Hepatocyte nuclear factor 4 alpha

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Hepatocyte nuclear factor 4, alpha
Protein HNF4A PDB 1m7w.png
PDB rendering based on 1m7w.
Available structures
PDB Ortholog search: PDBe, RCSB
Symbols HNF4A ; FRTS4; HNF4; HNF4a7; HNF4a8; HNF4a9; HNF4alpha; MODY; MODY1; NR2A1; NR2A21; TCF; TCF14
External IDs OMIM600281 MGI109128 HomoloGene395 IUPHAR: 608 ChEMBL: 5398 GeneCards: HNF4A Gene
RNA expression pattern
PBB GE HNF4A 216889 s at tn.png
PBB GE HNF4A 208429 x at tn.png
PBB GE HNF4A 214832 at tn.png
More reference expression data
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 [1] [2]
See also: MODY 1

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]

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[edit]

Mutations in this gene have been associated with monogenic autosomal dominant non-insulin-dependent diabetes mellitus type I.[3] Recently, the Clinical Proteomic Tumor Analysis Consortium identified increased amplification of Hepatocyte nuclear factor 4 alpha in colorectal cancer.[6]


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

See also[edit]


  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. ^ a b "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. ^ Zhang, Bing, et al. "Proteogenomic characterization of human colon and rectal cancer." Nature 513.7518 (2014): 382-387.
  7. ^ 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. 
  8. ^ 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. 
  9. ^ 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. 
  10. ^ 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. 
  11. ^ 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. 
  12. ^ 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. 
  13. ^ 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[edit]

External links[edit]

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