Hepatocyte nuclear factor 4 alpha

Hepatocyte nuclear factor 4, alpha
PDB rendering based on 1m7w.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1PZL​, 3CBB​, 3FS1​, 4B7W​, 4IQR​
Identifiers
Symbols	HNF4A ; FRTS4; HNF4; HNF4a7; HNF4a8; HNF4a9; HNF4alpha; MODY; MODY1; NR2A1; NR2A21; TCF; TCF14
External IDs	OMIM: 600281 MGI: 109128 HomoloGene: 395 IUPHAR: 608 ChEMBL: 5398 GeneCards: HNF4A Gene
Gene ontology Molecular function • RNA polymerase II core promoter sequence-specific DNA binding • transcriptional activator activity, RNA polymerase II core promoter proximal region sequence-specific binding • RNA polymerase II activating transcription factor binding • DNA binding • transcription factor activity, sequence-specific DNA binding • transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding • steroid hormone receptor activity • RNA polymerase II transcription factor activity, ligand-activated sequence-specific DNA binding • receptor binding • fatty acid binding • protein binding • zinc ion binding • protein homodimerization activity • transcription regulatory region DNA binding Cellular component • nucleus • nucleoplasm • cytoplasm Biological process • regulation of transcription from RNA polymerase II promoter • transcription initiation from RNA polymerase II promoter • ornithine metabolic process • lipid metabolic process • xenobiotic metabolic process • sex differentiation • blood coagulation • negative regulation of cell proliferation • response to glucose • gene expression • regulation of gastrulation • regulation of lipid metabolic process • signal transduction involved in regulation of gene expression • negative regulation of cell growth • intracellular receptor signaling pathway • endocrine pancreas development • glucose homeostasis • steroid hormone mediated signaling pathway • positive regulation of transcription, DNA-templated • positive regulation of transcription from RNA polymerase II promoter • regulation of insulin secretion • lipid homeostasis • phospholipid homeostasis • SMAD protein signal transduction • regulation of growth hormone receptor signaling pathway • triglyceride homeostasis • positive regulation of cholesterol homeostasis Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	3172	15378
Ensembl	ENSG00000101076	ENSMUSG00000017950
UniProt	P41235	P49698
RefSeq (mRNA)	NM_000457	NM_008261
RefSeq (protein)	NP_000448	NP_032287
Location (UCSC)	Chr 20: 44.36 – 44.43 Mb	Chr 2: 163.51 – 163.57 Mb
PubMed search

Hepatocyte nuclear factor 4 alpha (HNF4A) also known as NR2A1 (nuclear receptor subfamily 2, group A, member 1) is a nuclear receptor that in humans is encoded by the HNF4A gene.^[1][2]

Function

HNF-4α is a nuclear transcription factor 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 , kidney , and intestines . Alternative splicing of this gene results in multiple transcript variants.^[3]

HNF4A is required for the PXR and CAR-mediated transcriptional activation of CYP3A4.^[4]

The alkaloid berberine upregulates the expression of HNF4A.^[5]

This gene also plays a pivotal role in the expression and synthesis of SHBG, an important glycoprotein made primarily in the liver, which in addition to lowering insulin-resistance also serves in reducing levels of free Oestrogen as-well as prolonging the half-life of Testosterone.

Clinical significance

Mutations in the HNF4A gene are associated with a form of diabetes called maturity onset diabetes of the young (MODY).^[6]

Increased amplification of hepatocyte nuclear factor 4 alpha has been observed in colorectal cancer.^[7]

Interactions

Hepatocyte nuclear factor 4 alpha has been shown to interact with:

• Beta-catenin,^[8]
• CREB binding protein,^[9][10]
• MED1,^[11][12]
• MED14,^[11][12]
• Small heterodimer partner^[13]
• Testicular receptor 4,^[14]

