Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Jul 1;365(Pt 1):223–228. doi: 10.1042/BJ20020340

Activation of glucokinase gene expression by hepatic nuclear factor 4alpha in primary hepatocytes.

Ulrike Roth 1, Kurt Jungermann 1, Thomas Kietzmann 1
PMCID: PMC1222650  PMID: 11950391

Abstract

Glucokinase (GK) is a key enzyme for glucose utilization in liver and shows a higher expression in the perivenous zone. In primary rat hepatocytes, the GK gene expression was activated by HNF (hepatic nuclear factor)-4alpha via the sequence -52/-39 of the GK promoter. Venous pO2 enhanced HNF-4 levels and HNF-4 binding to the GK-HNF-4 element. Thus, HNF-4alpha could play the role of a regulator for zonated GK expression.

Full Text

The Full Text of this article is available as a PDF (180.3 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Bogan A. A., Dallas-Yang Q., Ruse M. D., Jr, Maeda Y., Jiang G., Nepomuceno L., Scanlan T. S., Cohen F. E., Sladek F. M. Analysis of protein dimerization and ligand binding of orphan receptor HNF4alpha. J Mol Biol. 2000 Sep 29;302(4):831–851. doi: 10.1006/jmbi.2000.4099. [DOI] [PubMed] [Google Scholar]
  2. Bossard P., Parsa R., Decaux J. F., Iynedjian P., Girard J. Glucose administration induces the premature expression of liver glucokinase gene in newborn rats. Relation with DNase-I-hypersensitive sites. Eur J Biochem. 1993 Aug 1;215(3):883–892. doi: 10.1111/j.1432-1033.1993.tb18106.x. [DOI] [PubMed] [Google Scholar]
  3. Brinkmann A., Katz N., Sasse D., Jungermann K. Increase of the gluconeogenic and decrease of the glycolytic capacity of rat liver with a change of the metabolic zonation after partial hepatectomy. Hoppe Seylers Z Physiol Chem. 1978 Nov;359(11):1561–1571. doi: 10.1515/bchm2.1978.359.2.1561. [DOI] [PubMed] [Google Scholar]
  4. Chartier F. L., Bossu J. P., Laudet V., Fruchart J. C., Laine B. Cloning and sequencing of cDNAs encoding the human hepatocyte nuclear factor 4 indicate the presence of two isoforms in human liver. Gene. 1994 Sep 30;147(2):269–272. doi: 10.1016/0378-1119(94)90079-5. [DOI] [PubMed] [Google Scholar]
  5. Chen W. S., Manova K., Weinstein D. C., Duncan S. A., Plump A. S., Prezioso V. R., Bachvarova R. F., Darnell J. E., Jr Disruption of the HNF-4 gene, expressed in visceral endoderm, leads to cell death in embryonic ectoderm and impaired gastrulation of mouse embryos. Genes Dev. 1994 Oct 15;8(20):2466–2477. doi: 10.1101/gad.8.20.2466. [DOI] [PubMed] [Google Scholar]
  6. Decaux J. F., Antoine B., Kahn A. Regulation of the expression of the L-type pyruvate kinase gene in adult rat hepatocytes in primary culture. J Biol Chem. 1989 Jul 15;264(20):11584–11590. [PubMed] [Google Scholar]
  7. Diaz Guerra M. J., Bergot M. O., Martinez A., Cuif M. H., Kahn A., Raymondjean M. Functional characterization of the L-type pyruvate kinase gene glucose response complex. Mol Cell Biol. 1993 Dec;13(12):7725–7733. doi: 10.1128/mcb.13.12.7725. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Dignam J. D., Lebovitz R. M., Roeder R. G. Accurate transcription initiation by RNA polymerase II in a soluble extract from isolated mammalian nuclei. Nucleic Acids Res. 1983 Mar 11;11(5):1475–1489. doi: 10.1093/nar/11.5.1475. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Drewes T., Senkel S., Holewa B., Ryffel G. U. Human hepatocyte nuclear factor 4 isoforms are encoded by distinct and differentially expressed genes. Mol Cell Biol. 1996 Mar;16(3):925–931. doi: 10.1128/mcb.16.3.925. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Fajans S. S. Maturity-onset diabetes of the young (MODY). Diabetes Metab Rev. 1989 Nov;5(7):579–606. doi: 10.1002/dmr.5610050705. [DOI] [PubMed] [Google Scholar]
