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HNF4A  -  hepatocyte nuclear factor 4, alpha

Homo sapiens

Synonyms: FRTS4, HNF-4-alpha, HNF4, HNF4a7, HNF4a8, ...
 
 
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Disease relevance of HNF4A

  • To complement our previous studies of HNF4A, we examined the other five known MODY genes for association with type 2 diabetes in Finnish individuals [1].
  • In this study, we evaluated 23 SNPs spanning 111 kb including the HNF4A gene for association with type 2 diabetes in a collection of Caucasian type 2 diabetic patients with end-stage renal disease (n = 300) and control subjects (n = 310) [2].
  • This finding shows that the majority of MODY mutations in a central European population are local and that other MODY genes could be responsible for autosomal dominant transmission of diabetes mellitus [3].
  • In contrast to patients with Type II diabetes and with adult latent autoimmune diabetes, MODY patients showed only a modest deterioration in insulin sensitivity at onset of diabetes [4].
  • AIMS/HYPOTHESIS: Impaired beta cell function is the hallmark of gestational diabetes mellitus (GDM) and MODY [5].
 

Psychiatry related information on HNF4A

  • In revealing distinct mechanisms through which HLH motifs modulate the activity of TCFs, our results therefore provide further insight into the role of HLH motifs in regulating TCF function and how the inhibitory properties of the trans-acting Id HLH proteins are themselves regulated by phosphorylation [6].
  • A critique of Mody, Studdert-Kennedy, and Brady's "Speech perception deficits in poor readers: auditory processing or phonological coding?" [7].
 

High impact information on HNF4A

  • The transactivation of TCF target genes induced by Wnt pathway mutations constitutes the primary transforming event in colorectal cancer (CRC) [8].
  • We show here that beta-catenin and TCF inversely control the expression of the EphB2/EphB3 receptors and their ligand ephrin-B1 in colorectal cancer and along the crypt-villus axis [9].
  • Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB [9].
  • In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with beta-catenin in nuclei [10].
  • Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes [10].
 

Chemical compound and disease context of HNF4A

 

Biological context of HNF4A

  • This is the first case of MODY due to a balanced translocation, and it provides evidence to confirm the crucial role of an upstream regulator of HNF4A gene expression in the beta-cell [15].
  • We genotyped haplotype-tagging SNPs (htSNPs) across the two promoter regions and the coding region of HNF4A in individuals with type 2 diabetes (n = 137), impaired glucose tolerance (IGT) (n = 139), and normal glucose tolerance (n = 342) from the Amish Family Diabetes Study (AFDS) to test for association with type 2 diabetes [16].
  • Hepatocyte nuclear factor 4alpha (HNF4A), the gene for the maturity-onset diabetes of the young type 1 monogenic form of type 2 diabetes, is within the type 2 diabetes-linked region on chromosome 20q12-q13.1 and, consequently, is a positional candidate gene for type 2 diabetes in the general population [2].
  • Our results and the independent observation of association of SNPs near the P2 promoter with diabetes in a separate study population of Ashkenazi Jewish origin suggests that variant(s) located near or within HNF4A increases susceptibility to type 2 diabetes [17].
  • Hepatocyte nuclear factor 4-alpha (HNF4A) is a transcription factor located on chromosome 20q13 that regulates expression of genes involved in glucose metabolism and homeostasis [16].
 

Anatomical context of HNF4A

 

Associations of HNF4A with chemical compounds

  • Sensitivity to treatment with sulfonylurea tablets is a feature of both HNF1A and HNF4A mutations [23].
  • Here we show that MODY1 is the gene encoding HNF-4alpha (gene symbol, TCF14), a member of the steroid/thyroid hormone receptor superfamily and an upstream regulator of HNF-1alpha expression [24].
  • We also show that HNF-4 and TRAP/SMCC/Mediator can interact physically [25].
  • Eight nucleotide substitutions were noted, of which one resulted in the mutation of a conserved arginine residue, Arg127 (CGG)-->Trp (TGG) (designated R127W), located in the T-box, a region of the protein that may play a role in HNF-4 alpha dimerization and DNA binding [26].
  • The binding of HNF4 alpha to its cognate sites is specifically inhibited by polyunsaturated fatty acyl coenzyme A in vitro [18].
 

