Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 2002 Dec 15;368(Pt 3):931–937. doi: 10.1042/BJ20020605

Overexpression of c-myc in diabetic mice restores altered expression of the transcription factor genes that regulate liver metabolism.

Efren Riu 1, Tura Ferre 1, Alex Mas 1, Antonio Hidalgo 1, Sylvie Franckhauser 1, Fatima Bosch 1
PMCID: PMC1223040  PMID: 12230428

Abstract

Overexpression of the c-Myc transcription factor in liver induces glucose uptake and utilization. Here we examined the effects of c- myc overexpression on the expression of hepatocyte-specific transcription factor genes which regulate the expression of genes controlling hepatic metabolism. At 4 months after streptozotocin (STZ) treatment, most diabetic control mice were highly hyperglycaemic and died, whereas in STZ-treated transgenic mice hyperglycaemia was markedly lower, the serum levels of beta-hydroxybutyrate, triacylglycerols and non-esterified fatty acids were normal, and they had greater viability in the absence of insulin. Furthermore, long-term STZ-treated transgenic mice showed similar glucose utilization and storage to healthy controls. This was consistent with the expression of glycolytic genes becoming normalized. In addition, restoration of gene expression of the transcription factor, sterol receptor element binding protein 1c, was observed in the livers of these transgenic mice. Further, in STZ-treated transgenic mice the expression of genes involved in the control of gluconeogenesis (phosphoenolpyruvate carbokykinase), ketogenesis (3-hydroxy-3-methylglutaryl-CoA synthase) and energy metabolism (uncoupling protein 2) had returned to normal. These findings were correlated with decreased expression of genes encoding the transcription factors hepatocyte nuclear factor 3gamma, peroxisome proliferator-activated receptor alpha and retinoid X receptor. These results indicate that c- myc overexpression may counteract diabetic changes by controlling hepatic glucose metabolism, both directly by altering the expression of metabolic genes and through the expression of key transcription factor genes.

Full Text

The Full Text of this article is available as a PDF (157.1 KB).