  11. Foretz M., Guichard C., Ferré P., Foufelle F. Sterol regulatory element binding protein-1c is a major mediator of insulin action on the hepatic expression of glucokinase and lipogenesis-related genes. Proc Natl Acad Sci U S A. 1999 Oct 26;96(22):12737–12742. doi: 10.1073/pnas.96.22.12737. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Fraser J. D., Martinez V., Straney R., Briggs M. R. DNA binding and transcription activation specificity of hepatocyte nuclear factor 4. Nucleic Acids Res. 1998 Jun 1;26(11):2702–2707. doi: 10.1093/nar/26.11.2702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Galson D. L., Tsuchiya T., Tendler D. S., Huang L. E., Ren Y., Ogura T., Bunn H. F. The orphan receptor hepatic nuclear factor 4 functions as a transcriptional activator for tissue-specific and hypoxia-specific erythropoietin gene expression and is antagonized by EAR3/COUP-TF1. Mol Cell Biol. 1995 Apr;15(4):2135–2144. doi: 10.1128/mcb.15.4.2135. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Hall R. K., Sladek F. M., Granner D. K. The orphan receptors COUP-TF and HNF-4 serve as accessory factors required for induction of phosphoenolpyruvate carboxykinase gene transcription by glucocorticoids. Proc Natl Acad Sci U S A. 1995 Jan 17;92(2):412–416. doi: 10.1073/pnas.92.2.412. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hata S., Inoue T., Kosuga K., Nakashima T., Tsukamoto T., Osumi T. Identification of two splice isoforms of mRNA for mouse hepatocyte nuclear factor 4 (HNF-4). Biochim Biophys Acta. 1995 Jan 2;1260(1):55–61. doi: 10.1016/0167-4781(94)00177-5. [DOI] [PubMed] [Google Scholar]
  16. Holewa B., Zapp D., Drewes T., Senkel S., Ryffel G. U. HNF4beta, a new gene of the HNF4 family with distinct activation and expression profiles in oogenesis and embryogenesis of Xenopus laevis. Mol Cell Biol. 1997 Feb;17(2):687–694. doi: 10.1128/mcb.17.2.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Immenschuh S., Hinke V., Ohlmann A., Gifhorn-Katz S., Katz N., Jungermann K., Kietzmann T. Transcriptional activation of the haem oxygenase-1 gene by cGMP via a cAMP response element/activator protein-1 element in primary cultures of rat hepatocytes. Biochem J. 1998 Aug 15;334(Pt 1):141–146. doi: 10.1042/bj3340141. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Iynedjian P. B. Identification of upstream stimulatory factor as transcriptional activator of the liver promoter of the glucokinase gene. Biochem J. 1998 Aug 1;333(Pt 3):705–712. doi: 10.1042/bj3330705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Iynedjian P. B. Identification of upstream stimulatory factor as transcriptional activator of the liver promoter of the glucokinase gene. Biochem J. 1998 Aug 1;333(Pt 3):705–712. doi: 10.1042/bj3330705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Iynedjian P. B. Mammalian glucokinase and its gene. Biochem J. 1993 Jul 1;293(Pt 1):1–13. doi: 10.1042/bj2930001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Iynedjian P. B., Pilot P. R., Nouspikel T., Milburn J. L., Quaade C., Hughes S., Ucla C., Newgard C. B. Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7838–7842. doi: 10.1073/pnas.86.20.7838. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Jetton T. L., Liang Y., Pettepher C. C., Zimmerman E. C., Cox F. G., Horvath K., Matschinsky F. M., Magnuson M. A. Analysis of upstream glucokinase promoter activity in transgenic mice and identification of glucokinase in rare neuroendocrine cells in the brain and gut. J Biol Chem. 1994 Feb 4;269(5):3641–3654. [PubMed] [Google Scholar]
