hepatocyte nuclear factor 4 alpha

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.{{cite web | title = Entrez Gene: HNF4A hepatocyte nuclear factor 4, alpha| url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3172}}

HNF4A is required for the PXR and CAR-mediated transcriptional activation of CYP3A4.{{cite journal | vauthors = Tirona RG, Lee W, Leake BF, Lan LB, Cline CB, Lamba V, Parviz F, Duncan SA, Inoue Y, Gonzalez FJ, Schuetz EG, Kim RB | title = The orphan nuclear receptor HNF4alpha determines PXR- and CAR-mediated xenobiotic induction of CYP3A4 | journal = Nature Medicine | volume = 9 | issue = 2 | pages = 220–4 | date = Feb 2003 | pmid = 12514743 | doi = 10.1038/nm815 | s2cid = 8925996 }} Genetic mutations in the HNF4A gene can influence the activity of HNF4α's downstream proteins such as CYP2D6, in vitro and in vivo.{{cite journal | vauthors = Lee SS, Cha EY, Jung HJ, Shon JH, Kim EY, Yeo CW, Shin JG | title = Genetic polymorphism of hepatocyte nuclear factor-4alpha influences human cytochrome P450 2D6 activity | journal = Hepatology | volume = 48 | issue = 2 | pages = 635–45 | year = 2008 | pmid = 18666237 | doi = 10.1002/hep.22396 | s2cid = 205866107 | doi-access = free }}{{cite journal | vauthors = Jiang F, Yeo CW, Lee SS, Oh MK, Ghim JL, Shon JH, Kim HS, Kim EY, Kim DH, Shin JG | title = Effect of HNF4α genetic polymorphism G60D on the pharmacokinetics of CYP2D6 substrate tolterodine in healthy Korean individuals | journal = Pharmacogenetics and Genomics | volume = 23 | issue = 3 | pages = 175–9 | year = 2013 | pmid = 23292115 | doi = 10.1097/FPC.0b013e32835de25e | s2cid = 19230792 }}

The alkaloid berberine upregulates HNF4A expression.{{cite journal | vauthors = Wang ZQ, Lu FE, Leng SH, Fang XS, Chen G, Wang ZS, Dong LP, Yan ZQ | title = Facilitating effects of berberine on rat pancreatic islets through modulating hepatic nuclear factor 4 alpha expression and glucokinase activity | journal = World Journal of Gastroenterology | volume = 14 | issue = 39 | pages = 6004–11 | date = Oct 2008 | pmid = 18932278 | pmc = 2760199 | doi = 10.3748/wjg.14.6004 | doi-access = free }}

This gene plays a pivotal role in the expression and synthesis of SHBG, an important glycoprotein made primarily in the liver,{{cite journal | vauthors = Hammond GL, Bocchinfuso WP | title = Sex hormone-binding globulin: gene organization and structure/function analyses | journal = Hormone Research | volume = 45 | issue = 3–5 | pages = 197–201 | date = 2008-12-09 | pmid = 8964583 | doi = 10.1159/000184787 }} which in addition to lowering insulin-resistance also reduces levels of free Estrogen as-well as prolonging the half-life of testosterone.{{citation needed|date=March 2016}}

Function of HNF4A gene can be effectively examined by siRNA knockdown based on an independent validation.{{cite journal | vauthors = Munkácsy G, Sztupinszki Z, Herman P, Bán B, Pénzváltó Z, Szarvas N, Győrffy B | title = Validation of RNAi Silencing Efficiency Using Gene Array Data shows 18.5% Failure Rate across 429 Independent Experiments | journal = Molecular Therapy. Nucleic Acids | volume = 5 | issue = 9 | pages = e366 | date = September 2016 | pmid = 27673562 | pmc = 5056990 | doi = 10.1038/mtna.2016.66 }}

Mutations in the HNF4A gene are associated with a form of diabetes called maturity onset diabetes of the young (MODY),{{cite journal | vauthors = Yamagata K | title = Roles of HNF1α and HNF4α in pancreatic β-cells: lessons from a monogenic form of diabetes (MODY) | journal = Vitamins and Hormones | volume = 95 | pages = 407–23 | year = 2014 | pmid = 24559927 | doi = 10.1016/B978-0-12-800174-5.00016-8 }} specifically MODY 1. At least 56 disease-causing mutations in this gene have been discovered.{{cite journal | vauthors = Šimčíková D, Heneberg P | title = Refinement of evolutionary medicine predictions based on clinical evidence for the manifestations of Mendelian diseases | journal = Scientific Reports | volume = 9 | issue = 1 | pages = 18577 | date = December 2019 | pmid = 31819097 | pmc = 6901466 | doi = 10.1038/s41598-019-54976-4| bibcode = 2019NatSR...918577S }}