Selected References

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

  1. Amemiya-Kudo M., Shimano H., Yoshikawa T., Yahagi N., Hasty A. H., Okazaki H., Tamura Y., Shionoiri F., Iizuka Y., Ohashi K. Promoter analysis of the mouse sterol regulatory element-binding protein-1c gene. J Biol Chem. 2000 Oct 6;275(40):31078–31085. doi: 10.1074/jbc.M005353200. [DOI] [PubMed] [Google Scholar]
  2. Asayama K., Sandhir R., Sheikh F. G., Hayashibe H., Nakane T., Singh I. Increased peroxisomal fatty acid beta-oxidation and enhanced expression of peroxisome proliferator-activated receptor-alpha in diabetic rat liver. Mol Cell Biochem. 1999 Apr;194(1-2):227–234. doi: 10.1023/a:1006930513476. [DOI] [PubMed] [Google Scholar]
  3. Boss O., Muzzin P., Giacobino J. P. The uncoupling proteins, a review. Eur J Endocrinol. 1998 Jul;139(1):1–9. doi: 10.1530/eje.0.1390001. [DOI] [PubMed] [Google Scholar]
  4. Casals N., Roca N., Guerrero M., Gil-Gómez G., Ayté J., Ciudad C. J., Hegardt F. G. Regulation of the expression of the mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene. Its role in the control of ketogenesis. Biochem J. 1992 Apr 1;283(Pt 1):261–264. doi: 10.1042/bj2830261. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Cereghini S. Liver-enriched transcription factors and hepatocyte differentiation. FASEB J. 1996 Feb;10(2):267–282. [PubMed] [Google Scholar]
  6. Chirgwin J. M., Przybyla A. E., MacDonald R. J., Rutter W. J. Isolation of biologically active ribonucleic acid from sources enriched in ribonuclease. Biochemistry. 1979 Nov 27;18(24):5294–5299. doi: 10.1021/bi00591a005. [DOI] [PubMed] [Google Scholar]
  7. Dang C. V. c-Myc target genes involved in cell growth, apoptosis, and metabolism. Mol Cell Biol. 1999 Jan;19(1):1–11. doi: 10.1128/mcb.19.1.1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Desvergne B., Wahli W. Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocr Rev. 1999 Oct;20(5):649–688. doi: 10.1210/edrv.20.5.0380. [DOI] [PubMed] [Google Scholar]
  9. Ferre T., Pujol A., Riu E., Bosch F., Valera A. Correction of diabetic alterations by glucokinase. Proc Natl Acad Sci U S A. 1996 Jul 9;93(14):7225–7230. doi: 10.1073/pnas.93.14.7225. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Ferre T., Riu E., Bosch F., Valera A. Evidence from transgenic mice that glucokinase is rate limiting for glucose utilization in the liver. FASEB J. 1996 Aug;10(10):1213–1218. doi: 10.1096/fasebj.10.10.8751724. [DOI] [PubMed] [Google Scholar]
  11. Fleury C., Neverova M., Collins S., Raimbault S., Champigny O., Levi-Meyrueis C., Bouillaud F., Seldin M. F., Surwit R. S., Ricquier D. Uncoupling protein-2: a novel gene linked to obesity and hyperinsulinemia. Nat Genet. 1997 Mar;15(3):269–272. doi: 10.1038/ng0397-269. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Foretz M., Pacot C., Dugail I., Lemarchand P., Guichard C., Le Lièpvre X., Berthelier-Lubrano C., Spiegelman B., Kim J. B., Ferré P. ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. Mol Cell Biol. 1999 May;19(5):3760–3768. doi: 10.1128/mcb.19.5.3760. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Fukasawa M., Takayama E., Shinomiya N., Okumura A., Rokutanda M., Yamamoto N., Sakakibara R. Identification of the promoter region of human placental 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase gene. Biochem Biophys Res Commun. 2000 Jan 27;267(3):703–708. doi: 10.1006/bbrc.1999.2022. [DOI] [PubMed] [Google Scholar]