  23. Jiang G., Nepomuceno L., Hopkins K., Sladek F. M. Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors. Mol Cell Biol. 1995 Sep;15(9):5131–5143. doi: 10.1128/mcb.15.9.5131. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Jungermann K., Kietzmann T. Zonation of parenchymal and nonparenchymal metabolism in liver. Annu Rev Nutr. 1996;16:179–203. doi: 10.1146/annurev.nu.16.070196.001143. [DOI] [PubMed] [Google Scholar]
  25. Kietzmann T., Roth U., Freimann S., Jungermann K. Arterial oxygen partial pressures reduce the insulin-dependent induction of the perivenously located glucokinase in rat hepatocyte cultures: mimicry of arterial oxygen pressures by H2O2. Biochem J. 1997 Jan 1;321(Pt 1):17–20. doi: 10.1042/bj3210017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kietzmann T., Roth U., Jungermann K. Induction of the plasminogen activator inhibitor-1 gene expression by mild hypoxia via a hypoxia response element binding the hypoxia-inducible factor-1 in rat hepatocytes. Blood. 1999 Dec 15;94(12):4177–4185. [PubMed] [Google Scholar]
  27. Kritis A. A., Argyrokastritis A., Moschonas N. K., Power S., Katrakili N., Zannis V. I., Cereghini S., Talianidis I. Isolation and characterization of a third isoform of human hepatocyte nuclear factor 4. Gene. 1996 Sep 16;173(2):275–280. doi: 10.1016/0378-1119(96)00183-7. [DOI] [PubMed] [Google Scholar]
  28. Ladias J. A., Hadzopoulou-Cladaras M., Kardassis D., Cardot P., Cheng J., Zannis V., Cladaras C. Transcriptional regulation of human apolipoprotein genes ApoB, ApoCIII, and ApoAII by members of the steroid hormone receptor superfamily HNF-4, ARP-1, EAR-2, and EAR-3. J Biol Chem. 1992 Aug 5;267(22):15849–15860. [PubMed] [Google Scholar]
  29. Laemmli U. K. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. doi: 10.1038/227680a0. [DOI] [PubMed] [Google Scholar]
  30. Li J., Ning G., Duncan S. A. Mammalian hepatocyte differentiation requires the transcription factor HNF-4alpha. Genes Dev. 2000 Feb 15;14(4):464–474. [PMC free article] [PubMed] [Google Scholar]
  31. Lindros K. O., Oinonen T., Issakainen J., Nagy P., Thorgeirsson S. S. Zonal distribution of transcripts of four hepatic transcription factors in the mature rat liver. Cell Biol Toxicol. 1997 Jul;13(4-5):257–262. doi: 10.1023/a:1007479223229. [DOI] [PubMed] [Google Scholar]
  32. Magnuson M. A., Shelton K. D. An alternate promoter in the glucokinase gene is active in the pancreatic beta cell. J Biol Chem. 1989 Sep 25;264(27):15936–15942. [PubMed] [Google Scholar]
  33. Metzger S., Halaas J. L., Breslow J. L., Sladek F. M. Orphan receptor HNF-4 and bZip protein C/EBP alpha bind to overlapping regions of the apolipoprotein B gene promoter and synergistically activate transcription. J Biol Chem. 1993 Aug 5;268(22):16831–16838. [PubMed] [Google Scholar]
  34. Mietus-Snyder M., Sladek F. M., Ginsburg G. S., Kuo C. F., Ladias J. A., Darnell J. E., Jr, Karathanasis S. K. Antagonism between apolipoprotein AI regulatory protein 1, Ear3/COUP-TF, and hepatocyte nuclear factor 4 modulates apolipoprotein CIII gene expression in liver and intestinal cells. Mol Cell Biol. 1992 Apr;12(4):1708–1718. doi: 10.1128/mcb.12.4.1708. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Oliver I. T., Edwards A. M., Pitot H. C. Hormonal regulation of phosphoenolpyruvate carboxykinase in primary cultures of adult-rat liver parenchymal cells. Eur J Biochem. 1978 Jun 15;87(2):221–227. doi: 10.1111/j.1432-1033.1978.tb12369.x. [DOI] [PubMed] [Google Scholar]
  36. Parry M. J., Walker D. G. Purification and properties of adenosine 5'-triphospae-D-glucose 6-phosphotransferase from rat liver. Biochem J. 1966 May;99(2):266–274. doi: 10.1042/bj0990266. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Postic C., Leturque A., Printz R. L., Maulard P., Loizeau M., Granner D. K., Girard J. Development and regulation of glucose transporter and hexokinase expression in rat. Am J Physiol. 1994 Apr;266(4 Pt 1):E548–E559. doi: 10.1152/ajpendo.1994.266.4.E548. [DOI] [PubMed] [Google Scholar]
