Hepatocyte nuclear factor 4 alpha
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| Location (UCSC) | Chr 20: 44.36 – 44.43 Mb | Chr 2: 163.35 – 163.41 Mb | |||||||
| PubMed search | [3] | [4] | |||||||
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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.[5][6]
Function
HNF-4α is a nuclear
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 the expression of HNF4A.[11]
This gene also 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 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.[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:
- Beta-catenin,[18]
- MED1,[21][22]
- MED14,[21][22]
- Small heterodimer partner[23]
- Testicular receptor 4,[24]
See also
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.
- PMID 7926813.
- S2CID 10943721.
- ^ "Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha".
- S2CID 8925996.
- S2CID 205866107.
- S2CID 19230792.
- PMID 18932278.
- PMID 8964583.
- PMID 27673562.
- PMID 24559927.
- PMID 31819097.
- PMID 25043054.
- PMID 31474092.
- S2CID 9301471.
- PMID 9434765.
- PMID 10085149.
- ^ PMID 12089346.
- ^ PMID 12101254.
- PMID 10594021.
- 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. 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. 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. 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. S2CID 1661923.
- 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. S2CID 10318597.
- 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. 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. 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. 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. 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. 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. 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. S2CID 4253951.
- 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. 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. S2CID 10943721.
- 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. 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. 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. 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. 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. 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. PMID 9371825.
External links
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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