s and bind to DNA either as homodimers or RXR heterodimers. * HNF4α/TCF14/ MODY1 * HNF4γ

HNF6

The HNF6 subfamily members contain a cut-homeodomain ( ONECUT) bind to DNA as monomers. * HNF6α/OC-1/ ONECUT1 () * HNF6β/OC-2/ONECUT2 ()

References

Additional images

Image:HNF1a w DNA N1ic8.png, Hepatocyte nuclear factor 1A bound to DN

Image:HNF1a bound to DNA.jpg, Different rendering of HNF1a bound to DNA

External links

*
Transcription networks in the liver

transthyretin promoter, an example of a regulatory region containing HNF binding sites

HNF4 in genetics of diabetes
{{Transcription factors, g3 Metabolism Signal transduction Transcription factors