  38. Postic C., Niswender K. D., Decaux J. F., Parsa R., Shelton K. D., Gouhot B., Pettepher C. C., Granner D. K., Girard J., Magnuson M. A. Cloning and characterization of the mouse glucokinase gene locus and identification of distal liver-specific DNase I hypersensitive sites. Genomics. 1995 Oct 10;29(3):740–750. doi: 10.1006/geno.1995.9943. [DOI] [PubMed] [Google Scholar]
  39. Printz R. L., Magnuson M. A., Granner D. K. Mammalian glucokinase. Annu Rev Nutr. 1993;13:463–496. doi: 10.1146/annurev.nu.13.070193.002335. [DOI] [PubMed] [Google Scholar]
  40. Probst I., Schwartz P., Jungermann K. Induction in primary culture of 'gluconeogenic' and 'glycolytic' hepatocytes resembling periportal and perivenous cells. Eur J Biochem. 1982 Aug;126(2):271–278. doi: 10.1111/j.1432-1033.1982.tb06775.x. [DOI] [PubMed] [Google Scholar]
  41. Semenza G. L., Wang G. L. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol. 1992 Dec;12(12):5447–5454. doi: 10.1128/mcb.12.12.5447. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Sladek F. M. Orphan receptor HNF-4 and liver-specific gene expression. Receptor. 1993 Fall;3(3):223–232. [PubMed] [Google Scholar]
  43. Sladek F. M., Zhong W. M., Lai E., Darnell J. E., Jr Liver-enriched transcription factor HNF-4 is a novel member of the steroid hormone receptor superfamily. Genes Dev. 1990 Dec;4(12B):2353–2365. doi: 10.1101/gad.4.12b.2353. [DOI] [PubMed] [Google Scholar]
  44. Stoffel M., Duncan S. A. The maturity-onset diabetes of the young (MODY1) transcription factor HNF4alpha regulates expression of genes required for glucose transport and metabolism. Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13209–13214. doi: 10.1073/pnas.94.24.13209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Vandercammen A., Van Schaftingen E. Competitive inhibition of liver glucokinase by its regulatory protein. Eur J Biochem. 1991 Sep 1;200(2):545–551. doi: 10.1111/j.1432-1033.1991.tb16217.x. [DOI] [PubMed] [Google Scholar]
  46. Vandercammen A., Van Schaftingen E. The mechanism by which rat liver glucokinase is inhibited by the regulatory protein. Eur J Biochem. 1990 Jul 31;191(2):483–489. doi: 10.1111/j.1432-1033.1990.tb19147.x. [DOI] [PubMed] [Google Scholar]
  47. Vaulont S., Munnich A., Decaux J. F., Kahn A. Transcriptional and post-transcriptional regulation of L-type pyruvate kinase gene expression in rat liver. J Biol Chem. 1986 Jun 15;261(17):7621–7625. [PubMed] [Google Scholar]
  48. Viollet B., Kahn A., Raymondjean M. Protein kinase A-dependent phosphorylation modulates DNA-binding activity of hepatocyte nuclear factor 4. Mol Cell Biol. 1997 Aug;17(8):4208–4219. doi: 10.1128/mcb.17.8.4208. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Vionnet N., Stoffel M., Takeda J., Yasuda K., Bell G. I., Zouali H., Lesage S., Velho G., Iris F., Passa P. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature. 1992 Apr 23;356(6371):721–722. doi: 10.1038/356721a0. [DOI] [PubMed] [Google Scholar]
  50. Wiesener M. S., Turley H., Allen W. E., Willam C., Eckardt K. U., Talks K. L., Wood S. M., Gatter K. C., Harris A. L., Pugh C. W. Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha. Blood. 1998 Oct 1;92(7):2260–2268. [PubMed] [Google Scholar]
  51. Yamagata K., Furuta H., Oda N., Kaisaki P. J., Menzel S., Cox N. J., Fajans S. S., Signorini S., Stoffel M., Bell G. I. Mutations in the hepatocyte nuclear factor-4alpha gene in maturity-onset diabetes of the young (MODY1) Nature. 1996 Dec 5;384(6608):458–460. doi: 10.1038/384458a0. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES