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Gene Review

Hnf4a  -  hepatic nuclear factor 4, alpha

Mus musculus

Synonyms: HNF-4, HNF-4-alpha, HNF4 alpha, Hepatocyte nuclear factor 4-alpha, Hnf-4, ...
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Disease relevance of Hnf4a

  • 5. HNF-4 mRNA was first detected in embryonic tissues at day 8.5, in the liver diverticulum and the hindgut [1].
  • Of these, only HNF4alpha (nuclear receptor 2A1) and HNF1alpha appear to be correlated with the differentiated phenotype of cultured hepatoma cells [2].
  • The disease maturity-onset diabetes of the young (MODY) is a genetically heterogeneous monogenic form of non-insulin-dependent (type 2) diabetes mellitus (NIDDM), characterized by early onset, usually before 25 years of age and often in adolescence or childhood, and by autosomal dominant inheritance [3].
  • HNF3 and HNF4 synergistically activate DHBV pregenomic RNA synthesis and viral replication [4].
  • Hepatocyte nuclear factor 4 (HNF4) binding to the proximal nuclear hormone receptor recognition sequence in the nucleocapsid promoter appears to limit RNA synthesis from the precore transcription initiation site [5].

High impact information on Hnf4a


Biological context of Hnf4a


Anatomical context of Hnf4a


Associations of Hnf4a with chemical compounds

  • Hepatocyte nuclear factor 4 (HNF-4) is a liver-enriched transcription factor and a member of the steroid hormone receptor superfamily [10].
  • TCPOBOP, a CAR agonist that increases the interaction of CAR with coactivators, potentiated CAR inhibition of HNF-4 transactivation [14].
  • Here, it is shown that CBP can acetylate hepatocyte nuclear factor-4 (HNF-4), a member of the nuclear hormone receptor family, at lysine residues within the nuclear localization sequence [15].
  • We have also identified the mutation in the HNF-1alpha gene in the Jutland pedigree, one of the original MODY pedigrees reported in the literature, as being a T-->G substitution in codon 241, resulting in the replacement of a conserved Cys by Gly (C241G) [16].
  • Phosphoenolpyruvate carboxykinase (GTP): characterization of the human PCK1 gene and localization distal to MODY on chromosome 20 [17].

Physical interactions of Hnf4a


Regulatory relationships of Hnf4a

  • Consistent with our earlier finding that HNF-6 stimulates the hnf4 and hnf3beta gene promoters, GH treatment of hypophysectomized rats increased the liver concentration of HNF-4 and HNF-3beta mRNAs [19].
  • GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo [8].
  • It appears, therefore, that HNF-4 activates the hepatic transcription of Cyp2a-4 gene through its direct binding to the regulatory element regardless of the methylation at position -50 [20].

Other interactions of Hnf4a

  • Taken together, these data suggest a model in which GATA6 lies upstream of HNF4 in a transcriptional cascade that regulates differentiation of the visceral endoderm [8].
  • Analysis of differentiation markers confirms that vHNF1 is part of a genetic network that directs the expression of HNF4 and downstream endodermal genes [21].
  • Transcriptional regulation by HNF-4 of the steroid 15alpha-hydroxylase P450 (Cyp2a-4) gene in mouse liver [20].
  • At later times HNF-4 transcripts were observed in the mesonephric tubules, pancreas, stomach, and intestine and, still later, in the metanephric tubules of the developing kidney [1].
  • HNF-4 could play an important role in the formation and function of visceral yolk sac and in the development of the liver and kidney since its mRNA, as determined by in situ hybridization, appears upon primary differentiation of these organs [22].