  15. Gimeno R. E., Dembski M., Weng X., Deng N., Shyjan A. W., Gimeno C. J., Iris F., Ellis S. J., Woolf E. A., Tartaglia L. A. Cloning and characterization of an uncoupling protein homolog: a potential molecular mediator of human thermogenesis. Diabetes. 1997 May;46(5):900–906. doi: 10.2337/diab.46.5.900. [DOI] [PubMed] [Google Scholar]
  16. Girard J., Ferré P., Foufelle F. Mechanisms by which carbohydrates regulate expression of genes for glycolytic and lipogenic enzymes. Annu Rev Nutr. 1997;17:325–352. doi: 10.1146/annurev.nutr.17.1.325. [DOI] [PubMed] [Google Scholar]
  17. Girard J., Perdereau D., Foufelle F., Prip-Buus C., Ferré P. Regulation of lipogenic enzyme gene expression by nutrients and hormones. FASEB J. 1994 Jan;8(1):36–42. doi: 10.1096/fasebj.8.1.7905448. [DOI] [PubMed] [Google Scholar]
  18. Glass C. K. Some new twists in the regulation of gene expression by thyroid hormone and retinoic acid receptors. J Endocrinol. 1996 Sep;150(3):349–357. doi: 10.1677/joe.0.1500349. [DOI] [PubMed] [Google Scholar]
  19. Hanson R. W., Reshef L. Regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression. Annu Rev Biochem. 1997;66:581–611. doi: 10.1146/annurev.biochem.66.1.581. [DOI] [PubMed] [Google Scholar]
  20. Hasty A. H., Shimano H., Yahagi N., Amemiya-Kudo M., Perrey S., Yoshikawa T., Osuga J., Okazaki H., Tamura Y., Iizuka Y. Sterol regulatory element-binding protein-1 is regulated by glucose at the transcriptional level. J Biol Chem. 2000 Oct 6;275(40):31069–31077. doi: 10.1074/jbc.M003335200. [DOI] [PubMed] [Google Scholar]
  21. Hegardt F. G. Mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase: a control enzyme in ketogenesis. Biochem J. 1999 Mar 15;338(Pt 3):569–582. [PMC free article] [PubMed] [Google Scholar]
  22. Iynedjian P. B., Gjinovci A., Renold A. E. Stimulation by insulin of glucokinase gene transcription in liver of diabetic rats. J Biol Chem. 1988 Jan 15;263(2):740–744. [PubMed] [Google Scholar]
  23. 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]
  24. Kaestner K. H., Hiemisch H., Schütz G. Targeted disruption of the gene encoding hepatocyte nuclear factor 3gamma results in reduced transcription of hepatocyte-specific genes. Mol Cell Biol. 1998 Jul;18(7):4245–4251. doi: 10.1128/mcb.18.7.4245. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Kaestner K. H. The hepatocyte nuclear factor 3 (HNF3 or FOXA) family in metabolism. Trends Endocrinol Metab. 2000 Sep;11(7):281–285. doi: 10.1016/s1043-2760(00)00271-x. [DOI] [PubMed] [Google Scholar]
  26. Kageyama H., Suga A., Kashiba M., Oka J., Osaka T., Kashiwa T., Hirano T., Nemoto K., Namba Y., Ricquier D. Increased uncoupling protein-2 and -3 gene expressions in skeletal muscle of STZ-induced diabetic rats. FEBS Lett. 1998 Dec 4;440(3):450–453. doi: 10.1016/s0014-5793(98)01506-3. [DOI] [PubMed] [Google Scholar]
  27. Kato G. J., Dang C. V. Function of the c-Myc oncoprotein. FASEB J. 1992 Sep;6(12):3065–3072. doi: 10.1096/fasebj.6.12.1521738. [DOI] [PubMed] [Google Scholar]
  28. Kelly L. J., Vicario P. P., Thompson G. M., Candelore M. R., Doebber T. W., Ventre J., Wu M. S., Meurer R., Forrest M. J., Conner M. W. Peroxisome proliferator-activated receptors gamma and alpha mediate in vivo regulation of uncoupling protein (UCP-1, UCP-2, UCP-3) gene expression. Endocrinology. 1998 Dec;139(12):4920–4927. doi: 10.1210/endo.139.12.6384. [DOI] [PubMed] [Google Scholar]
  29. Kersten S., Desvergne B., Wahli W. Roles of PPARs in health and disease. Nature. 2000 May 25;405(6785):421–424. doi: 10.1038/35013000. [DOI] [PubMed] [Google Scholar]
  30. Kim H. I., Kim J. W., Kim S. H., Cha J. Y., Kim K. S., Ahn Y. H. Identification and functional characterization of the peroxisomal proliferator response element in rat GLUT2 promoter. Diabetes. 2000 Sep;49(9):1517–1524. doi: 10.2337/diabetes.49.9.1517. [DOI] [PubMed] [Google Scholar]