Physical interactions of HNF4A

  • The TGF-beta pathway activates SMAD3/4 proteins which interact with HNF-4 bound to the apoCIII promoter and enhancer and increase its activity [21].
  • Three TCF/LEF-binding sites within human CER1 promoter were conserved in chimpanzee CER1 promoter, two in cow and dog Cer1 promoters, but not in rodent Cer1 promoters [27].
  • These data strongly suggest that the mechanism by which PUFA suppress the glucose-6-phosphatase gene transcription involves an inhibition of the binding of HNF4 alpha to its cognate sites in the presence of polyunsaturated fatty acyl-CoA thioesters [18].
  • FKHR interacted with the DNA binding domain of HNF-4 and inhibited HNF-4 binding to the cognate DNA [28].
  • Complex interactions between SP1 bound to multiple distal regulatory sites and HNF-4 bound to the proximal promoter lead to transcriptional activation of liver-specific human APOCIII gene [29].
 

Enzymatic interactions of HNF4A

  • Furthermore, the binding affinity of HNF-4 with phosphorylated FKHR significantly decreased in comparison to that with unphosphorylated FKHR [28].
 

Regulatory relationships of HNF4A

 

Co-localisations of HNF4A

 

Other interactions of HNF4A

  • In contrast to the glucokinase and HNF-1alpha genes, mutations in the HNF-4alpha gene are a relatively uncommon cause of MODY, and our understanding of the MODY1 form of diabetes is based on studies of only a single family, the R-W pedigree [35].
  • IL-1beta inhibited human CYP7A1 reporter activity via the HNF4 alpha binding site [36].
  • These results indicate that two nuclear receptors, HNF-4 and FXR, are closely involved in MTP gene expression, and the results provide evidence for a novel interaction between bile acids and lipoprotein metabolism [30].
  • OBJECTIVE: Heterozygous mutations in the transcription factors hepatocyte nuclear factor (HNF)-1 alpha, HNF-1 beta, and HNF-4 alpha are associated with maturity-onset diabetes of the young (MODY) and are believed to cause this form of diabetes by impairing pancreatic beta-cell function [37].
  • Recently, we found that transcriptional factors, hepatocyte nuclear factor (HNF)-1 alpha, HNF-4 alpha and HNF-4 gamma were essential for the expression of DD4 mRNA, which is a major form of DDs [38].
 

