c-Myc Is Required for the Glucose-mediated Induction of Metabolic Enzyme Genes

Glucose exerts powerful effects on hepatocyte gene transcription by mechanisms that are incompletely understood. c-Myc regulates hepatic glucose metabolism by increasing glycolytic enzyme gene transcription while concomitantly decreasing gluconeogenic and ketogenic enzyme gene expression. However, the molecular mechanisms by which c-Myc exerts these effects is not known. In this study, the glucose-mediated induction of L-type pyruvate kinase and glucose-6-phosphatase mRNA levels was diminished by maneuvers involving recombinant adenoviral vectors that interfere with (i) c-Myc protein levels by antisense expression or (ii) c-Myc function through a dominant-negative Max protein. These results were obtained using both HL1C rat hepatoma cells and primary rat hepatocytes. Furthermore, a decrease in c-Myc abundance reduced glucose production in HL1C cells, presumably by decreasing glucose-6-phosphatase activity. The repression of hormone-activated phosphoenolpyruvate carboxykinase gene transcription by glucose was not affected by a reduction in c-Myc levels. The basal mRNA levels for L-pyruvate kinase and glucose-6-phosphatase were not altered to any significant degree by adenoviral treatment. Furthermore, adenoviral overexpression of the c-Myc protein induced glucose-6-phosphatase mRNA in the absence of glucose stimulation. We conclude that multiple mechanisms exist to communicate the glucose-derived signal and that c-Myc has a key role in the hepatic glucose signaling pathway. Glucose exerts powerful effects on hepatocyte gene transcription by mechanisms that are incompletely understood. c-Myc regulates hepatic glucose metabolism by increasing glycolytic enzyme gene transcription while concomitantly decreasing gluconeogenic and ketogenic enzyme gene expression. However, the molecular mechanisms by which c-Myc exerts these effects is not known. In this study, the glucose-mediated induction of L-type pyruvate kinase and glucose-6-phosphatase mRNA levels was diminished by maneuvers involving recombinant adenoviral vectors that interfere with (i) c-Myc protein levels by antisense expression or (ii) c-Myc function through a dominant-negative Max protein. These results were obtained using both HL1C rat hepatoma cells and primary rat hepatocytes. Furthermore, a decrease in c-Myc abundance reduced glucose production in HL1C cells, presumably by decreasing glucose-6-phosphatase activity. The repression of hormone-activated phosphoenolpyruvate carboxykinase gene transcription by glucose was not affected by a reduction in c-Myc levels. The basal mRNA levels for L-pyruvate kinase and glucose-6-phosphatase were not altered to any significant degree by adenoviral treatment. Furthermore, adenoviral overexpression of the c-Myc protein induced glucose-6-phosphatase mRNA in the absence of glucose stimulation. We conclude that multiple mechanisms exist to communicate the glucose-derived signal and that c-Myc has a key role in the hepatic glucose signaling pathway. Insulin and glucose act jointly to influence glucose homeostasis by altering hepatic gene expression patterns. Insulin increases glucokinase (GK) 1The abbreviations used are: GK, glucokinase; L-PK, liver-type pyruvate kinase; Glc-6-Pase, glucose-6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; bHLH-LZ, basic helix-loop-helix leucine-zipper; GLUT2, glucose transporter isoform 2; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; CAT, chloramphenicol acetyltransferase; RT, reverse transcription; pfu, plaque-forming units; ChREBP, carbohydrate-response element-binding protein; FBS, fetal bovine serum; m.o.i., multiplicity of infection; ChoRE, carbohydrate-response elements 1The abbreviations used are: GK, glucokinase; L-PK, liver-type pyruvate kinase; Glc-6-Pase, glucose-6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; bHLH-LZ, basic helix-loop-helix leucine-zipper; GLUT2, glucose transporter isoform 2; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; CAT, chloramphenicol acetyltransferase; RT, reverse transcription; pfu, plaque-forming units; ChREBP, carbohydrate-response element-binding protein; FBS, fetal bovine serum; m.o.i., multiplicity of infection; ChoRE, carbohydrate-response elements gene transcription and protein levels