Hepatocyte nuclear factor 4 alpha

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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]


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] Genetic mutations in the HNF4A gene can influence the activity of HNF4α's downstream proteins such as CYP2D6, in vitro and in vivo.[5][6]

The alkaloid berberine upregulates the expression of HNF4A.[7]

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 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.[8]

Clinical significance

Mutations in the HNF4A gene are associated with a form of diabetes called maturity onset diabetes of the young (MODY).[9]

Increased amplification of hepatocyte nuclear factor 4 alpha has been observed in colorectal cancer.[10]


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

See also


  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. 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.
  6. 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.
  7. 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.
  8. Munkácsy, Gyöngyi; Sztupinszki, Zsófia; Herman, Péter; Bán, Bence; Pénzváltó, Zsófia; Szarvas, Nóra; Győrffy, Balázs (2016-01-01). "Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments". Molecular Therapy - Nucleic Acids. 5. doi:10.1038/mtna.2016.66. ISSN 2162-2531. PMC 5056990. PMID 27673562.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 14.0 14.1 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.
  15. 15.0 15.1 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.
  16. 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.
  17. 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

External links

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