Analytical, diagnostic and therapeutic context of HNF4A

References

  1. Common variants in maturity-onset diabetes of the young genes contribute to risk of type 2 diabetes in Finns. Bonnycastle, L.L., Willer, C.J., Conneely, K.N., Jackson, A.U., Burrill, C.P., Watanabe, R.M., Chines, P.S., Narisu, N., Scott, L.J., Enloe, S.T., Swift, A.J., Duren, W.L., Stringham, H.M., Erdos, M.R., Riebow, N.L., Buchanan, T.A., Valle, T.T., Tuomilehto, J., Bergman, R.N., Mohlke, K.L., Boehnke, M., Collins, F.S. Diabetes (2006) [Pubmed]
  2. Genetic analysis of HNF4A polymorphisms in Caucasian-American type 2 diabetes. Bagwell, A.M., Bento, J.L., Mychaleckyj, J.C., Freedman, B.I., Langefeld, C.D., Bowden, D.W. Diabetes (2005) [Pubmed]
  3. Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha. Pruhova, S., Ek, J., Lebl, J., Sumnik, Z., Saudek, F., Andel, M., Pedersen, O., Hansen, T. Diabetologia (2003) [Pubmed]
  4. Insulin secretion and insulin sensitivity in diabetic subgroups: studies in the prediabetic and diabetic state. Tripathy, D., Carlsson, A.L., Lehto, M., Isomaa, B., Tuomi, T., Groop, L. Diabetologia (2000) [Pubmed]
  5. Common variants in MODY genes increase the risk of gestational diabetes mellitus. Shaat, N., Karlsson, E., Lernmark, A., Ivarsson, S., Lynch, K., Parikh, H., Almgren, P., Berntorp, K., Groop, L. Diabetologia (2006) [Pubmed]
  6. Regulation of TCF ETS-domain transcription factors by helix-loop-helix motifs. Stinson, J., Inoue, T., Yates, P., Clancy, A., Norton, J.D., Sharrocks, A.D. Nucleic Acids Res. (2003) [Pubmed]
  7. A critique of Mody, Studdert-Kennedy, and Brady's "Speech perception deficits in poor readers: auditory processing or phonological coding?". Denenberg, V.H. Journal of learning disabilities. (1999) [Pubmed]
  8. The beta-catenin/TCF-4 complex imposes a crypt progenitor phenotype on colorectal cancer cells. van de Wetering, M., Sancho, E., Verweij, C., de Lau, W., Oving, I., Hurlstone, A., van der Horn, K., Batlle, E., Coudreuse, D., Haramis, A.P., Tjon-Pon-Fong, M., Moerer, P., van den Born, M., Soete, G., Pals, S., Eilers, M., Medema, R., Clevers, H. Cell (2002) [Pubmed]
  9. Beta-catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Batlle, E., Henderson, J.T., Beghtel, H., van den Born, M.M., Sancho, E., Huls, G., Meeldijk, J., Robertson, J., van de Wetering, M., Pawson, T., Clevers, H. Cell (2002) [Pubmed]
  10. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Satoh, S., Daigo, Y., Furukawa, Y., Kato, T., Miwa, N., Nishiwaki, T., Kawasoe, T., Ishiguro, H., Fujita, M., Tokino, T., Sasaki, Y., Imaoka, S., Murata, M., Shimano, T., Yamaoka, Y., Nakamura, Y. Nat. Genet. (2000) [Pubmed]
  11. Glucocorticoid stimulates primate but inhibits rodent alpha-fetoprotein gene promoter. Nakabayashi, H., Koyama, Y., Sakai, M., Li, H.M., Wong, N.C., Nishi, S. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  12. Hemophilia B Leyden: substitution of thymine for guanine at position -21 results in a disruption of a hepatocyte nuclear factor 4 binding site in the factor IX promoter. Reijnen, M.J., Peerlinck, K., Maasdam, D., Bertina, R.M., Reitsma, P.H. Blood (1993) [Pubmed]
  13. Reduced pancreatic polypeptide response to hypoglycemia and amylin response to arginine in subjects with a mutation in the HNF-4alpha/MODY1 gene. Ilag, L.L., Tabaei, B.P., Herman, W.H., Zawacki, C.M., D'Souza, E., Bell, G.I., Fajans, S.S. Diabetes (2000) [Pubmed]
  14. Positive regulation of the human macrophage stimulating protein gene transcription. Identification of a new hepatocyte nuclear factor-4 (HNF-4) binding element and evidence that indicates direct association between NF-Y and HNF-4. Ueda, A., Takeshita, F., Yamashiro, S., Yoshimura, T. J. Biol. Chem. (1998) [Pubmed]
  15. Maturity-onset diabetes of the young caused by a balanced translocation where the 20q12 break point results in disruption upstream of the coding region of hepatocyte nuclear factor-4alpha (HNF4A) gene. Gloyn, A.L., Ellard, S., Shepherd, M., Howell, R.T., Parry, E.M., Jefferson, A., Levy, E.R., Hattersley, A.T. Diabetes (2002) [Pubmed]
  16. Polymorphisms in both promoters of hepatocyte nuclear factor 4-alpha are associated with type 2 diabetes in the Amish. Damcott, C.M., Hoppman, N., Ott, S.H., Reinhart, L.J., Wang, J., Pollin, T.I., O'Connell, J.R., Mitchell, B.D., Shuldiner, A.R. Diabetes (2004) [Pubmed]
  17. Genetic variation near the hepatocyte nuclear factor-4 alpha gene predicts susceptibility to type 2 diabetes. Silander, K., Mohlke, K.L., Scott, L.J., Peck, E.C., Hollstein, P., Skol, A.D., Jackson, A.U., Deloukas, P., Hunt, S., Stavrides, G., Chines, P.S., Erdos, M.R., Narisu, N., Conneely, K.N., Li, C., Fingerlin, T.E., Dhanjal, S.K., Valle, T.T., Bergman, R.N., Tuomilehto, J., Watanabe, R.M., Boehnke, M., Collins, F.S. Diabetes (2004) [Pubmed]
  18. Polyunsaturated fatty acyl coenzyme A suppress the glucose-6-phosphatase promoter activity by modulating the DNA binding of hepatocyte nuclear factor 4 alpha. Rajas, F., Gautier, A., Bady, I., Montano, S., Mithieux, G. J. Biol. Chem. (2002) [Pubmed]
  19. Activation of the insulin gene promoter through a direct effect of hepatocyte nuclear factor 4 alpha. Bartoov-Shifman, R., Hertz, R., Wang, H., Wollheim, C.B., Bar-Tana, J., Walker, M.D. J. Biol. Chem. (2002) [Pubmed]
  20. Hepatocyte nuclear factor 4 alpha isoforms originated from the P1 promoter are expressed in human pancreatic beta-cells and exhibit stronger transcriptional potentials than P2 promoter-driven isoforms. Eeckhoute, J., Moerman, E., Bouckenooghe, T., Lukoviak, B., Pattou, F., Formstecher, P., Kerr-Conte, J., Vandewalle, B., Laine, B. Endocrinology (2003) [Pubmed]
  21. Transcriptional regulation of the human apolipoprotein genes. Zannis, V.I., Kan, H.Y., Kritis, A., Zanni, E., Kardassis, D. Front. Biosci. (2001) [Pubmed]
  22. Differentiation-dependent activation of the human intestinal alkaline phosphatase promoter by HNF-4 in intestinal cells. Olsen, L., Bressendorff, S., Troelsen, J.T., Olsen, J. Am. J. Physiol. Gastrointest. Liver Physiol. (2005) [Pubmed]
  23. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha (HNF1A) and 4 alpha (HNF4A) in maturity-onset diabetes of the young. Ellard, S., Colclough, K. Hum. Mutat. (2006) [Pubmed]
  24. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1). Yamagata, K., Furuta, H., Oda, N., Kaisaki, P.J., Menzel, S., Cox, N.J., Fajans, S.S., Signorini, S., Stoffel, M., Bell, G.I. Nature (1996) [Pubmed]
  25. TRAP/SMCC/mediator-dependent transcriptional activation from DNA and chromatin templates by orphan nuclear receptor hepatocyte nuclear factor 4. Malik, S., Wallberg, A.E., Kang, Y.K., Roeder, R.G. Mol. Cell. Biol. (2002) [Pubmed]
  26. 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. 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, G.I. Diabetes (1997) [Pubmed]
  27. CER1 is a common target of WNT and NODAL signaling pathways in human embryonic stem cells. Katoh, M., Katoh, M. Int. J. Mol. Med. (2006) [Pubmed]
