Hepatocyte nuclear factors

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Hepatocyte nuclear factors (HNFs) are a group of phylogenetically unrelated transcription factors that regulate the transcription of a diverse group of genes into proteins. These proteins include blood clotting factors and in addition, enzymes and transporters involved with glucose, cholesterol, and fatty acid transport and metabolism. [1] [2]

Contents

Function

As the name suggests, hepatocyte nuclear factors are expressed predominantly in the liver. 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 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 and metabolic homeostasis of the organism. For example, HNFs influence expression of the insulin 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 liver, kidney, and intestines.

Disease implication

Variants of the genes can cause several relatively rare forms of MODY, an inherited, early onset form of diabetes. Mutations in the HNF4α, HNF1α, or HNF1β genes are linked to MODY 1, MODY 3, and MODY 5 respectively. [3] Mutations in HNF genes are also associated with a number of others diseases including hepatic adenomas and renal cysts.

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.

hepatocyte nuclear factor 1, alpha
1IC8.png
Structure of the hepatocyte nuclear factor 1A (green cartoon) bound to DNA (magenta) based on the crystallographic coordinates PDB: 1IC8 .
Identifiers
Symbol HNF1A
Alt. symbolsMODY3, HNF1, LFB1, TCF1
NCBI gene 6927
HGNC 11621
OMIM 142410
PDB 1JB6
RefSeq NM_000545
UniProt P20823
Other data
Locus Chr. 12 q24.3-12q24.3
Search for
Structures Swiss-model
Domains InterPro
hepatocyte nuclear factor 1, beta
Identifiers
Symbol HNF1B
Alt. symbolsTCF2, HNF1beta, LFB3 MODY5, VHNF1
NCBI gene 6928
HGNC 11630
OMIM 189907
PDB 2H8R
RefSeq NM_000458
UniProt P35680
Other data
Locus Chr. 17 q12-17q12
Search for
Structures Swiss-model
Domains InterPro

HNF3

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

hepatocyte nuclear factor 3,
alpha
Identifiers
Symbol FOXA1
Alt. symbolsHNF3A
NCBI gene 3169
HGNC 5021
OMIM 602294
RefSeq NM_004496
UniProt P55317
Other data
Locus Chr. 14 q12-q13
Search for
Structures Swiss-model
Domains InterPro
hepatocyte nuclear factor 3,
beta
Identifiers
Symbol FOXA2
Alt. symbolsHNF3B
NCBI gene 3170
HGNC 5022
OMIM 600288
RefSeq NM_021784
UniProt Q9Y261
Other data
Locus Chr. 20 p1120p11
Search for
Structures Swiss-model
Domains InterPro
hepatocyte nuclear factor 3,
gamma
Identifiers
Symbol FOXA3
Alt. symbolsHNF3G
NCBI gene 3171
HGNC 5023
OMIM 602295
RefSeq NM_004497
UniProt P55318
Other data
Locus Chr. 19 q13.2-q13.4
Search for
Structures Swiss-model
Domains InterPro

HNF4

Members of the HNF4 subfamily are nuclear receptors and bind to DNA either as homodimers or RXR heterodimers.

hepatocyte nuclear factor 4
alpha
Identifiers
Symbol HNF4A
Alt. symbolsMODY, MODY1, NR2A1, TCF14
NCBI gene 3172
HGNC 5024
OMIM 600281
PDB 1M7W
RefSeq NM_001030004
UniProt P41235
Other data
Locus Chr. 20 q12-20q13.1
Search for
Structures Swiss-model
Domains InterPro
hepatocyte nuclear factor 4
gamma
Identifiers
Symbol HNF4G
Alt. symbolsNR2A2
NCBI gene 3174
HGNC 5026
OMIM 605966
PDB 1LV2
RefSeq NM_004133
UniProt Q14541
Other data
Locus Chr. 8 q21-q22
Search for
Structures Swiss-model
Domains InterPro

HNF6

The HNF6 subfamily members contain a cut-homeodomain (ONECUT) bind to DNA as monomers.

hepatocyte nuclear factor 6, alpha
Identifiers
Symbol ONECUT1
Alt. symbolsHNF6, HNF6A
NCBI gene 3175
HGNC 8138
OMIM 604164
RefSeq NM_004498
UniProt Q9UBC0
Other data
Locus Chr. 15 q21-q21.2
Search for
Structures Swiss-model
Domains InterPro
hepatocyte nuclear factor 6, beta
Identifiers
SymbolONECUT2
Alt. symbolsHNF6B, OC-2
NCBI gene 9480
HGNC 8139
OMIM 604894
RefSeq NM_004852
UniProt O95948
Other data
Locus Chr. 18 q21.1-21.2
Search for
Structures Swiss-model
Domains InterPro

See also

Related Research Articles

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Glucokinase is an enzyme that facilitates phosphorylation of glucose to glucose-6-phosphate. Glucokinase occurs in cells in the liver and pancreas of humans and most other vertebrates. In each of these organs it plays an important role in the regulation of carbohydrate metabolism by acting as a glucose sensor, triggering shifts in metabolism or cell function in response to rising or falling levels of glucose, such as occur after a meal or when fasting. Mutations of the gene for this enzyme can cause unusual forms of diabetes or hypoglycemia.

HNF4 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 paralogs of HNF4, HNF4α and HNF4γ,encoded by two separate genes HNF4A and HNF4G respectively.