Increased amplification of hepatocyte nuclear factor 4 alpha has been observed in colorectal cancer.{{cite journal | vauthors = 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 | title = Proteogenomic characterization of human colon and rectal cancer | journal = Nature | volume = 513 | issue = 7518 | pages = 382–7 | year = 2014 | pmid = 25043054 | pmc = 4249766 | doi = 10.1038/nature13438 | bibcode = 2014Natur.513..382. }}

It has also associations with the appearance of Fanconi syndrome phenotypes which occurs due to a missense mutation of the gene.{{cite journal | vauthors = Kashoor I, Batlle D | title = Proximal renal tubular acidosis with and without Fanconi syndrome | journal = Kidney Research and Clinical Practice | volume = 38 | issue = 3 | pages = 267–281 | date = September 2019 | pmid = 31474092 | doi = 10.23876/j.krcp.19.056 | pmc = 6727890 | doi-access = free }}

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

• Beta-catenin,{{cite journal | vauthors = Mulholland DJ, Read JT, Rennie PS, Cox ME, Nelson CC | title = 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 | journal = Oncogene | volume = 22 | issue = 36 | pages = 5602–13 | date = Aug 2003 | pmid = 12944908 | doi = 10.1038/sj.onc.1206802 | s2cid = 9301471 | doi-access = }}
• CREB binding protein,{{cite journal | vauthors = Yoshida E, Aratani S, Itou H, Miyagishi M, Takiguchi M, Osumu T, Murakami K, Fukamizu A | title = Functional association between CBP and HNF4 in trans-activation | journal = Biochemical and Biophysical Research Communications | volume = 241 | issue = 3 | pages = 664–9 | date = Dec 1997 | pmid = 9434765 | doi = 10.1006/bbrc.1997.7871 }}{{cite journal | vauthors = Dell H, Hadzopoulou-Cladaras M | title = CREB-binding protein is a transcriptional coactivator for hepatocyte nuclear factor-4 and enhances apolipoprotein gene expression | journal = The Journal of Biological Chemistry | volume = 274 | issue = 13 | pages = 9013–21 | date = Mar 1999 | pmid = 10085149 | doi = 10.1074/jbc.274.13.9013 | doi-access = free }}
• MED1,
• MED14,{{cite journal | vauthors = Maeda Y, Rachez C, Hawel L, Byus CV, Freedman LP, Sladek FM | title = Polyamines modulate the interaction between nuclear receptors and vitamin D receptor-interacting protein 205 | journal = Molecular Endocrinology | volume = 16 | issue = 7 | pages = 1502–10 | date = Jul 2002 | pmid = 12089346 | doi = 10.1210/mend.16.7.0883 | doi-access = free }}{{cite journal | vauthors = Malik S, Wallberg AE, Kang YK, Roeder RG | title = TRAP/SMCC/mediator-dependent transcriptional activation from DNA and chromatin templates by orphan nuclear receptor hepatocyte nuclear factor 4 | journal = Molecular and Cellular Biology | volume = 22 | issue = 15 | pages = 5626–37 | date = Aug 2002 | pmid = 12101254 | pmc = 133960 | doi = 10.1128/MCB.22.15.5626-5637.2002 }}
• Small heterodimer partner{{cite journal | vauthors = Lee YK, Dell H, Dowhan DH, Hadzopoulou-Cladaras M, Moore DD | title = The orphan nuclear receptor SHP inhibits hepatocyte nuclear factor 4 and retinoid X receptor transactivation: two mechanisms for repression | journal = Molecular and Cellular Biology | volume = 20 | issue = 1 | pages = 187–95 | date = Jan 2000 | pmid = 10594021 | pmc = 85074 | doi = 10.1128/MCB.20.1.187-195.2000 }}
• Testicular receptor 4,{{cite journal | vauthors = Lin WJ, Li J, Lee YF, Yeh SD, Altuwaijri S, Ou JH, Chang C | title = Suppression of hepatitis B virus core promoter by the nuclear orphan receptor TR4 | journal = The Journal of Biological Chemistry | volume = 278 | issue = 11 | pages = 9353–60 | date = Mar 2003 | pmid = 12522137 | doi = 10.1074/jbc.M205944200 | doi-access = free }}