See also

• Hepatocyte nuclear factor 4
• Hepatocyte nuclear factors

References

1. Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (Sep 1994). "Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver". Gene 147 (2): 269–72. doi:10.1016/0378-1119(94)90079-5. PMID 7926813.
2. Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, Moschonas NK (Feb 1997). "Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17". Human Genetics 99 (2): 233–6. doi:10.1007/s004390050345. PMID 9048927.
3. "Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha".
4. Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V, Parviz F, Duncan SA, Inoue Y, Gonzalez FJ, Schuetz EG, Kim RB (Feb 2003). "The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4". Nature Medicine 9 (2): 220–4. doi:10.1038/nm815. PMID 12514743.
5. Wang ZQ, Lu FE, Leng SH, Fang XS, Chen G, Wang ZS, Dong LP, Yan ZQ (Oct 2008). "Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity". World Journal of Gastroenterology 14 (39): 6004–11. doi:10.3748/wjg.14.6004. PMC 2760199. PMID 18932278.
6. Yamagata K (2014). "Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY)". Vitamins and Hormones 95: 407–23. doi:10.1016/B978-0-12-800174-5.00016-8. PMID 24559927.
7. Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, et al. (2014). "Proteogenomic characterization of human colon and rectal cancer". Nature 513 (7518): 382–7. doi:10.1038/nature13438. PMC 4249766. PMID 25043054.
8. Mulholland DJ, Read JT, Rennie PS, Cox ME, Nelson CC (Aug 2003). "Functional localization and competition between the androgen receptor and T-cell factor for nuclear beta-catenin: a means for inhibition of the Tcf signaling axis". Oncogene 22 (36): 5602–13. doi:10.1038/sj.onc.1206802. PMID 12944908.
9. Yoshida E, Aratani S, Itou H, Miyagishi M, Takiguchi M, Osumu T, Murakami K, Fukamizu A (Dec 1997). "Functional association between CBP and HNF4 in trans-activation". Biochemical and Biophysical Research Communications 241 (3): 664–9. doi:10.1006/bbrc.1997.7871. PMID 9434765.
10. Dell H, Hadzopoulou-Cladaras M (Mar 1999). "CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression". The Journal of Biological Chemistry 274 (13): 9013–21. doi:10.1074/jbc.274.13.9013. PMID 10085149.
11. Maeda Y, Rachez C, Hawel L, Byus CV, Freedman LP, Sladek FM (Jul 2002). "Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205". Molecular Endocrinology 16 (7): 1502–10. doi:10.1210/mend.16.7.0883. PMID 12089346.
12. Malik S, Wallberg AE, Kang YK, Roeder RG (Aug 2002). "TRAP/SMCC/mediator-dependent transcriptional activation from DNA and chromatin templates by orphan nuclear receptor hepatocyte nuclear factor 4". Molecular and Cellular Biology 22 (15): 5626–37. doi:10.1128/MCB.22.15.5626-5637.2002. PMC 133960. PMID 12101254.
13. Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD (Jan 2000). "The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression". Molecular and Cellular Biology 20 (1): 187–95. doi:10.1128/MCB.20.1.187-195.2000. PMC 85074. PMID 10594021.
14. Lin WJ, Li J, Lee YF, Yeh SD, Altuwaijri S, Ou JH, Chang C (Mar 2003). "Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4". The Journal of Biological Chemistry 278 (11): 9353–60. doi:10.1074/jbc.M205944200. PMID 12522137.