in hepatocytes (1Iynedjian P.B. Jotterand D. Nouspikel T. Asfari M. Pilot P.R. J. Biol. Chem. 1989; 264: 21824-21829Google Scholar). The phosphorylation of glucose by GK leads to increased glucose flux and metabolism, generating signaling metabolites that modify the gene expression profile of the liver (2Vaulont S. Vasseur-Cognet M. Kahn A. J. Biol. Chem. 2000; 275: 31555-31558Google Scholar). For example, the L-pyruvate kinase (L-PK) and glucose-6-phosphatase (Glc-6-Pase) genes (encoding key glycolytic and gluconeogenic enzymes, respectively) are stimulated by increases in hepatic glucose metabolism (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, 4Argaud D. Zhang Q. Pan W. Maitra S. Pilkis S.J. Lange A.J. Diabetes. 1996; 45: 1563-1571Google Scholar, 5Massillon D. J. Biol. Chem. 2001; 276: 4055-4062Google Scholar). Conversely, glucose metabolism can also negatively regulate gene transcription, exemplified by the repression of hormone-activated phosphoenolpyruvate carboxykinase (PEPCK) gene promoter activity (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar, 7Cournarie F. D. M. F. Scholar). glucose metabolism the gene expression of key glycolytic and gluconeogenic enzymes, the signaling mechanisms and transcription are not transcription that is a for hepatic gene expression is the helix-loop-helix transcription c-Myc F. A. S. A. 1996; Scholar, A. A. J. F. J. Scholar). The of in of and metabolism S. T. 2000; Scholar, Biol. 2000; Scholar). c-Myc by with the a with protein. The or transcription on the gene Biol. 2000; Scholar, J. 1996; Scholar). to the are in the carbohydrate-response elements of the L-pyruvate kinase and gene (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, M. Kahn A. Scholar, Towle H.C. J. Biol. Chem. 1989; 264: overexpression of c-Myc in the liver of by the increases hepatic glucose metabolism and presumably of the in GK activity in isoform activity was A. A. J. F. J. Scholar). The expression of glucose transporter L-PK, and liver that hepatic glucose metabolism is Furthermore, in c-Myc with and glucose and production decrease F. A. S. A. 1996; Scholar). These are by a decrease in mRNA levels for and and this hepatic in c-Myc protein levels in is to glucose levels and F. A. S. A. 1996; Scholar). these results are with c-Myc a role in the of hepatic glucose metabolism in However, the molecular mechanisms these not the study, the abundance of the c-Myc protein using a recombinant that antisense to this transcription is for gene expression in hepatocytes. with c-Myc protein cells with of a reduction in c-Myc was to the expression of genes in both HL1C rat hepatoma cells and rat primary hepatocytes. Furthermore, a recombinant a dominant-negative Max protein the of c-Myc levels glucose production in HL1C hepatoma cells, presumably by decreasing activity. In with a recombinant that c-Myc increased gene expression cells were in the of repression of hormone-activated gene promoter activity by glucose was not by a reduction in c-Myc multiple for glucose is a of hepatic gene transcription (2Vaulont S. Vasseur-Cognet M. Kahn A. J. Biol. Chem. 2000; 275: 31555-31558Google H.C. J. Biol. Chem. Scholar). glucose metabolism increases the expression of glycolytic and enzyme genes and the expression of ketogenic and gluconeogenic enzyme c-Myc regulates hepatic glucose metabolism in by increasing the expression and activity of glycolytic and the reverse on of glucose and production F. A. S. A. 1996; Scholar, A. A. J. F. J. Scholar). In this study, the role of c-Myc in hepatic glucose metabolism that in a reduction of c-Myc protein levels were to the induction of and in both HL1C rat hepatoma cells and rat primary hepatocytes. expression of a Max dominant-negative protein the c-Myc levels. The abundance of c-Myc glucose presumably by altering activity. The for or were not affected by in c-Myc protein levels in c-Myc overexpression leads to induction of the gene in cells with The signal for a glucose-mediated repression of hormone-activated is by diminished c-Myc protein overexpression of c-Myc by the promoter in the liver of increases GK, PFK2, and gene expression by F. A. S. A. 1996; Scholar). These in gene expression are to hepatic glucose flux and glucose the the In the study, a reduction of c-Myc in rat hepatoma cells and primary hepatocytes