• Hepatocyte nuclear factor 4
• Hepatocyte nuclear factors

{{Reflist|2}}

{{refbegin | 2}}

• {{cite journal | vauthors = Winter WE, Nakamura M, House DV | title = Monogenic diabetes mellitus in youth. The MODY syndromes | journal = Endocrinology and Metabolism Clinics of North America | volume = 28 | issue = 4 | pages = 765–85 | date = Dec 1999 | pmid = 10609119 | doi = 10.1016/S0889-8529(05)70101-8 }}
• {{cite journal | vauthors = Zannis VI, Kan HY, Kritis A, Zanni E, Kardassis D | title = Transcriptional regulation of the human apolipoprotein genes | journal = Frontiers in Bioscience | volume = 6 | pages = D456-504 | date = Mar 2001 | pmid = 11229886 | doi = 10.2741/Zannis | doi-access = free }}
• {{cite journal | vauthors = Gupta RK, Kaestner KH | title = HNF-4alpha: from MODY to late-onset type 2 diabetes | journal = Trends in Molecular Medicine | volume = 10 | issue = 11 | pages = 521–4 | date = Nov 2004 | pmid = 15519277 | doi = 10.1016/j.molmed.2004.09.004 }}
• {{cite journal | vauthors = Mohlke KL, Boehnke M | title = The role of HNF4A variants in the risk of type 2 diabetes | journal = Current Diabetes Reports | volume = 5 | issue = 2 | pages = 149–56 | date = Apr 2005 | pmid = 15794920 | doi = 10.1007/s11892-005-0043-y | s2cid = 1661923 }}
• {{cite journal | vauthors = Love-Gregory L, Permutt MA | title = HNF4A genetic variants: role in diabetes | journal = Current Opinion in Clinical Nutrition and Metabolic Care | volume = 10 | issue = 4 | pages = 397–402 | date = Jul 2007 | pmid = 17563455 | doi = 10.1097/MCO.0b013e3281e3888d | s2cid = 10318597 }}
• {{cite journal | vauthors = Bell GI, Xiang KS, Newman MV, Wu SH, Wright LG, Fajans SS, Spielman RS, Cox NJ | title = Gene for non-insulin-dependent diabetes mellitus (maturity-onset diabetes of the young subtype) is linked to DNA polymorphism on human chromosome 20q | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 88 | issue = 4 | pages = 1484–8 | date = Feb 1991 | pmid = 1899928 | pmc = 51043 | doi = 10.1073/pnas.88.4.1484 | bibcode = 1991PNAS...88.1484B | doi-access = free }}
• {{cite journal | vauthors = Ktistaki E, Ktistakis NT, Papadogeorgaki E, Talianidis I | title = Recruitment of hepatocyte nuclear factor 4 into specific intranuclear compartments depends on tyrosine phosphorylation that affects its DNA-binding and transactivation potential | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 92 | issue = 21 | pages = 9876–80 | date = Oct 1995 | pmid = 7568236 | pmc = 40905 | doi = 10.1073/pnas.92.21.9876 | bibcode = 1995PNAS...92.9876K | doi-access = free }}
• {{cite journal | vauthors = Ginsburg GS, Ozer J, Karathanasis SK | title = 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 | journal = The Journal of Clinical Investigation | volume = 96 | issue = 1 | pages = 528–38 | date = Jul 1995 | pmid = 7615825 | pmc = 185227 | doi = 10.1172/JCI118065 }}
• {{cite journal | vauthors = Jiang G, Nepomuceno L, Hopkins K, Sladek FM | title = Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors | journal = Molecular and Cellular Biology | volume = 15 | issue = 9 | pages = 5131–43 | date = Sep 1995 | pmid = 7651430 | pmc = 230760 | doi = 10.1128/mcb.15.9.5131}}
• {{cite journal | vauthors = Chartier FL, Bossu JP, Laudet V, Fruchart JC, Laine B | title = Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver | journal = Gene | volume = 147 | issue = 2 | pages = 269–72 | date = Sep 1994 | pmid = 7926813 | doi = 10.1016/0378-1119(94)90079-5 }}
• {{cite journal | vauthors = Drewes T, Senkel S, Holewa B, Ryffel GU | title = Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes | journal = Molecular and Cellular Biology | volume = 16 | issue = 3 | pages = 925–31 | date = Mar 1996 | pmid = 8622695 | pmc = 231074 | doi = 10.1128/mcb.16.3.925}}
• {{cite journal | vauthors = Yamagata K, Furuta H, Oda N, Kaisaki PJ, Menzel S, Cox NJ, Fajans SS, Signorini S, Stoffel M, Bell GI | title = Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) | journal = Nature | volume = 384 | issue = 6608 | pages = 458–60 | date = Dec 1996 | pmid = 8945471 | doi = 10.1038/384458a0 | bibcode = 1996Natur.384..458Y | hdl = 2027.42/62605 | s2cid = 4253951 | hdl-access = free }}
• {{cite journal | vauthors = Kritis AA, Argyrokastritis A, Moschonas NK, Power S, Katrakili N, Zannis VI, Cereghini S, Talianidis I | title = Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4 | journal = Gene | volume = 173 | issue = 2 | pages = 275–80 | date = Sep 1996 | pmid = 8964514 | doi = 10.1016/0378-1119(96)00183-7 }}
• {{cite journal | vauthors = Argyrokastritis A, Kamakari S, Kapsetaki M, Kritis A, Talianidis I, Moschonas NK | title = Human hepatocyte nuclear factor-4 (hHNF-4) gene maps to 20q12-q13.1 between PLCG1 and D20S17 | journal = Human Genetics | volume = 99 | issue = 2 | pages = 233–6 | date = Feb 1997 | pmid = 9048927 | doi = 10.1007/s004390050345 | s2cid = 10943721 }}
• {{cite journal | vauthors = Thénot S, Henriquet C, Rochefort H, Cavaillès V | title = Differential interaction of nuclear receptors with the putative human transcriptional coactivator hTIF1 | journal = The Journal of Biological Chemistry | volume = 272 | issue = 18 | pages = 12062–8 | date = May 1997 | pmid = 9115274 | doi = 10.1074/jbc.272.18.12062 | doi-access = free }}
• {{cite journal | vauthors = Bulman MP, Dronsfield MJ, Frayling T, Appleton M, Bain SC, Ellard S, Hattersley AT | title = A missense mutation in the hepatocyte nuclear factor 4 alpha gene in a UK pedigree with maturity-onset diabetes of the young | journal = Diabetologia | volume = 40 | issue = 7 | pages = 859–62 | date = Jul 1997 | pmid = 9243109 | doi = 10.1007/s001250050760 | doi-access = free }}
• {{cite journal | vauthors = Møller AM, Urhammer SA, Dalgaard LT, Reneland R, Berglund L, Hansen T, Clausen JO, Lithell H, Pedersen O | title = Studies of the genetic variability of the coding region of the hepatocyte nuclear factor-4alpha in Caucasians with maturity onset NIDDM | journal = Diabetologia | volume = 40 | issue = 8 | pages = 980–3 | date = Aug 1997 | pmid = 9267996 | doi = 10.1007/s001250050778 | doi-access = free }}
• {{cite journal | vauthors = Lindner T, Gragnoli C, Furuta H, Cockburn BN, Petzold C, Rietzsch H, Weiss U, Schulze J, Bell GI | title = Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4alpha/MODY1 gene | journal = The Journal of Clinical Investigation | volume = 100 | issue = 6 | pages = 1400–5 | date = Sep 1997 | pmid = 9294105 | pmc = 508318 | doi = 10.1172/JCI119660 }}
• {{cite journal | vauthors = 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 | title = 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 | journal = Diabetes | volume = 46 | issue = 10 | pages = 1652–7 | date = Oct 1997 | pmid = 9313765 | doi = 10.2337/diabetes.46.10.1652 }}
• {{cite journal | vauthors = Stoffel M, Duncan SA | title = The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 94 | issue = 24 | pages = 13209–14 | date = Nov 1997 | pmid = 9371825 | pmc = 24288 | doi = 10.1073/pnas.94.24.13209 | bibcode = 1997PNAS...9413209S | doi-access = free }}

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Category:Intracellular receptors

Category:Transcription factors