Hepatocyte nuclear factor 4 alpha

HNF4A
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1PZL, 3CBB, 3FS1, 4B7W, 4IQR
Identifiers
Aliases	HNF4A, HNF4, HNF4a7, HNF4a8, HNF4a9, HNF4alpha, MODY, MODY1, NR2A1, NR2A21, TCF, TCF14, FRTS4, Hepatocyte nuclear factor 4 alpha, TCF-14
External IDs	OMIM: 600281; MGI: 109128; HomoloGene: 395; GeneCards: HNF4A; OMA:HNF4A - orthologs
Gene location (Human)
Chr.	Chromosome 20 (human)
End	44,432,845 bp
Gene location (Mouse)
Chr.	Chromosome 2 (mouse)
End	163,414,830 bp
RNA expression pattern
	Top expressed in
	right lobe of liver; ; mucosa of transverse colon; ; duodenum; ; rectum; ; mucosa of sigmoid colon; ; jejunal mucosa; ; human kidney; ; mucosa of ileum; ; islet of Langerhans; ; body of pancreas;
	Top expressed in
	Paneth cell; ; left colon; ; jejunum; ; crypt of lieberkuhn of small intestine; ; left lobe of liver; ; duodenum; ; yolk sac; ; pyloric antrum; ; human kidney; ; right kidney;
	More reference expression data
	; ; ; ;
	More reference expression data
Gene ontology
Molecular function	DNA binding; sequence-specific DNA binding; DNA-binding transcription factor activity; DNA-binding transcription activator activity, RNA polymerase II-specific; zinc ion binding; metal ion binding; steroid hormone receptor activity; nuclear receptor activity; protein binding; transcription factor activity, RNA polymerase II distal enhancer sequence-specific binding; signaling receptor binding; fatty acid binding; protein homodimerization activity; RNA polymerase II cis-regulatory region sequence-specific DNA binding; DNA-binding transcription factor activity, RNA polymerase II-specific;
Cellular component	nucleus; cytoplasm; nucleoplasm;
Biological process	triglyceride homeostasis; ornithine metabolic process; phospholipid homeostasis; regulation of transcription, DNA-templated; SMAD protein signal transduction; glucose homeostasis; regulation of insulin secretion; lipid metabolism; regulation of transcription by RNA polymerase II; signal transduction involved in regulation of gene expression; sex differentiation; blood coagulation; response to glucose; transcription, DNA-templated; positive regulation of transcription, DNA-templated; regulation of lipid metabolic process; intracellular receptor signaling pathway; regulation of growth hormone receptor signaling pathway; negative regulation of cell growth; lipid homeostasis; xenobiotic metabolic process; transcription initiation from RNA polymerase II promoter; regulation of gastrulation; steroid hormone mediated signaling pathway; positive regulation of transcription by RNA polymerase II; negative regulation of cell population proliferation; cholesterol homeostasis; type B pancreatic cell development; hepatocyte differentiation; regulation of circadian rhythm; negative regulation of transcription, DNA-templated; rhythmic process;
	Sources:Amigo / QuickGO
Orthologs
	3172
	15378
	ENSG00000101076
	ENSMUSG00000017950
	P41235
	P49698
NM_000457; NM_001030003; NM_001030004; NM_001258355; NM_001287182;
	NM_001287183; NM_001287184; NM_175914; NM_178849; NM_178850
	NM_008261; NM_001312906; NM_001312907
NP_000448; NP_001025174; NP_001025175; NP_001245284; NP_001274111;
	NP_001274112; NP_001274113; NP_787110; NP_849180; NP_849181
	NP_001299835; NP_001299836; NP_032287
	Wikidata
View/Edit Human	View/Edit Mouse

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.^[5]^[6]

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 that 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.^[7]

HNF4A is required for the PXR and CAR-mediated transcriptional activation of CYP3A4.^[8] Genetic mutations in the HNF4A gene can influence the activity of HNF4α's downstream proteins such as CYP2D6, in vitro and in vivo.^[9]^[10]

The alkaloid berberine upregulates HNF4A expression.^[11]

This gene plays a pivotal role in the expression and synthesis of SHBG, an important glycoprotein made primarily in the liver,^[12] which in addition to lowering insulin-resistance also reduces levels of free Estrogen as-well as prolonging the half-life of testosterone.^{[citation needed]}

Function of HNF4A gene can be effectively examined by siRNA knockdown based on an independent validation.^[13]

Clinical significance

Mutations in the HNF4A gene are associated with a form of diabetes called maturity onset diabetes of the young (MODY),^[14] specifically MODY 1. At least 56 disease-causing mutations in this gene have been discovered.^[15]

Increased amplification of hepatocyte nuclear factor 4 alpha has been observed in colorectal cancer.^[16]

It has also associations with the appearance of Fanconi syndrome phenotypes which occurs due to a missense mutation of the gene.^[17]

Interactions

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

References

^ ^a ^b ^c GRCh38: Ensembl release 89: ENSG00000101076 – Ensembl, May 2017
^ ^a ^b ^c GRCm38: Ensembl release 89: ENSMUSG00000017950 – Ensembl, May 2017
^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^ 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.
^ 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. S2CID 10943721.
^ "Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha".
^ 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. S2CID 8925996.
^ Lee SS, Cha EY, Jung HJ, Shon JH, Kim EY, Yeo CW, Shin JG (2008). "Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity". Hepatology. 48 (2): 635–45. doi:10.1002/hep.22396. PMID 18666237. S2CID 205866107.
^ Jiang F, Yeo CW, Lee SS, Oh MK, Ghim JL, Shon JH, Kim HS, Kim EY, Kim DH, Shin JG (2013). "Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals". Pharmacogenetics and Genomics. 23 (3): 175–9. doi:10.1097/FPC.0b013e32835de25e. PMID 23292115. S2CID 19230792.
^ 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.
^ Hammond GL, Bocchinfuso WP (2008-12-09). "Sex hormone-binding globulin: gene organization and structure/function analyses". Hormone Research. 45 (3–5): 197–201. doi:10.1159/000184787. PMID 8964583.
^ Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, Győrffy B (September 2016). "Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments". Molecular Therapy. Nucleic Acids. 5 (9): e366. doi:10.1038/mtna.2016.66. PMC 5056990. PMID 27673562.
^ 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.
^ Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.
^ Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, Davies SR, Wang S, Wang P, Kinsinger CR, Rivers RC, Rodriguez H, Townsend RR, Ellis MJ, Carr SA, Tabb DL, Coffey RJ, Slebos RJ, Liebler DC (2014). "Proteogenomic characterization of human colon and rectal cancer". Nature. 513 (7518): 382–7. Bibcode:2014Natur.513..382.. doi:10.1038/nature13438. PMC 4249766. PMID 25043054.
^ Kashoor I, Batlle D (September 2019). "Proximal renal tubular acidosis with and without Fanconi syndrome". Kidney Research and Clinical Practice. 38 (3): 267–281. doi:10.23876/j.krcp.19.056. PMC 6727890. PMID 31474092.
^ 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. S2CID 9301471.
^ 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.
^ 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.
^ ^a ^b 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.
^ ^a ^b 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.
^ 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.
^ 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.

External links

FactorBook HNF4A

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

[refGRCh38Ensembl-1] GRCh38: Ensembl release 89: ENSG00000101076 – Ensembl, May 2017

[refGRCm38Ensembl-2] GRCm38: Ensembl release 89: ENSMUSG00000017950 – Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid7926813-5] 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.

[pmid9048927-6] 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. S2CID 10943721.

[entrez-7] "Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha".

[pmid12514743-8] 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. S2CID 8925996.

[pmid18666237-9] Lee SS, Cha EY, Jung HJ, Shon JH, Kim EY, Yeo CW, Shin JG (2008). "Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity". Hepatology. 48 (2): 635–45. doi:10.1002/hep.22396. PMID 18666237. S2CID 205866107.

[pmid23292115-10] Jiang F, Yeo CW, Lee SS, Oh MK, Ghim JL, Shon JH, Kim HS, Kim EY, Kim DH, Shin JG (2013). "Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals". Pharmacogenetics and Genomics. 23 (3): 175–9. doi:10.1097/FPC.0b013e32835de25e. PMID 23292115. S2CID 19230792.

[pmid18932278-11] 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.

[12] Hammond GL, Bocchinfuso WP (2008-12-09). "Sex hormone-binding globulin: gene organization and structure/function analyses". Hormone Research. 45 (3–5): 197–201. doi:10.1159/000184787. PMID 8964583.

[13] Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, Győrffy B (September 2016). "Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments". Molecular Therapy. Nucleic Acids. 5 (9): e366. doi:10.1038/mtna.2016.66. PMC 5056990. PMID 27673562.

[pmid24559927-14] 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.

[Šimčíková_2019_-_supplementary_table_S7-15] Šimčíková D, Heneberg P (December 2019). "Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases". Scientific Reports. 9 (1): 18577. Bibcode:2019NatSR...918577S. doi:10.1038/s41598-019-54976-4. PMC 6901466. PMID 31819097.

[pmid25043054-16] Zhang B, Wang J, Wang X, Zhu J, Liu Q, Shi Z, Chambers MC, Zimmerman LJ, Shaddox KF, Kim S, Davies SR, Wang S, Wang P, Kinsinger CR, Rivers RC, Rodriguez H, Townsend RR, Ellis MJ, Carr SA, Tabb DL, Coffey RJ, Slebos RJ, Liebler DC (2014). "Proteogenomic characterization of human colon and rectal cancer". Nature. 513 (7518): 382–7. Bibcode:2014Natur.513..382.. doi:10.1038/nature13438. PMC 4249766. PMID 25043054.

[pmid31474092-17] Kashoor I, Batlle D (September 2019). "Proximal renal tubular acidosis with and without Fanconi syndrome". Kidney Research and Clinical Practice. 38 (3): 267–281. doi:10.23876/j.krcp.19.056. PMC 6727890. PMID 31474092.

[pmid12944908-18] 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. S2CID 9301471.

[pmid9434765-19] 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.

[pmid10085149-20] 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.

[pmid12089346-21] 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.

[pmid12101254-22] 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.

[pmid10594021-23] 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.

[pmid12522137-24] 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.

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