the of glucose to expression of the and genes and In overexpression of c-Myc the glucose in primary hepatocytes are with the these that c-Myc is for hepatic gene expression and is a key in the of gene expression by this study, a dominant-negative Max protein was by to a is for the glucose of of the which a dominant-negative by not the in mRNA levels that a is for the glucose this regulates gene transcription with glucose is metabolism increases mRNA and protein levels D. J. Biol. Chem. 2001; 276: 4055-4062Google D. Newgard C.B. Lange A.J. J. Biol. Chem. Scholar, D. W. M. J. Biol. Chem. 1996; Scholar). c-Myc levels the of glucose to mRNA levels and this affected the of the to and We that decreasing c-Myc levels diminished the glucose production of HL1C cells glucose production can by altering levels of of glucose a on and a on PEPCK, both gluconeogenic enzymes, has (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar, 7Cournarie F. D. M. F. Scholar). are for the glucose-mediated induction of is that a glucose-mediated in activity a to decrease the signal by increased glucose flux and this the in decrease the abundance of glucose and signaling the of S. R.M. J. Biol. Chem. has diminished the of the the of glucose signaling and a to the of this is that overexpression of Glc-6-Pase, in to a of c-Myc and to regulate hepatic enzyme and the hepatic glucose metabolism in O'Doherty R.M. Lange A.J. Newgard C.B. J. Biol. Chem. 1998; 273: glucose-mediated induction of the and presumably GK expression and glucose metabolism in primary rat and in D. Newgard C.B. Lange A.J. J. Biol. Chem. Scholar, Kahn A. J. Biol. Chem. Scholar). Furthermore, the repression of hormone-activated promoter activity is the metabolism of glucose and in the absence of GK is (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar). glucose production in the liver a the that glucose However, is not the mechanisms for increasing gene transcription are the for the repression of gene In the study, that c-Myc levels on the glucose repression of the promoter that multiple glucose signaling regulates gene transcription by through promoter elements (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, H.C. J. Biol. Chem. Scholar). These elements were in the of the gene promoter and a to the of the gene to (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, Towle H.C. J. Biol. Chem. 2001; 276: Scholar). The by The for the of the gene promoter are the c-Myc by a (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, M. Kahn A. Scholar). a carbohydrate-response of and in the gene is and to regulate transcription in to glucose Towle H.C. J. Biol. Chem. 2000; 275: Scholar). of the leads to the by of a that Towle H.C. J. Biol. Chem. 2001; 276: Towle H.C. J. Biol. Chem. 2000; 275: for of genes was by the of a transcription carbohydrate-response element-binding protein that regulates hepatic gene expression in M. M. W. D. S. A. 2001; Scholar, T. M. T. S. A. 2001; Scholar). ChREBP, is by phosphorylation which and T. M. T. S. A. 2001; Scholar). In the of is to the and in gene by to the in the promoter M. M. W. D. S. A. 2001; Scholar, T. M. T. S. A. 2001; Scholar). the protein which is the of rat ChREBP, with a of the c-Myc of transcription S. F. A. A. 2001; Scholar). The and that the is c-Myc or the is a carbohydrate-response element-binding protein. We cells M. J. Biol. Chem. 2001; 276: glucose not the abundance of or protein in that the to are the of c-Myc for gene expression. These are not to the The signal by increased glucose metabolism in a the of the to to with or of the and that to the activity of that of these is that by the expression or activity of of S. Q. M. D. J. Biol. Chem. 2000; 275: that c-Myc glycolytic genes in rat and in in hepatocytes. These that mRNA levels for the glycolytic enzyme and were in Furthermore, the gene expression profile was in hepatocytes were with c-Myc S. Q. M. D. J. Biol. Chem. 2000; 275: Scholar). In which genes are c-Myc using a protein that has c-Myc to the The induction of and in rat increases the protein is by is not by the protein that these genes are of the c-Myc protein S. Q. M. D. J. Biol. Chem. 2000; 275: Scholar). c-Myc regulate the expression of glycolytic enzyme genes and or in the by glucose of enzyme and the results of the a role for c-Myc in the