<span class="mw-page-title-main">Small heterodimer partner</span> Protein-coding gene in the species Homo sapiens

The small heterodimer partner (SHP) also known as NR0B2 is a protein that in humans is encoded by the NR0B2 gene. SHP is a member of the nuclear receptor family of intracellular transcription factors. SHP is unusual for a nuclear receptor in that it lacks a DNA binding domain. Therefore, it is technically neither a transcription factor nor nuclear receptor but nevertheless it is still classified as such due to relatively high sequence homology with other nuclear receptor family members.

<span class="mw-page-title-main">FOXP1</span> Protein-coding gene in the species Homo sapiens

Forkhead box protein P1 is a protein that in humans is encoded by the FOXP1 gene. FOXP1 is necessary for the proper development of the brain, heart, and lung in mammals. It is a member of the large FOX family of transcription factors.

<span class="mw-page-title-main">Hepatocyte nuclear factor 4 alpha</span> Protein-coding gene in the species Homo sapiens

Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 is a nuclear receptor that in humans is encoded by the HNF4A gene.

<span class="mw-page-title-main">HNF1A</span> Protein-coding gene in the species Homo sapiens

HNF1 homeobox A, also known as HNF1A, is a human gene on chromosome 12. It is ubiquitously expressed in many tissues and cell types. The protein encoded by this gene is a transcription factor that is highly expressed in the liver and is involved in the regulation of the expression of several liver-specific genes. Mutations in the HNF1A gene have been known to cause diabetes. The HNF1A gene also contains a SNP associated with increased risk of coronary artery disease.

<span class="mw-page-title-main">HNF1B</span> Mammalian protein found in Homo sapiens

HNF1 homeobox B, also known as HNF1B or transcription factor 2 (TCF2), is a human gene.

<span class="mw-page-title-main">Hepatocyte nuclear factor 4 gamma</span> Protein-coding gene in the species Homo sapiens

Hepatocyte nuclear factor 4 gamma (HNF4G) also known as NR2A2 is a nuclear receptor that in humans is encoded by the HNF4Ggene.

<span class="mw-page-title-main">USF1</span> Protein-coding gene in the species Homo sapiens

Upstream stimulatory factor 1 is a protein that in humans is encoded by the USF1 gene.

<span class="mw-page-title-main">PCBD1</span> Protein-coding gene in the species Homo sapiens

Pterin-4-alpha-carbinolamine dehydratase is an enzyme that in humans is encoded by the PCBD1 gene.

<span class="mw-page-title-main">FOXE1</span> Mammalian protein found in Homo sapiens

Forkhead box protein E1 is a protein that in humans is encoded by the FOXE1 gene.

<span class="mw-page-title-main">Fork head domain</span> DNA-binding protein domain found in transcription factors

The fork head domain is a type of protein domain that is often found in transcription factors and whose purpose is to bind DNA.

<span class="mw-page-title-main">Forkhead box protein O1</span> Protein

Forkhead box protein O1 (FOXO1), also known as forkhead in rhabdomyosarcoma (FKHR), is a protein that in humans is encoded by the FOXO1 gene. FOXO1 is a transcription factor that plays important roles in regulation of gluconeogenesis and glycogenolysis by insulin signaling, and is also central to the decision for a preadipocyte to commit to adipogenesis. It is primarily regulated through phosphorylation on multiple residues; its transcriptional activity is dependent on its phosphorylation state.

<span class="mw-page-title-main">MODY 1</span> Medical condition

MODY 1 or HNF4A-MODY is a form of maturity onset diabetes of the young.

MODY 3 or 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, accounting for about 70% of all cases in Europe. HNF1α is a transcription factor that is thought to control a regulatory network important for differentiation of beta cells. Mutations of this gene lead to reduced beta cell mass or impaired function. MODY 1 and MODY 3 diabetes are clinically similar. About 70% of people develop this type of diabetes by age 25 years, but it occurs at much later ages in a few. This type of diabetes can often be treated with sulfonylureas with excellent results for decades. However, the loss of insulin secretory capacity is slowly progressive and most eventually need insulin.

<span class="mw-page-title-main">FOXA1</span> Protein-coding gene in the species Homo sapiens

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.

<span class="mw-page-title-main">FOXA2</span> Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">FOXA3</span> Protein-coding gene in the species Homo sapiens

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.

Most cases of type 2 diabetes involved many genes contributing small amount to the overall condition. As of 2011 more than 36 genes have been found that contribute to the risk of type 2 diabetes. All of these genes together still only account for 10% of the total genetic component of the disease.

<span class="mw-page-title-main">ONECUT1</span> Protein-coding gene in the species Homo sapiens

One cut homeobox 1 is a protein that in humans is encoded by the ONECUT1 gene.

References

  1. Costa RH, Kalinichenko VV, Holterman AX, Wang X (2003). "Transcription factors in liver development, differentiation, and regeneration". Hepatology. 38 (6): 1331–47. doi: 10.1016/j.hep.2003.09.034 . PMID   14647040. S2CID   2646966.
  2. Mitchell SM, Frayling TM (2002). "The role of transcription factors in maturity-onset diabetes of the young". Mol Genet Metab. 77 (1–2): 35–43. doi:10.1016/S1096-7192(02)00150-6. PMID   12359128.
  3. Ryffel GU (2001). "Mutations in the human genes encoding the transcription factors of the hepatocyte nuclear factor (HNF)1 and HNF4 families: functional and pathological consequences". J Mol Endocrinol. 27 (1): 11–29. doi: 10.1677/jme.0.0270011 . PMID   11463573.

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