  31. Lüscher B., Eisenman R. N. New light on Myc and Myb. Part I. Myc. Genes Dev. 1990 Dec;4(12A):2025–2035. doi: 10.1101/gad.4.12a.2025. [DOI] [PubMed] [Google Scholar]
  32. Mangelsdorf D. J., Evans R. M. The RXR heterodimers and orphan receptors. Cell. 1995 Dec 15;83(6):841–850. doi: 10.1016/0092-8674(95)90200-7. [DOI] [PubMed] [Google Scholar]
  33. Marcu K. B., Bossone S. A., Patel A. J. myc function and regulation. Annu Rev Biochem. 1992;61:809–860. doi: 10.1146/annurev.bi.61.070192.004113. [DOI] [PubMed] [Google Scholar]
  34. Mason T. M., Gupta N., Goh T., El-Bahrani B., Zannis J., van de Werve G., Giacca A. Chronic intraperitoneal insulin delivery, as compared with subcutaneous delivery, improves hepatic glucose metabolism in streptozotocin diabetic rats. Metabolism. 2000 Nov;49(11):1411–1416. doi: 10.1053/meta.2000.17731. [DOI] [PubMed] [Google Scholar]
  35. Narravula S., Colgan S. P. Hypoxia-inducible factor 1-mediated inhibition of peroxisome proliferator-activated receptor alpha expression during hypoxia. J Immunol. 2001 Jun 15;166(12):7543–7548. doi: 10.4049/jimmunol.166.12.7543. [DOI] [PubMed] [Google Scholar]
  36. Ortiz J. A., Mallolas J., Nicot C., Bofarull J., Rodríguez J. C., Hegardt F. G., Haro D., Marrero P. F. Isolation of pig mitochondrial 3-hydroxy-3-methylglutaryl-CoA synthase gene promoter: characterization of a peroxisome proliferator-responsive element. Biochem J. 1999 Jan 15;337(Pt 2):329–335. [PMC free article] [PubMed] [Google Scholar]
  37. Osthus R. C., Shim H., Kim S., Li Q., Reddy R., Mukherjee M., Xu Y., Wonsey D., Lee L. A., Dang C. V. Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc. J Biol Chem. 2000 Jul 21;275(29):21797–21800. doi: 10.1074/jbc.C000023200. [DOI] [PubMed] [Google Scholar]
  38. Pilkis S. J., Granner D. K. Molecular physiology of the regulation of hepatic gluconeogenesis and glycolysis. Annu Rev Physiol. 1992;54:885–909. doi: 10.1146/annurev.ph.54.030192.004321. [DOI] [PubMed] [Google Scholar]
  39. Rausa F. M., Tan Y., Zhou H., Yoo K. W., Stolz D. B., Watkins S. C., Franks R. R., Unterman T. G., Costa R. H. Elevated levels of hepatocyte nuclear factor 3beta in mouse hepatocytes influence expression of genes involved in bile acid and glucose homeostasis. Mol Cell Biol. 2000 Nov;20(21):8264–8282. doi: 10.1128/mcb.20.21.8264-8282.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Riu E., Bosch F., Valera A. Prevention of diabetic alterations in transgenic mice overexpressing Myc in the liver. Proc Natl Acad Sci U S A. 1996 Mar 5;93(5):2198–2202. doi: 10.1073/pnas.93.5.2198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Rothwell N. J., Stock M. J. A role for insulin in the diet-induced thermogenesis of cafeteria-fed rats. Metabolism. 1981 Jul;30(7):673–678. doi: 10.1016/0026-0495(81)90082-2. [DOI] [PubMed] [Google Scholar]
  42. Scott D. K., Mitchell J. A., Granner D. K. The orphan receptor COUP-TF binds to a third glucocorticoid accessory factor element within the phosphoenolpyruvate carboxykinase gene promoter. J Biol Chem. 1996 Dec 13;271(50):31909–31914. doi: 10.1074/jbc.271.50.31909. [DOI] [PubMed] [Google Scholar]
  43. Scott D. K., O'Doherty R. M., Stafford J. M., Newgard C. B., Granner D. K. The repression of hormone-activated PEPCK gene expression by glucose is insulin-independent but requires glucose metabolism. J Biol Chem. 1998 Sep 11;273(37):24145–24151. doi: 10.1074/jbc.273.37.24145. [DOI] [PubMed] [Google Scholar]
