Hepatocyte nuclear factor 4 alpha

Hepatocyte nuclear factor 4, alpha
PDB rendering based on 1m7w.
Available structures PDB 1PZL, 3CBB, 3FS1
Identifiers
Symbols	HNF4A; FLJ39654; HNF4; HNF4a7; HNF4a8; HNF4a9; HNF4alpha; MODY; MODY1; NR2A1; NR2A21; TCF; TCF14
External IDs	OMIM: 600281 MGI: 109128 HomoloGene: 395 IUPHAR: NR2A1 GeneCards: HNF4A Gene
Gene Ontology Molecular function • fatty-acyl-CoA binding • RNA polymerase II core promoter proximal region sequence-specific DNA binding transcription factor activity involved in positive regulation of transcription • DNA binding • sequence-specific DNA binding transcription factor activity • sequence-specific enhancer binding RNA polymerase II transcription factor activity • steroid hormone receptor activity • receptor binding • fatty acid binding • protein binding • zinc ion binding • palmitoyl-CoA hydrolase activity • activating transcription factor binding • protein homodimerization activity • sequence-specific DNA binding • transcription regulatory region DNA binding • metal ion binding • repressing transcription factor binding Cellular component • nucleus • nucleoplasm • transcription factor complex • cytoplasm Biological process • transcription, DNA-dependent • regulation of transcription from RNA polymerase II promoter • regulation of transcription from RNA polymerase II promoter • ornithine metabolic process • acyl-CoA metabolic process • xenobiotic metabolic process • establishment of tissue polarity • sex differentiation • blood coagulation • negative regulation of cell proliferation • response to glucose stimulus • gene expression • regulation of gastrulation • regulation of lipid metabolic process • cell differentiation • negative regulation of cell growth • endocrine pancreas development • regulation of microvillus assembly • negative regulation of protein import into nucleus, translocation • regulation of transcription from RNA polymerase II promoter by nuclear hormone receptor • response to drug • negative regulation of tyrosine phosphorylation of Stat5 protein • glucose homeostasis • negative regulation of sequence-specific DNA binding transcription factor activity • cell-cell junction organization • positive regulation of gluconeogenesis • positive regulation of fatty acid biosynthetic process • positive regulation of transcription, DNA-dependent • negative regulation of mitotic cell cycle • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • positive regulation of transcription from RNA polymerase II promoter • negative regulation of peptidyl-tyrosine phosphorylation • regulation of insulin secretion • response to cAMP • 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	Q3UNX3
RefSeq (mRNA)	NM_000457.3	NM_008261.2
RefSeq (protein)	NP_000448.3	NP_032287.2
Location (UCSC)	Chr 20: 42.98 – 43.06 Mb	Chr 2: 163.33 – 163.4 Mb
PubMed search	[1]	[2]

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]

Clinical significance

Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type II.^[3]

Interactions

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

• Beta-catenin,^[6]
• CREB binding protein,^[7][8]
• MED1,^[9][10]
• MED14,^[9][10]
• Small heterodimer partner^[11]
• Testicular receptor 4,^[12]

See also

• Hepatocyte nuclear factor 4
• Hepatocyte nuclear factors

References

1. ^ Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B (September 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 (February 1997). "Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17". Hum. Genet. 99 (2): 233–6. doi:10.1007/s004390050345. PMID 9048927. 
3. ^ ^{a b} "Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3172. 
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 (February 2003). "The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4". Nat. Med. 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 (October 2008). "Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity". World J. Gastroenterol. 14 (39): 6004–11. doi:10.3748/wjg.14.6004. PMC 2760199. PMID 18932278. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2760199. 
6. ^ Mulholland DJ, Read JT, Rennie PS, Cox ME, Nelson CC (August 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. 
7. ^ Yoshida E, Aratani S, Itou H, Miyagishi M, Takiguchi M, Osumu T, Murakami K, Fukamizu A (December 1997). "Functional association between CBP and HNF4 in trans-activation". Biochem. Biophys. Res. Commun. 241 (3): 664–9. doi:10.1006/bbrc.1997.7871. PMID 9434765. 
8. ^ Dell H, Hadzopoulou-Cladaras M (March 1999). "CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression". J. Biol. Chem. 274 (13): 9013–21. doi:10.1074/jbc.274.13.9013. PMID 10085149. 
9. ^ ^{a b} Maeda Y, Rachez C, Hawel L, Byus CV, Freedman LP, Sladek FM (July 2002). "Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205". Mol. Endocrinol. 16 (7): 1502–10. doi:10.1210/me.16.7.1502. PMID 12089346. 
10. ^ ^{a b} Malik S, Wallberg AE, Kang YK, Roeder RG (August 2002). "TRAP/SMCC/Mediator-Dependent Transcriptional Activation from DNA and Chromatin Templates by Orphan Nuclear Receptor Hepatocyte Nuclear Factor 4". Mol. Cell. Biol. 22 (15): 5626–37. doi:10.1128/MCB.22.15.5626-5637.2002. PMC 133960. PMID 12101254. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=133960. 
11. ^ Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD (January 2000). "The Orphan Nuclear Receptor SHP Inhibits Hepatocyte Nuclear Factor 4 and Retinoid X Receptor Transactivation: Two Mechanisms for Repression". Mol. Cell. Biol. 20 (1): 187–95. doi:10.1128/MCB.20.1.187-195.2000. PMC 85074. PMID 10594021. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=85074. 
12. ^ Lin WJ, Li J, Lee YF, Yeh SD, Altuwaijri S, Ou JH, Chang C (March 2003). "Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4". J. Biol. Chem. 278 (11): 9353–60. doi:10.1074/jbc.M205944200. PMID 12522137. 

Further reading

• Winter WE, Nakamura M, House DV (2000). "Monogenic diabetes mellitus in youth. The MODY syndromes". Endocrinol. Metab. Clin. North Am. 28 (4): 765–85. doi:10.1016/S0889-8529(05)70101-8. PMID 10609119. 
• Zannis VI, Kan HY, Kritis A et al. (2001). "Transcriptional regulation of the human apolipoprotein genes". Front. Biosci. 6: D456–504. doi:10.2741/Zannis. PMID 11229886. 
• Gupta RK, Kaestner KH (2005). "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 (2005). "The role of HNF4A variants in the risk of type 2 diabetes". Curr. Diab. Rep. 5 (2): 149–56. doi:10.1007/s11892-005-0043-y. PMID 15794920. 
• Love-Gregory L, Permutt MA (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 et al. (1991). "Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q". Proc. Natl. Acad. Sci. U.S.A. 88 (4): 1484–8. doi:10.1073/pnas.88.4.1484. PMC 51043. PMID 1899928. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=51043. 
• Ktistaki E, Ktistakis NT, Papadogeorgaki E, Talianidis I (1995). "Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential". Proc. Natl. Acad. Sci. U.S.A. 92 (21): 9876–80. doi:10.1073/pnas.92.21.9876. PMC 40905. PMID 7568236. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=40905. 
• Ginsburg GS, Ozer J, Karathanasis SK (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". J. Clin. Invest. 96 (1): 528–38. doi:10.1172/JCI118065. PMC 185227. PMID 7615825. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=185227. 
• Jiang G, Nepomuceno L, Hopkins K, Sladek FM (1995). "Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors". Mol. Cell. Biol. 15 (9): 5131–43. PMC 230760. PMID 7651430. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=230760. 
• Chartier FL, Bossu JP, Laudet V et al. (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 (1996). "Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes". Mol. Cell. Biol. 16 (3): 925–31. PMC 231074. PMID 8622695. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=231074. 
• Yamagata K, Furuta H, Oda N et al. (1997). "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 et al. (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 et al. (1997). "Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17". Hum. Genet. 99 (2): 233–6. doi:10.1007/s004390050345. PMID 9048927. 
• Thénot S, Henriquet C, Rochefort H, Cavaillès V (1997). "Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1". J. Biol. Chem. 272 (18): 12062–8. doi:10.1074/jbc.272.18.12062. PMID 9115274. 
• Bulman MP, Dronsfield MJ, Frayling T et al. (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 et al. (1998). "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 et al. (1997). "Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4alpha/MODY1 gene". J. Clin. Invest. 100 (6): 1400–5. doi:10.1172/JCI119660. PMC 508318. PMID 9294105. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=508318. 
• Furuta H, Iwasaki N, Oda N et al. (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 (1998). "The maturity-onset diabetes of the young (MODY1) transcription factor HNF4α regulates expression of genes required for glucose transport and metabolism". Proc. Natl. Acad. Sci. U.S.A. 94 (24): 13209–14. doi:10.1073/pnas.94.24.13209. PMC 24288. PMID 9371825. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=24288. 

External links

• FactorBook HNF4A

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