  28. Hepatocyte nuclear factor-4 is a novel downstream target of insulin via FKHR as a signal-regulated transcriptional inhibitor. Hirota, K., Daitoku, H., Matsuzaki, H., Araya, N., Yamagata, K., Asada, S., Sugaya, T., Fukamizu, A. J. Biol. Chem. (2003) [Pubmed]
  29. Complex interactions between SP1 bound to multiple distal regulatory sites and HNF-4 bound to the proximal promoter lead to transcriptional activation of liver-specific human APOCIII gene. Talianidis, I., Tambakaki, A., Toursounova, J., Zannis, V.I. Biochemistry (1995) [Pubmed]
  30. Bile acid reduces the secretion of very low density lipoprotein by repressing microsomal triglyceride transfer protein gene expression mediated by hepatocyte nuclear factor-4. Hirokane, H., Nakahara, M., Tachibana, S., Shimizu, M., Sato, R. J. Biol. Chem. (2004) [Pubmed]
  31. P53 mutation as a source of aberrant beta-catenin accumulation in cancer cells. Cagatay, T., Ozturk, M. Oncogene (2002) [Pubmed]
  32. Hepatocyte nuclear factor 1 alpha: a key mediator of the effect of bile acids on gene expression. Jung, D., Kullak-Ublick, G.A. Hepatology (2003) [Pubmed]
  33. Expression of Wilms' tumor suppressor in the liver with cirrhosis: relation to hepatocyte nuclear factor 4 and hepatocellular function. Berasain, C., Herrero, J.I., García-Trevijano, E.R., Avila, M.A., Esteban, J.I., Mato, J.M., Prieto, J. Hepatology (2003) [Pubmed]
  34. Cooperative interaction between hepatocyte nuclear factor 4 alpha and GATA transcription factors regulates ATP-binding cassette sterol transporters ABCG5 and ABCG8. Sumi, K., Tanaka, T., Uchida, A., Magoori, K., Urashima, Y., Ohashi, R., Ohguchi, H., Okamura, M., Kudo, H., Daigo, K., Maejima, T., Kojima, N., Sakakibara, I., Jiang, S., Hasegawa, G., Kim, I., Osborne, T.F., Naito, M., Gonzalez, F.J., Hamakubo, T., Kodama, T., Sakai, J. Mol. Cell. Biol. (2007) [Pubmed]
  35. Hepatic function in a family with a nonsense mutation (R154X) in the hepatocyte nuclear factor-4alpha/MODY1 gene. Lindner, T., Gragnoli, C., Furuta, H., Cockburn, B.N., Petzold, C., Rietzsch, H., Weiss, U., Schulze, J., Bell, G.I. J. Clin. Invest. (1997) [Pubmed]
  36. Bile acids and cytokines inhibit the human cholesterol 7 alpha-hydroxylase gene via the JNK/c-jun pathway in human liver cells. Li, T., Jahan, A., Chiang, J.Y. Hepatology (2006) [Pubmed]
  37. Liver and kidney function in Japanese patients with maturity-onset diabetes of the young. Iwasaki, N., Ogata, M., Tomonaga, O., Kuroki, H., Kasahara, T., Yano, N., Iwamoto, Y. Diabetes Care (1998) [Pubmed]
  38. Hepatocyte nuclear factor-4 alpha/gamma and hepatocyte nuclear factor-1 alpha as causal factors of interindividual difference in the expression of human dihydrodiol dehydrogenase 4 mRNA in human livers. Ozeki, T., Takahashi, Y., Nakayama, K., Funayama, M., Nagashima, K., Kodama, T., Kamataki, T. Pharmacogenetics (2003) [Pubmed]
  39. Half of clinically defined maturity-onset diabetes of the young patients in Denmark do not have mutations in HNF4A, GCK, and TCF1. Johansen, A., Ek, J., Mortensen, H.B., Pedersen, O., Hansen, T. J. Clin. Endocrinol. Metab. (2005) [Pubmed]
  40. Sterol regulatory element-binding protein-2 interacts with hepatocyte nuclear factor-4 to enhance sterol isomerase gene expression in hepatocytes. Misawa, K., Horiba, T., Arimura, N., Hirano, Y., Inoue, J., Emoto, N., Shimano, H., Shimizu, M., Sato, R. J. Biol. Chem. (2003) [Pubmed]
  41. Monogenic diabetes mellitus in youth. The MODY syndromes. Winter, W.E., Nakamura, M., House, D.V. Endocrinol. Metab. Clin. North Am. (1999) [Pubmed]
 
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