  44. Seoane J., Pouponnot C., Staller P., Schader M., Eilers M., Massagué J. TGFbeta influences Myc, Miz-1 and Smad to control the CDK inhibitor p15INK4b. Nat Cell Biol. 2001 Apr;3(4):400–408. doi: 10.1038/35070086. [DOI] [PubMed] [Google Scholar]
  45. Shimomura I., Bashmakov Y., Ikemoto S., Horton J. D., Brown M. S., Goldstein J. L. Insulin selectively increases SREBP-1c mRNA in the livers of rats with streptozotocin-induced diabetes. Proc Natl Acad Sci U S A. 1999 Nov 23;96(24):13656–13661. doi: 10.1073/pnas.96.24.13656. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Staller P., Peukert K., Kiermaier A., Seoane J., Lukas J., Karsunky H., Möröy T., Bartek J., Massagué J., Hänel F. Repression of p15INK4b expression by Myc through association with Miz-1. Nat Cell Biol. 2001 Apr;3(4):392–399. doi: 10.1038/35070076. [DOI] [PubMed] [Google Scholar]
  47. Steineger H. H., Arntsen B. M., Spydevold O., Sørensen H. N. Gene transcription of the retinoid X receptor alpha (RXRalpha) is regulated by fatty acids and hormones in rat hepatic cells. J Lipid Res. 1998 Apr;39(4):744–754. [PubMed] [Google Scholar]
  48. Tisch R., McDevitt H. Insulin-dependent diabetes mellitus. Cell. 1996 May 3;85(3):291–297. doi: 10.1016/s0092-8674(00)81106-x. [DOI] [PubMed] [Google Scholar]
  49. Unterman T. G., Fareeduddin A., Harris M. A., Goswami R. G., Porcella A., Costa R. H., Lacson R. G. Hepatocyte nuclear factor-3 (HNF-3) binds to the insulin response sequence in the IGF binding protein-1 (IGFBP-1) promoter and enhances promoter function. Biochem Biophys Res Commun. 1994 Sep 30;203(3):1835–1841. doi: 10.1006/bbrc.1994.2401. [DOI] [PubMed] [Google Scholar]
  50. Valera A., Pujol A., Gregori X., Riu E., Visa J., Bosch F. Evidence from transgenic mice that myc regulates hepatic glycolysis. FASEB J. 1995 Aug;9(11):1067–1078. doi: 10.1096/fasebj.9.11.7649406. [DOI] [PubMed] [Google Scholar]
  51. Valera A., Rodriguez-Gil J. E., Bosch F. Vanadate treatment restores the expression of genes for key enzymes in the glucose and ketone bodies metabolism in the liver of diabetic rats. J Clin Invest. 1993 Jul;92(1):4–11. doi: 10.1172/JCI116580. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Vaulont S., Kahn A. Transcriptional control of metabolic regulation genes by carbohydrates. FASEB J. 1994 Jan;8(1):28–35. doi: 10.1096/fasebj.8.1.8299888. [DOI] [PubMed] [Google Scholar]
  53. Vaulont S., Puzenat N., Levrat F., Cognet M., Kahn A., Raymondjean M. Proteins binding to the liver-specific pyruvate kinase gene promoter. A unique combination of known factors. J Mol Biol. 1989 Sep 20;209(2):205–219. doi: 10.1016/0022-2836(89)90273-8. [DOI] [PubMed] [Google Scholar]
  54. Vaulont S., Vasseur-Cognet M., Kahn A. Glucose regulation of gene transcription. J Biol Chem. 2000 Oct 13;275(41):31555–31558. doi: 10.1074/jbc.R000016200. [DOI] [PubMed] [Google Scholar]
  55. Wan Y. J., An D., Cai Y., Repa J. J., Hung-Po Chen T., Flores M., Postic C., Magnuson M. A., Chen J., Chien K. R. Hepatocyte-specific mutation establishes retinoid X receptor alpha as a heterodimeric integrator of multiple physiological processes in the liver. Mol Cell Biol. 2000 Jun;20(12):4436–4444. doi: 10.1128/mcb.20.12.4436-4444.2000. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Xanthopoulos K. G., Prezioso V. R., Chen W. S., Sladek F. M., Cortese R., Darnell J. E., Jr The different tissue transcription patterns of genes for HNF-1, C/EBP, HNF-3, and HNF-4, protein factors that govern liver-specific transcription. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3807–3811. doi: 10.1073/pnas.88.9.3807. [DOI] [PMC free article] [PubMed] [Google Scholar]

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

RESOURCES