glucose-mediated of the and genes not in the glucose-mediated repression of the hormone-activated the of and glucose signaling c-Myc gene expression of both the and genes not the glucose repression of hormone-activated We these to that multiple signaling exist to communicate the glucose signal to a Max dominant-negative protein has the of the of a for glucose of the and Furthermore, overexpression of c-Myc the of increased glucose these role for c-Myc in hepatic glucose-mediated gene expression. Insulin and glucose act jointly to influence glucose homeostasis by altering hepatic gene expression patterns. Insulin increases glucokinase (GK) 1The abbreviations used are: GK, glucokinase; L-PK, liver-type pyruvate kinase; Glc-6-Pase, glucose-6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; bHLH-LZ, basic helix-loop-helix leucine-zipper; GLUT2, glucose transporter isoform 2; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; CAT, chloramphenicol acetyltransferase; RT, reverse transcription; pfu, plaque-forming units; ChREBP, carbohydrate-response element-binding protein; FBS, fetal bovine serum; m.o.i., multiplicity of infection; ChoRE, carbohydrate-response elements 1The abbreviations used are: GK, glucokinase; L-PK, liver-type pyruvate kinase; Glc-6-Pase, glucose-6-phosphatase; PEPCK, phosphoenolpyruvate carboxykinase; bHLH-LZ, basic helix-loop-helix leucine-zipper; GLUT2, glucose transporter isoform 2; PFK2, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase; CAT, chloramphenicol acetyltransferase; RT, reverse transcription; pfu, plaque-forming units; ChREBP, carbohydrate-response element-binding protein; FBS, fetal bovine serum; m.o.i., multiplicity of infection; ChoRE, carbohydrate-response elements gene transcription and protein levels in hepatocytes (1Iynedjian P.B. Jotterand D. Nouspikel T. Asfari M. Pilot P.R. J. Biol. Chem. 1989; 264: 21824-21829Google Scholar). The phosphorylation of glucose by GK leads to increased glucose flux and metabolism, generating signaling metabolites that modify the gene expression profile of the liver (2Vaulont S. Vasseur-Cognet M. Kahn A. J. Biol. Chem. 2000; 275: 31555-31558Google Scholar). For example, the L-pyruvate kinase (L-PK) and glucose-6-phosphatase (Glc-6-Pase) genes (encoding key glycolytic and gluconeogenic enzymes, respectively) are stimulated by increases in hepatic glucose metabolism (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, 4Argaud D. Zhang Q. Pan W. Maitra S. Pilkis S.J. Lange A.J. Diabetes. 1996; 45: 1563-1571Google Scholar, 5Massillon D. J. Biol. Chem. 2001; 276: 4055-4062Google Scholar). Conversely, glucose metabolism can also negatively regulate gene transcription, exemplified by the repression of hormone-activated phosphoenolpyruvate carboxykinase (PEPCK) gene promoter activity (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar, 7Cournarie F. D. M. F. Scholar). glucose metabolism the gene expression of key glycolytic and gluconeogenic enzymes, the signaling mechanisms and transcription are not transcription that is a for hepatic gene expression is the helix-loop-helix transcription c-Myc F. A. S. A. 1996; Scholar, A. A. J. F. J. Scholar). The of in of and metabolism S. T. 2000; Scholar, Biol. 2000; Scholar). c-Myc by with the a with protein. The or transcription on the gene Biol. 2000; Scholar, J. 1996; Scholar). to the are in the carbohydrate-response elements of the L-pyruvate kinase and gene (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, M. Kahn A. Scholar, Towle H.C. J. Biol. Chem. 1989; 264: Scholar). overexpression of c-Myc in the liver of by the increases hepatic glucose metabolism and presumably of the in GK activity in isoform activity was A. A. J. F. J. Scholar). The expression of glucose transporter L-PK, and liver that hepatic glucose metabolism is Furthermore, in c-Myc with and glucose and production decrease F. A. S. A. 1996; Scholar). These are by a decrease in mRNA levels for and and this hepatic in c-Myc protein levels in is to glucose levels and F. A. S. A. 1996; Scholar). these results are with c-Myc a role in the of hepatic glucose metabolism in However, the molecular mechanisms these not In the study, the abundance of the c-Myc protein using a recombinant that antisense to this transcription is for gene expression in hepatocytes. with c-Myc protein