Glucose Regulation of Gene Transcription (2000)

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 Text PDF PubMed Scopus (63) Google Scholar). Guillemain et al. (11Guillemain G. Loizeau M. Pincon-Raymond M. Girard J. Leturque A. J. Cell Sci. 2000; 113: 841-847PubMed Google Scholar) have recently suggested that the large intracytoplasmic loop of GLUT2 could also play the role of a signaling molecule. Indeed, hyperexpression of this loop in mhAT3F hepatoma cells (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) abrogates glucose responsiveness. After its entry into liver, adipocytes, and β cells, glucose has to be metabolized to generate an intracellular signal that allows for transcriptional regulation of metabolic genes. Although it is now clear that the first step of glycolysis, namely phosphorylation of glucose to glucose 6-phosphate, is instrumental for glucose-dependent regulation (either positive or negative), the subsequent steps are still disputed and the exact nature of the active intermediate remains obscure (3Girard J. Ferre P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (302) 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). In the liver, glucose 6-phosphate can be used in glycolysis, the pentose phosphate pathway, glycogen synthesis, and hexosamine synthesis. Work from our laboratory using xylitol, an intermediate of the pentose phosphate pathway, has suggested that in hepatocytes in primary culture the glucose signal could be generated through the non-oxidative branch of the pentose phosphate pathway (12Doiron B. Cuif M.H. Chen R. Kahn A. J. Biol. Chem. 1996; 271: 5321-5324Abstract Full Text Full Text PDF PubMed Scopus (117) Google Scholar). This result has been further extended in vivo by Massillonet al. (13Massillon D. Chen W. Barzilai N. Prus-Wertheimer D. Hawkins M. Liu R. Taub R. Rossetti L. J. Biol. Chem. 1998; 273: 228-234Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar), who noted that xylitol mimics the effect of hyperglycemia on glucose-regulated genes without a change in intracellular glucose 6-phosphate concentration in the liver. Alternatively, there are several reports suggesting that glucose 6-phosphate itself is a signaling molecule (3Girard J. Ferre P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (302) Google Scholar, 14Goya L. de la Puente A. Ramos S. Martin M.A. Escriva F. Pascual-Leone A.M. J. Biol. Chem. 1999; 274: 24633-24640Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). According to Mourrieras et al. (15Mourrieras F. Foufelle F. Foretz M. Morin J. Bouche S. Ferré P. Biochem. J. 1997; 326: 345-349Crossref PubMed Scopus (69) Google Scholar), only production of glucose 6-phosphate correlates accurately with the induction of glucose-regulated genes. Finally, for a specific subset of genes regulated by glucose through its metabolism in muscle and fat, the hexosamine biosynthetic pathway was reported to mediate the transcriptional effects of glucose on gene expression (16Sayeski P.P. Kudlow J.E. J. Biol. Chem. 1996; 271: 15237-15243Abstract Full Text Full Text PDF PubMed Scopus (137) Google Scholar, 17Wang J. Liu R. Hawkins M. Barzilai N. Rossetti L. Nature. 1998; 393: 684-688Crossref PubMed Scopus (695) Google Scholar). It is likely that a phosphorylation/dephosphorylation cycle is involved in signaling the availability of glucose to the transcriptional machinery. In this regard, protein phosphatase inhibitors prevent the effects of glucose on L-PK gene expression 2B. Doiron, unpublished data. and other glucose-regulated genes (18Daniel S. Zhang S. DePaoli-Roach A.A. Kim K.H. J. Biol. Chem. 1996; 271: 14692-14697Abstract Full Text Full Text PDF PubMed Scopus (130) Google Scholar, 19Foretz M. Carling D. Guichard C. Ferré P. Foufelle F. J. Biol. Chem. 1998; 273: 14767-14771Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 20Datta U. Wexler I.D. Kerr