Glucose Regulation of Gene Transcription

Abstract

L-type pyruvate kinase acetyl-CoA carboxylase spot 14 AMP-activated protein kinase glucose response element carbohydrate response element chicken ovalbumin upstream promoter-transcription factor upstream stimulatory factor sterol response element-binding protein phosphatidylinositol 3-kinase pancreatic duodenum homeobox 1 Nutrient gene regulation is an important adaptation allowing survival on intermittent food supplies. This adaptative process exists in all species from yeast to mammals. Glucose, the most abundant monosaccharide in nature, provides a very good example of how organisms have developed regulatory mechanisms to cope with a fluctuating level of nutrient supply. In yeast, glucose facilitates its own use by inducing expression of genes involved in its metabolism while repressing that of those involved in the utilization of alternative carbon sources (for review, see Ref. 1Johnston M. Trends Genet. 1999; 15: 29-33Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar). The mechanisms by which glucose affects gene expression in yeast are now relatively well understood. In mammals the response to dietary glucose is more complex because it combines effects related to glucose metabolism itself and effects secondary to glucose-dependent hormonal modifications, mainly pancreatic stimulation of insulin secretion and inhibition of glucagon secretion. In the pancreatic β cells, glucose is the primary physiological stimulus for the regulation of insulin synthesis and secretion. In the liver, glucose, in the presence of insulin, induces expression of genes encoding glucose transporters and glycolytic and lipogenic enzymes, e.g. L-type pyruvate kinase (L-PK),1 acetyl-CoA carboxylase (ACC), and fatty acid synthase, and represses genes of the gluconeogenic pathway, such as the phosphoenolpyruvate carboxykinase gene (for review, see Refs. 2Vaulont S. Kahn A. FASEB J. 1994; 8: 28-35Crossref PubMed Scopus (174) Google Scholar, 3Girard J. Ferre P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (302) Google Scholar, 4Towle H.C. Kaytor E.N. Shih H.M. Annu. Rev. Nutr. 1997; 17: 405-433Crossref PubMed Scopus (248) Google Scholar). Although insulin and glucagon were long known as critical in regulating gene expression, it is only recently that carbohydrates also have been shown to play a key role in transcriptional regulation (3Girard J. Ferre P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (302) Google Scholar, 4Towle H.C. Kaytor E.N. Shih H.M. Annu. Rev. Nutr. 1997; 17: 405-433Crossref PubMed Scopus (248) Google Scholar, 5Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). DNA sequences and DNA binding complexes involved in the glucose-regulated gene expression have been characterized recently in liver and β cells. In most glucose-sensitive tissues, glucose entry is mediated through specific glucose transporters; these include GLUT2, in the liver and β cells, and GLUT4, an insulin-sensitive transporter, in adipocytes and muscle (6Olson A.L. Pessin J.E. Annu. Rev. Nutr. 1996; 16: 235-256Crossref PubMed Scopus (382) Google Scholar). It seems likely that the main role of GLUT2 in gluconeogenic tissues, such as the liver, is to allow for a rapid equilibrium between intra- and extracellular glucose, in particular an easy secretion of glucose under gluconeogenic conditions. In hepatoma cells devoid of GLUT2 and cultured without glucose, the concentration of intracellular glucose 6-phosphate remains high, thus explaining the continuous stimulation of glucose-sensitive genes and consequent loss of glucose responsiveness (7Antoine B. Lefrançois-Martinez A.M. Le Guillou G. Leturque A. Vandewalle A. Kahn A. J. Biol. Chem. 1997; 272: 17937-17943Abstract Full Text Full Text PDF PubMed Scopus (31) Google Scholar). Accordingly, in GLUT2 −/− mice the intracellular glucose 6-phosphate concentration is high in fasting animals (8Guillam M.T. Burcelin R. Thorens B. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 12317-12321Crossref PubMed Scopus (99) Google Scholar, 9Burcelin R. del Carmen Munoz M. Guillam M.T. Thorens B. J. Biol. Chem. 2000; 275: 10930-10936Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar); and in patients with mutation in the GLUT2 gene (the Fanconi-Bickel syndrome), there is an associated accumulation of intrahepatic glycogen (10Santer R. Schneppenheim R. Dombrowski A. Gotze H. Steinmann B. Schaub J. Nat. Genet. 1997; 17: 324-326Crossref PubMed Scopus (234) Google Scholar). Transcription of the gene for L-PK is also abnormally stimulated in the liver of fasted GLUT2 −/− mice. Transfer of a GLUT2 transgene reestablishes a normal inhibition of glucose utilization by fasting and stimulation by carbohydrate feeding (9Burcelin R. del Carmen Munoz M. Guillam M.T. Thorens B. J. Biol. Chem. 2000; 275: 10930-10936Abstract Full Text Full T