cells with of a reduction in c-Myc was to the expression of genes in both HL1C rat hepatoma cells and rat primary hepatocytes. Furthermore, a recombinant a dominant-negative Max protein the of c-Myc levels glucose production in HL1C hepatoma cells, presumably by decreasing activity. In with a recombinant that c-Myc increased gene expression cells were in the of repression of hormone-activated gene promoter activity by glucose was not by a reduction in c-Myc multiple for glucose is a of hepatic gene transcription (2Vaulont S. Vasseur-Cognet M. Kahn A. J. Biol. Chem. 2000; 275: 31555-31558Google H.C. J. Biol. Chem. Scholar). glucose metabolism increases the expression of glycolytic and enzyme genes and the expression of ketogenic and gluconeogenic enzyme c-Myc regulates hepatic glucose metabolism in by increasing the expression and activity of glycolytic and the reverse on of glucose and production F. A. S. A. 1996; Scholar, A. A. J. F. J. Scholar). In this study, the role of c-Myc in hepatic glucose metabolism that in a reduction of c-Myc protein levels were to the induction of and in both HL1C rat hepatoma cells and rat primary hepatocytes. expression of a Max dominant-negative protein the c-Myc levels. The abundance of c-Myc glucose presumably by altering activity. The for or were not affected by in c-Myc protein levels in c-Myc overexpression leads to induction of the gene in cells with The signal for a glucose-mediated repression of hormone-activated is by diminished c-Myc protein overexpression of c-Myc by the promoter in the liver of increases GK, PFK2, and gene expression by F. A. S. A. 1996; Scholar). These in gene expression are to hepatic glucose flux and glucose the the In the study, a reduction of c-Myc in rat hepatoma cells and primary hepatocytes the of glucose to expression of the and genes and In overexpression of c-Myc the glucose in primary hepatocytes are with the these that c-Myc is for hepatic gene expression and is a key in the of gene expression by this study, a dominant-negative Max protein was by to a is for the glucose of of the which a dominant-negative by not the in mRNA levels that a is for the glucose this regulates gene transcription with glucose is metabolism increases mRNA and protein levels D. J. Biol. Chem. 2001; 276: 4055-4062Google D. Newgard C.B. Lange A.J. J. Biol. Chem. Scholar, D. W. M. J. Biol. Chem. 1996; Scholar). c-Myc levels the of glucose to mRNA levels and this affected the of the to and We that decreasing c-Myc levels diminished the glucose production of HL1C cells glucose production can by altering levels of of glucose a on and a on PEPCK, both gluconeogenic enzymes, has (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar, 7Cournarie F. D. M. F. Scholar). are for the glucose-mediated induction of is that a glucose-mediated in activity a to decrease the signal by increased glucose flux and this the in decrease the abundance of glucose and signaling the of S. R.M. J. Biol. Chem. has diminished the of the the of glucose signaling and a to the of this is that overexpression of Glc-6-Pase, in to a of c-Myc and to regulate hepatic enzyme and the hepatic glucose metabolism in O'Doherty R.M. Lange A.J. Newgard C.B. J. Biol. Chem. 1998; 273: glucose-mediated induction of the and presumably GK expression and glucose metabolism in primary rat and in D. Newgard C.B. Lange A.J. J. Biol. Chem. Scholar, Kahn A. J. Biol. Chem. Scholar). Furthermore, the repression of hormone-activated promoter activity is the metabolism of glucose and in the absence of GK is (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar). glucose production in the liver a the that glucose However, is not the mechanisms for increasing gene transcription are the for the repression of gene In the study, that c-Myc levels on the glucose repression of the promoter that multiple glucose signaling regulates gene transcription by through promoter elements (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, H.C. J. Biol. Chem. Scholar). These elements were in the of the gene promoter and a to the of the gene to (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, Towle H.C. J. Biol. Chem. 2001; 276: Scholar). The by The for the of the gene promoter are the c-Myc by a (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, M. Kahn A. Scholar). a