D.S. Raz I. Patel M.S. Biochim. Biophys. Acta. 1999; 1447: 236-243Crossref PubMed Scopus (17) Google Scholar). The involvement of the cAMP-dependent protein kinase in regulating the glucose-dependent signaling pathway is well documented (4Towle H.C. Kaytor E.N. Shih H.M. Annu. Rev. Nutr. 1997; 17: 405-433Crossref PubMed Scopus (248) Google Scholar,21Viollet B. Kahn A. Raymondjean M. Mol. Cell. Biol. 1997; 17: 4208-4219Crossref PubMed Scopus (148) Google Scholar, 22Gourdon L. Lou D.Q. Raymondjean M. Vasseur-Cognet M. Kahn A. FEBS Lett. 1999; 459: 9-14Crossref PubMed Scopus (17) Google Scholar). More recently, another protein kinase, the AMP-activated protein kinase (AMPK), has been suggested to play a key role in transmission of the glucose signal for transcription. AMPK is a serine/threonine kinase acting as a key metabolic "master switch" by phosphorylating target proteins involved in carbohydrate and fat metabolism in response to changes in cellular energy charge. AMPK is activated by stresses that deplete ATP, leading to a rise in the AMP/ATP ratio within the cell (23Hardie D.G. Carling D. Carlson M. Annu. Rev. Biochem. 1998; 67: 821-855Crossref PubMed Scopus (1270) Google Scholar). AMPK is a heterotrimeric complex of a catalytic (α) and two regulatory subunit (β and γ) proteins. Proteins related to all three subunits have been characterized in the yeast Snf1p complex (24Carlson M. Curr. Opin. Genet. Dev. 1998; 8: 560-564Crossref PubMed Scopus (72) Google Scholar). There are two catalytic subunit isoforms encoded by two different genes, namely α1 and α2 (23Hardie D.G. Carling D. Carlson M. Annu. Rev. Biochem. 1998; 67: 821-855Crossref PubMed Scopus (1270) Google Scholar). Interestingly, although α1-containing complexes are exclusively cytoplasmic, α2 complexes are found both in the nucleus and cytoplasm (25Salt I. Celler J.W. Hawley S.A. Prescott A. Woods A. Carling D. Hardie D.G. Biochem. J. 1998; 334: 177-187Crossref PubMed Scopus (376) Google Scholar, 26da Silva Xavier G. Leclerc I. Salt I.P. Doiron B. Hardie D.G. Kahn A. Rutter G.A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4023-4028Crossref PubMed Scopus (187) Google Scholar). AMPK activity was first reported to be decreased in β cell lines incubated in elevated glucose concentrations (26da Silva Xavier G. Leclerc I. Salt I.P. Doiron B. Hardie D.G. Kahn A. Rutter G.A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4023-4028Crossref PubMed Scopus (187) Google Scholar, 27Salt I.P. Johnson G. Ashcroft S.J.H. Hardie D.G. Biochem. J. 1998; 335: 533-539Crossref PubMed Scopus (336) Google Scholar). We and others have shown that the AMPK activator, 5-amino-4-imidazolecarboxamide riboside, inhibits the glucose-dependent activation of several genes in hepatocytes in primary culture (19Foretz M. Carling D. Guichard C. Ferré P. Foufelle F. J. Biol. Chem. 1998; 273: 14767-14771Abstract Full Text Full Text PDF PubMed Scopus (214) Google Scholar, 28Leclerc I. Kahn A. Doiron B. FEBS Lett. 1998; 431: 180-184Crossref PubMed Scopus (128) Google Scholar). Thus, inactivation of AMPK may restore the transcriptional activity of glucose-responsive genes. To test this hypothesis, the group of Rutter in collaboration with our laboratory (26da Silva Xavier G. Leclerc I. Salt I.P. Doiron B. Hardie D.G. Kahn A. Rutter G.A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4023-4028Crossref PubMed Scopus (187) Google Scholar) used the single-cell antibody microinjection strategy, coupled with dynamic imaging of luciferase reporter constructs. These studies demonstrated that microinjection of antibodies against α2, but not the α1 AMPK catalytic subunit, mimics the effects of elevated glucose on the L-PK and preproinsulin promoters in MIN6 β cells. Interestingly, in each case the effects were only observed when antibody injection was performed both in the nucleus and the cytosol, indicating the importance of either a cytosolic phosphorylation event and/or the subcellular localization of the α2 subunits. Incubation with 5-amino-4-imidazolecarboxamide riboside diminished, but did not abolish, the effect of glucose on preproinsulin transcription (26da Silva Xavier G. Leclerc I. Salt I.P. Doiron B. Hardie D.G. Kahn A. Rutter G.A. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 4023-4028Crossref PubMed Scopus (187) Google Scholar). These data suggest that glucose-induced changes in AMPK activity are necessary and sufficient for the regulation of the L-PK gene by this sugar (see Fig. 1) and that they play an important role in the regulation of the preproinsulin gene promoter. This result is of interest with regard to what is known about yeast. In Saccharomyces cerevisiae, the Snfp kinase complex is activated by glucose removal, which results in phosphorylation-dependent inactivation of transcription factors involved in gene repression, such as Mig1 (1Johnston M. Trends Genet. 1999; 15: 29-33Abstract Full Text Full Text PDF PubMed Scopus (318) Google Scholar, 24Carlson M. Curr. Opin. Genet. Dev. 1998; 8: 560-564Crossref PubMed Scopus (72) Google Scholar). In mammalian cells, AMPK seems to have the opposite effect on gene expression; instead of inhibiting a repressor, AMPK inhibits an activator or activates a repressor (Fig. 1). Possible targets of AMPK are currently being investigated in our laboratory, and the generation of AMPK knock-out mice is in progress. To assess the effect of glucose on gene transcription, our laboratory has extensively studied the regulation of the rat L-PK gene expression by glucose. We defined a DNA sequence responsible for mediating the positive response to glucose ex vivo andin vivo (29Bergot M.O. Diaz-Guerra M.J. Puzenat N. Raymondjean M. Kahn A. Nucleic Acids Res. 1992; 20: 1871-1877Crossref PubMed Scopus (153) Google Scholar, 30Cuif M.H. Porteu A. Kahn A. Vaulont S. J. Biol. Chem. 1993; 268: 13769-13772Abstract Full Text PDF PubMed Google Scholar, 31Diaz-Guerra M.J. Bergot M.O. Martinez A. Cuif M.H. Kahn A. Raymondjean M. Mol. Cell. Biol. 1993; 13: 7725-7733Crossref PubMed Scopus (97) Google Scholar, 32Lefrancois-Martinez A.M. Martinez A. Antoine B. Raymondjean M. Kahn A. J. Biol. Chem. 1995; 270: 2640-2643Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar). This sequence, termed the glucose response element (GlRE), is closely related to the carbohydrate response element (ChoRE) described by the group of Towle (33Shih H.M. Towle H.C. J. Biol. Chem. 1992; 267: 13222-13228Abstract Full Text PDF PubMed Google Scholar, 34Shih H.-M. Liu Z. Towle H.C. J. Biol. Chem. 1995; 270: 21991-21997Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar) in the regulatory region of the S14 gene. A similar glucose-activatable region has been recently identified in the promoter of the gene for the glucagon receptor (35Portois L. Maget B. Tastenoy M. Perret J. Svoboda M. J. Biol. Chem. 1999; 274: 8181-8190Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). The complex that binds to the GlRE/ChoRE of the L-PK and S14 genes cooperates with an adjacent DNA binding site, termed the auxiliary site, to confer strong glucose responsiveness (29Bergot M.O. Diaz-Guerra M.J. Puzenat N. Raymondjean M. Kahn A. Nucleic Acids Res. 1992; 20: 1871-1877Crossref PubMed Scopus (153) Google Scholar, 31Diaz-Guerra M.J. Bergot M.O. Martinez A. Cuif M.H. Kahn A. Raymondjean M. Mol. Cell. Biol. 1993; 13: 7725-7733Crossref PubMed Scopus (97) Google Scholar, 34Shih H.-M. Liu Z. Towle H.C. J. Biol. Chem. 1995; 270: 21991-21997Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). However, oligomerized GlRE/ChoRE sequences placed in front of a heterologous promoter are sufficient, in absence of the auxiliary site, to confer the carbohydrate response (29Bergot M.O. Diaz-Guerra M.J. Puzenat N. Raymondjean M. Kahn A. Nucleic Acids Res. 1992; 20: 1871-1877Crossref PubMed Scopus (153) Google Scholar, 31Diaz-Guerra M.J. Bergot M.O. Martinez A. Cuif M.H. Kahn A. Raymondjean M. Mol. Cell. Biol. 1993; 13: 7725-7733Crossref PubMed Scopus (97) Google Scholar, 34Shih H.