Analytical, diagnostic and therapeutic context of Hnf4a


  1. Expression of transcription factor HNF-4 in the extraembryonic endoderm, gut, and nephrogenic tissue of the developing mouse embryo: HNF-4 is a marker for primary endoderm in the implanting blastocyst. Duncan, S.A., Manova, K., Chen, W.S., Hoodless, P., Weinstein, D.C., Bachvarova, R.F., Darnell, J.E. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  2. Hepatocyte nuclear factor 4alpha (nuclear receptor 2A1) is essential for maintenance of hepatic gene expression and lipid homeostasis. Hayhurst, G.P., Lee, Y.H., Lambert, G., Ward, J.M., Gonzalez, F.J. Mol. Cell. Biol. (2001) [Pubmed]
  3. 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]
  4. Avian and Mammalian hepadnaviruses have distinct transcription factor requirements for viral replication. Tang, H., McLachlan, A. J. Virol. (2002) [Pubmed]
  5. Transcription and replication of a natural hepatitis B virus nucleocapsid promoter variant is regulated in vivo by peroxisome proliferators. Raney, A.K., Kline, E.F., Tang, H., McLachlan, A. Virology (2001) [Pubmed]
  6. A transcriptional hierarchy involved in mammalian cell-type specification. Kuo, C.J., Conley, P.B., Chen, L., Sladek, F.M., Darnell, J.E., Crabtree, G.R. Nature (1992) [Pubmed]
  7. A developmental transition in definitive erythropoiesis: erythropoietin expression is sequentially regulated by retinoic acid receptors and HNF4. Makita, T., Hernandez-Hoyos, G., Chen, T.H., Wu, H., Rothenberg, E.V., Sucov, H.M. Genes Dev. (2001) [Pubmed]
  8. GATA6 regulates HNF4 and is required for differentiation of visceral endoderm in the mouse embryo. Morrisey, E.E., Tang, Z., Sigrist, K., Lu, M.M., Jiang, F., Ip, H.S., Parmacek, M.S. Genes Dev. (1998) [Pubmed]
  9. Hepatocyte nuclear factor 4alpha is essential for embryonic development of the mouse colon. Garrison, W.D., Battle, M.A., Yang, C., Kaestner, K.H., Sladek, F.M., Duncan, S.A. Gastroenterology (2006) [Pubmed]
  10. Tissue-specific regulation of mouse hepatocyte nuclear factor 4 expression. Zhong, W., Mirkovitch, J., Darnell, J.E. Mol. Cell. Biol. (1994) [Pubmed]
  11. Transcriptional regulation of the phosphoenolpyruvate carboxykinase gene by cooperation between hepatic nuclear factors. Yanuka-Kashles, O., Cohen, H., Trus, M., Aran, A., Benvenisty, N., Reshef, L. Mol. Cell. Biol. (1994) [Pubmed]
  12. Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Chen, W.S., Manova, K., Weinstein, D.C., Duncan, S.A., Plump, A.S., Prezioso, V.R., Bachvarova, R.F., Darnell, J.E. Genes Dev. (1994) [Pubmed]
  13. 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. Ginsburg, G.S., Ozer, J., Karathanasis, S.K. J. Clin. Invest. (1995) [Pubmed]
  14. Functional inhibitory cross-talk between constitutive androstane receptor and hepatic nuclear factor-4 in hepatic lipid/glucose metabolism is mediated by competition for binding to the DR1 motif and to the common coactivators, GRIP-1 and PGC-1alpha. Miao, J., Fang, S., Bae, Y., Kemper, J.K. J. Biol. Chem. (2006) [Pubmed]
  15. Acetylation regulates transcription factor activity at multiple levels. Soutoglou, E., Katrakili, N., Talianidis, I. Mol. Cell (2000) [Pubmed]
  16. Mutations in the hepatocyte nuclear factor-1alpha gene in MODY and early-onset NIDDM: evidence for a mutational hotspot in exon 4. Kaisaki, P.J., Menzel, S., Lindner, T., Oda, N., Rjasanowski, I., Sahm, J., Meincke, G., Schulze, J., Schmechel, H., Petzold, C., Ledermann, H.M., Sachse, G., Boriraj, V.V., Menzel, R., Kerner, W., Turner, R.C., Yamagata, K., Bell, G.I. Diabetes (1997) [Pubmed]
  17. Phosphoenolpyruvate carboxykinase (GTP): characterization of the human PCK1 gene and localization distal to MODY on chromosome 20. Ting, C.N., Burgess, D.L., Chamberlain, J.S., Keith, T.P., Falls, K., Meisler, M.H. Genomics (1993) [Pubmed]
  18. Hepatocyte nuclear factor-4 alpha mediates the stimulatory effect of peroxisome proliferator-activated receptor gamma co-activator-1 alpha (PGC-1 alpha) on glucose-6-phosphatase catalytic subunit gene transcription in H4IIE cells. Boustead, J.N., Stadelmaier, B.T., Eeds, A.M., Wiebe, P.O., Svitek, C.A., Oeser, J.K., O'Brien, R.M. Biochem. J. (2003) [Pubmed]
  19. Involvement of STAT5 (signal transducer and activator of transcription 5) and HNF-4 (hepatocyte nuclear factor 4) in the transcriptional control of the hnf6 gene by growth hormone. Lahuna, O., Rastegar, M., Maiter, D., Thissen, J.P., Lemaigre, F.P., Rousseau, G.G. Mol. Endocrinol. (2000) [Pubmed]
  20. Transcriptional regulation by HNF-4 of the steroid 15alpha-hydroxylase P450 (Cyp2a-4) gene in mouse liver. Yokomori, N., Nishio, K., Aida, K., Negishi, M. J. Steroid Biochem. Mol. Biol. (1997) [Pubmed]
  21. Essential role for the homeoprotein vHNF1/HNF1beta in visceral endoderm differentiation. Coffinier, C., Thépot, D., Babinet, C., Yaniv, M., Barra, J. Development (1999) [Pubmed]
  22. Characterization of the mouse HNF-4 gene and its expression during mouse embryogenesis. Taraviras, S., Monaghan, A.P., Schütz, G., Kelsey, G. Mech. Dev. (1994) [Pubmed]
  23. Rapid modulation of liver-specific transcription factors after injury. Burke, P.A., Drotar, M., Luo, M., Yaffe, M., Forse, R.A. Surgery (1994) [Pubmed]
  24. An enhancer element 6 kb upstream of the mouse HNF4alpha1 promoter is activated by glucocorticoids and liver-enriched transcription factors. Bailly, A., Torres-Padilla, M.E., Tinel, A.P., Weiss, M.C. Nucleic Acids Res. (2001) [Pubmed]
  25. Hepatitis B virus transcription and replication. Tang, H., Banks, K.E., Anderson, A.L., McLachlan, A. Drug News Perspect. (2001) [Pubmed]
  26. Hepatocellular proliferation in response to a peroxisome proliferator does not require TNFalpha signaling. Anderson, S.P., Dunn, C.S., Cattley, R.C., Corton, J.C. Carcinogenesis (2001) [Pubmed]
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