carbohydrate-response of and in the gene is and to regulate transcription in to glucose Towle H.C. J. Biol. Chem. 2000; 275: Scholar). of the leads to the by of a that Towle H.C. J. Biol. Chem. 2001; 276: Towle H.C. J. Biol. Chem. 2000; 275: for of genes was by the of a transcription carbohydrate-response element-binding protein that regulates hepatic gene expression in M. M. W. D. S. A. 2001; Scholar, T. M. T. S. A. 2001; Scholar). ChREBP, is by phosphorylation which and T. M. T. S. A. 2001; Scholar). In the of is to the and in gene by to the in the promoter M. M. W. D. S. A. 2001; Scholar, T. M. T. S. A. 2001; Scholar). the protein which is the of rat ChREBP, with a of the c-Myc of transcription S. F. A. A. 2001; Scholar). The and that the is c-Myc or the is a carbohydrate-response element-binding protein. We cells M. J. Biol. Chem. 2001; 276: glucose not the abundance of or protein in that the to are the of c-Myc for gene expression. These are not to the The signal by increased glucose metabolism in a the of the to to with or of the and that to the activity of that of these is that by the expression or activity of of S. Q. M. D. J. Biol. Chem. 2000; 275: that c-Myc glycolytic genes in rat and in in hepatocytes. These that mRNA levels for the glycolytic enzyme and were in Furthermore, the gene expression profile was in hepatocytes were with c-Myc S. Q. M. D. J. Biol. Chem. 2000; 275: Scholar). In which genes are c-Myc using a protein that has c-Myc to the The induction of and in rat increases the protein is by is not by the protein that these genes are of the c-Myc protein S. Q. M. D. J. Biol. Chem. 2000; 275: Scholar). c-Myc regulate the expression of glycolytic enzyme genes and or in the by glucose of enzyme and the results of the a role for c-Myc in the glucose-mediated of the and genes not in the glucose-mediated repression of the hormone-activated the of and glucose signaling c-Myc gene expression of both the and genes not the glucose repression of hormone-activated We these to that multiple signaling exist to communicate the glucose signal to a Max dominant-negative protein has the of the of a for glucose of the and Furthermore, overexpression of c-Myc the of increased glucose these role for c-Myc in hepatic glucose-mediated gene expression. Glucose is a of hepatic gene transcription (2Vaulont S. Vasseur-Cognet M. Kahn A. J. Biol. Chem. 2000; 275: 31555-31558Google H.C. J. Biol. Chem. Scholar). glucose metabolism increases the expression of glycolytic and enzyme genes and the expression of ketogenic and gluconeogenic enzyme c-Myc regulates hepatic glucose metabolism in by increasing the expression and activity of glycolytic and the reverse on of glucose and production F. A. S. A. 1996; Scholar, A. A. J. F. J. Scholar). In this study, the role of c-Myc in hepatic glucose metabolism that in a reduction of c-Myc protein levels were to the induction of and in both HL1C rat hepatoma cells and rat primary hepatocytes. expression of a Max dominant-negative protein the c-Myc levels. The abundance of c-Myc glucose presumably by altering activity. The for or were not affected by in c-Myc protein levels in c-Myc overexpression leads to induction of the gene in cells with The signal for a glucose-mediated repression of hormone-activated is by diminished c-Myc protein levels. overexpression of c-Myc by the promoter in the liver of increases GK, PFK2, and gene expression by F. A. S. A. 1996; Scholar). These in gene expression are to hepatic glucose flux and glucose the the In the study, a reduction of c-Myc in rat hepatoma cells and primary hepatocytes the of glucose to expression of the and genes and In overexpression of c-Myc the glucose in primary hepatocytes are with the these that c-Myc is for hepatic gene expression and is a key in the of gene expression by In this study, a dominant-negative Max protein was by to a is for the glucose of of the which a dominant-negative by not the in mRNA levels that a is for the glucose this regulates gene transcription with glucose is Glucose metabolism increases mRNA and protein levels D. J. Biol. Chem. 2001; 276: 4055-4062Google D. Newgard C.B. Lange A.J. J. Biol. Chem. Scholar, D. W. M. J. Biol. Chem. 1996; Scholar). c-Myc levels the of glucose to mRNA levels and this affected the of the to and We that decreasing c-Myc levels