Hepatocyte nuclear factor 4 alpha (HNF4A) also known asNR2A1 (nuclear receptor subfamily 2, group A, member 1) is anuclear receptor that in humans is encoded by theHNF4Agene.[5][6]
HNF-4α is a nucleartranscription factor that bindsDNA as ahomodimer. The encoded protein controls the expression of several genes, includinghepatocyte nuclear factor 1 alpha, a transcription factor that regulates the expression of several hepatic genes. This gene plays a role in development of theliver,kidney, andintestines. Alternative splicing of this gene results in multiple transcript variants.[7]
HNF4A is required for thePXR andCAR-mediated transcriptional activation ofCYP3A4.[8] Genetic mutations in theHNF4A gene can influence the activity of HNF4α's downstream proteins such asCYP2D6,in vitro andin vivo.[9][10]
The alkaloidberberine upregulates HNF4A expression.[11]
This gene plays a pivotal role in the expression and synthesis ofSHBG, an importantglycoprotein made primarily in theliver,[12] which in addition to lowering insulin-resistance also reduces levels of freeEstrogen as-well as prolonging the half-life oftestosterone.[citation needed]
Function of HNF4A gene can be effectively examined bysiRNA knockdown based on an independent validation.[13]
Mutations in the HNF4A gene are associated with a form of diabetes calledmaturity onset diabetes of the young (MODY),[14] specificallyMODY 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 incolorectal cancer.[16]
It has also associations with the appearance ofFanconi syndrome phenotypes which occurs due to a missense mutation of the gene.[17]
^"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.PMID7926813.
^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.PMID9048927.S2CID10943721.
^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.PMID23292115.S2CID19230792.
^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.PMID24559927.
^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.PMID12944908.S2CID9301471.
^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.PMID9434765.
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.doi:10.1016/S0889-8529(05)70101-8.PMID10609119.
Gupta RK, Kaestner KH (Nov 2004). "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.PMID15519277.
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.PMID7926813.
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.Bibcode:1996Natur.384..458Y.doi:10.1038/384458a0.hdl:2027.42/62605.PMID8945471.S2CID4253951.
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.doi:10.1016/0378-1119(96)00183-7.PMID8964514.
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.PMID9048927.S2CID10943721.
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.doi:10.2337/diabetes.46.10.1652.PMID9313765.