-M. Liu Z. Towle H.C. J. Biol. Chem. 1995; 270: 21991-21997Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). The L-PK GlRE consists of two palindromic non-canonical E boxes (CANNTG) separated by 5 base pairs. These E boxes bind the upstream stimulatory factors (USFs), which are members of the basic helix-loop-helix leucine zipper family (31Diaz-Guerra M.J. Bergot M.O. Martinez A. Cuif M.H. Kahn A. Raymondjean M. Mol. Cell. Biol. 1993; 13: 7725-7733Crossref PubMed Scopus (97) Google Scholar, 34Shih H.-M. Liu Z. Towle H.C. J. Biol. Chem. 1995; 270: 21991-21997Abstract Full Text Full Text PDF PubMed Scopus (182) Google Scholar). We have shown that in the liver, as well as in most tissues tested, USF binding activity is mainly accounted for by the USF1/USF2 heterodimer (36Viollet B. Lefrancois-Martinez A.M. Henrion A. Kahn A. Raymondjean M. Martinez A. J. Biol. Chem. 1996; 271: 1405-1415Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar). Our results using cells and gene knock-out mice indicate that the endogenous USFs are important for a kinetically normal activation of various diet-dependent genes by glucose A.M. Martinez A. Antoine B. Raymondjean M. Kahn A. J. Biol. Chem. 1995; 270: 2640-2643Abstract Full Text Full Text PDF PubMed Scopus (112) Google Scholar, Henrion A.A. D. M. Raymondjean M. Kahn A. Vaulont S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Henrion A.A. D. Raymondjean M. Kahn A. Vaulont S. J. Biol. Chem. 1998; 273: Full Text Full Text PDF PubMed Scopus Google Scholar, M. Kahn A. Vaulont S. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). However, these factors by the transcriptional regulation of glucose-responsive genes by glucose. Indeed, most genes promoters include E boxes are not regulated by glucose. In the glucose responsiveness by is not to for USFs E.N. Shih H. Towle H.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). Finally, USF synthesis as well as DNA binding activity not to be regulated by the We of the glucose response complex using the in yeast. We in to chicken ovalbumin upstream promoter-transcription factor an receptor of the receptor binds to the GlRE in and complexes that with the GlRE are in liver D.Q. M. L. D. Kahn A. Vasseur-Cognet M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). The and USF binding are and binding of factor with binding of the of inhibits of the L-PK gene promoter and also represses its stimulation by glucose in hepatocytes in primary a GlRE binding with very for the glucose response because of activity under glucose D.Q. M. L. D. Kahn A. Vasseur-Cognet M. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar). We that are involved in a glucose by USFs in the absence of glucose. This complex could be regulated by with other to glucose, that are currently There are several reports GlRE proteins. et al. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar) reported that carbohydrate in an in the concentration of a L-PK GlRE binding activity in the liver. and as being involved in this the proteins have not been et al. Biochem. Cell Biol. 1999; Scholar) described the of two proteins that may be related to Finally, and Towle Towle H.C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar) have recently characterized a binding activity that correlates with glucose-dependent transcriptional This DNA binding activity is only with of a glucose response and not with of the that are in the glucose This binding activity not to be regulated by dietary glucose. The a for the of two E related to the sterol response element-binding protein P. Kim Mol. 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