diminished the glucose production of HL1C cells glucose production can by altering levels of The of glucose a on and a on PEPCK, both gluconeogenic enzymes, has (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar, 7Cournarie F. D. M. F. Scholar). are for the glucose-mediated induction of is that a glucose-mediated in activity a to decrease the signal by increased glucose flux and this the in decrease the abundance of glucose and signaling the of S. R.M. J. Biol. Chem. has diminished the of the the of glucose signaling and a to the of this is that overexpression of Glc-6-Pase, in to a of c-Myc and to regulate hepatic enzyme and the hepatic glucose metabolism in O'Doherty R.M. Lange A.J. Newgard C.B. J. Biol. Chem. 1998; 273: Scholar). The glucose-mediated induction of the and presumably GK expression and glucose metabolism in primary rat and in D. Newgard C.B. Lange A.J. J. Biol. Chem. Scholar, Kahn A. J. Biol. Chem. Scholar). Furthermore, the repression of hormone-activated promoter activity is the metabolism of glucose and in the absence of GK is (6Scott D.K. O'Doherty R.M. Stafford J.M. Newgard C.B. Granner D.K. J. Biol. Chem. 1998; 273: 24145-24151Google Scholar). glucose production in the liver a the that glucose However, is not the mechanisms for increasing gene transcription are the for the repression of gene In the study, that c-Myc levels on the glucose repression of the promoter that multiple glucose signaling Glucose regulates gene transcription by through promoter elements (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, H.C. J. Biol. Chem. Scholar). These elements were in the of the gene promoter and a to the of the gene to (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, Towle H.C. J. Biol. Chem. 2001; 276: Scholar). The by The for the of the gene promoter are the c-Myc by a (3Liu Z. Thompson K.S. Towle H.C. J. Biol. Chem. 1993; 268: 12787-12795Google Scholar, M. Kahn A. Scholar). a carbohydrate-response of and in the gene is and to regulate transcription in to glucose Towle H.C. J. Biol. Chem. 2000; 275: Scholar). of the leads to the by of a that Towle H.C. J. Biol. Chem. 2001; 276: Towle H.C. J. Biol. Chem. 2000; 275: Scholar). for of genes was by the of a transcription carbohydrate-response element-binding protein that regulates hepatic gene expression in M. M. W. D. S. A. 2001; Scholar, T. M. T. S. A. 2001; Scholar). ChREBP, is by phosphorylation which and T. M. T. S. A. 2001; Scholar). In the of is to the and in gene by to the in the promoter M. M. W. D. S. A. 2001; Scholar, T. M. T. S. A. 2001; Scholar). the protein which is the of rat ChREBP, with a of the c-Myc of transcription S. F. A. A. 2001; Scholar). The and The that the is c-Myc or the is a carbohydrate-response element-binding protein. We cells M. J. Biol. Chem. 2001; 276: glucose not the abundance of or protein in that the to are the of c-Myc for gene expression. These are not to the The signal by increased glucose metabolism in a the of the to to with or of the and that to the activity of that of these is that by the expression or activity of The of S. Q. M. D. J. Biol. Chem. 2000; 275: that c-Myc glycolytic genes in rat and in in hepatocytes. These that mRNA levels for the glycolytic enzyme and were in Furthermore, the gene expression profile was in hepatocytes were with c-Myc S. Q. M. D. J. Biol. Chem. 2000; 275: Scholar). In which genes are c-Myc using a protein that has c-Myc to the The induction of and in rat increases the protein is by is not by the protein that these genes are of the c-Myc protein S. Q. M. D. J. Biol. Chem. 2000; 275: Scholar). c-Myc regulate the expression of glycolytic enzyme genes and or in the by glucose of enzyme and the results of the a role for c-Myc in the glucose-mediated of the and genes not in the glucose-mediated repression of the hormone-activated the of and glucose signaling In c-Myc gene expression of both the and genes not the glucose repression of hormone-activated We these to that multiple signaling exist to communicate the glucose signal to a Max dominant-negative protein has the of the of a for glucose of the and Furthermore, overexpression of c-Myc the of increased glucose these role for c-Myc in hepatic glucose-mediated gene expression. We Granner for HL1C Newgard for the for for the and for the We also of the and for of the