Further reading

• Winter WE, Nakamura M, House DV (Dec 1999). "Monogenic diabetes mellitus in youth. The MODY syndromes". Endocrinology and Metabolism Clinics of North America 28 (4): 765–85. doi:10.1016/S0889-8529(05)70101-8. PMID 10609119.
• Zannis VI, Kan HY, Kritis A, Zanni E, Kardassis D (Mar 2001). "Transcriptional regulation of the human apolipoprotein genes". Frontiers in Bioscience 6: D456–504. doi:10.2741/Zannis. PMID 11229886.
• Gupta RK, Kaestner KH (Nov 2004). "HNF-4alpha: from MODY to late-onset type 2 diabetes". Trends in Molecular Medicine 10 (11): 521–4. doi:10.1016/j.molmed.2004.09.004. PMID 15519277.
• Mohlke KL, Boehnke M (Apr 2005). "The role of HNF4A variants in the risk of type 2 diabetes". Current Diabetes Reports 5 (2): 149–56. doi:10.1007/s11892-005-0043-y. PMID 15794920.
• Love-Gregory L, Permutt MA (Jul 2007). "HNF4A genetic variants: role in diabetes". Current Opinion in Clinical Nutrition and Metabolic Care 10 (4): 397–402. doi:10.1097/MCO.0b013e3281e3888d. PMID 17563455.
• Bell GI, Xiang KS, Newman MV, Wu SH, Wright LG, Fajans SS, Spielman RS, Cox NJ (Feb 1991). "Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q". Proceedings of the National Academy of Sciences of the United States of America 88 (4): 1484–8. doi:10.1073/pnas.88.4.1484. PMC 51043. PMID 1899928.
• Ktistaki E, Ktistakis NT, Papadogeorgaki E, Talianidis I (Oct 1995). "Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential". Proceedings of the National Academy of Sciences of the United States of America 92 (21): 9876–80. doi:10.1073/pnas.92.21.9876. PMC 40905. PMID 7568236.
• Ginsburg GS, Ozer J, Karathanasis SK (Jul 1995). "Intestinal apolipoprotein AI gene transcription is regulated by multiple distinct DNA elements and is synergistically activated by the orphan nuclear receptor, hepatocyte nuclear factor 4". The Journal of Clinical Investigation 96 (1): 528–38. doi:10.1172/JCI118065. PMC 185227. PMID 7615825.
• Jiang G, Nepomuceno L, Hopkins K, Sladek FM (Sep 1995). "Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors". Molecular and Cellular Biology 15 (9): 5131–43. doi:10.1128/mcb.15.9.5131. PMC 230760. PMID 7651430.
• Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (Sep 1994). "Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver". Gene 147 (2): 269–72. doi:10.1016/0378-1119(94)90079-5. PMID 7926813.
• Drewes T, Senkel S, Holewa B, Ryffel GU (Mar 1996). "Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes". Molecular and Cellular Biology 16 (3): 925–31. doi:10.1128/mcb.16.3.925. PMC 231074. PMID 8622695.
• Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI (Dec 1996). "Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1)". Nature 384 (6608): 458–60. doi:10.1038/384458a0. PMID 8945471.
• Kritis AA, Argyrokastritis A, Moschonas NK, Power S, Katrakili N, Zannis VI, Cereghini S, Talianidis I (Sep 1996). "Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4". Gene 173 (2): 275–80. doi:10.1016/0378-1119(96)00183-7. PMID 8964514.
• Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, Moschonas NK (Feb 1997). "Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17". Human Genetics 99 (2): 233–6. doi:10.1007/s004390050345. PMID 9048927.
• Thénot S, Henriquet C, Rochefort H, Cavaillès V (May 1997). "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". The Journal of Biological Chemistry 272 (18): 12062–8. doi:10.1074/jbc.272.18.12062. PMID 9115274.
• Bulman MP, Dronsfield MJ, Frayling T, Appleton M, Bain SC, Ellard S, Hattersley AT (Jul 1997). "A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young". Diabetologia 40 (7): 859–62. doi:10.1007/s001250050760. PMID 9243109.
• Møller AM, Urhammer SA, Dalgaard LT, Reneland R, Berglund L, Hansen T, Clausen JO, Lithell H, Pedersen O (Aug 1997). "Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM". Diabetologia 40 (8): 980–3. doi:10.1007/s001250050778. PMID 9267996.
• Lindner T, Gragnoli C, Furuta H, Cockburn BN, Petzold C, Rietzsch H, Weiss U, Schulze J, Bell GI (Sep 1997). "Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4alpha/MODY1 gene". The Journal of Clinical Investigation 100 (6): 1400–5. doi:10.1172/JCI119660. PMC 508318. PMID 9294105.
• Furuta H, Iwasaki N, Oda N, Hinokio Y, Horikawa Y, Yamagata K, Yano N, Sugahiro J, Ogata M, Ohgawara H, Omori Y, Iwamoto Y, Bell GI (Oct 1997). "Organization and partial sequence of the hepatocyte nuclear factor-4 alpha/MODY1 gene and identification of a missense mutation, R127W, in a Japanese family with MODY". Diabetes 46 (10): 1652–7. doi:10.2337/diabetes.46.10.1652. PMID 9313765.
• Stoffel M, Duncan SA (Nov 1997). "The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism". Proceedings of the National Academy of Sciences of the United States of America 94 (24): 13209–14. doi:10.1073/pnas.94.24.13209. PMC 24288. PMID 9371825.

External links

• FactorBook HNF4A

This article incorporates text from the United States National Library of Medicine, which is in the public domain.