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Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes. The sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic gene expression, but the extent to which its transcriptional effect is caused by an increased glucose metabolism remains unclear. Through the use of hepatic GK knockout mice (hGK-KO) we have shown that the acute stimulation by glucose of l-pyruvate kinase (l-PK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and Spot 14 genes requires GK expression. To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed both in vivo and in primary cultures of control and hGK-KO hepatocytes. Our results demonstrate that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction of l-PK, ACC, FAS, and Spot 14 gene expression. Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in low Km hexokinase activity. Our studies also reveal that the loss of glucose effect observed in hGK-KO hepatocytes is associated with a decreased in the carbohydrate responsive element-binding protein (ChREBP) gene expression, a transcription factor suggested to mediate glucose signaling in liver. Decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, thereby demonstrating the direct implication of ChREBP in glucose action. Together these results support a model whereby both SREBP-1c and glucose metabolism, acting via ChREBP, are necessary for the dietary induction of glycolytic and lipogenic gene expression in liver. Hepatic glucokinase (GK) catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a step which is essential for glucose metabolism in liver as well as for the induction of glycolytic and lipogenic genes. The sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic gene expression, but the extent to which its transcriptional effect is caused by an increased glucose metabolism remains unclear. Through the use of hepatic GK knockout mice (hGK-KO) we have shown that the acute stimulation by glucose of l-pyruvate kinase (l-PK), fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and Spot 14 genes requires GK expression. To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed both in vivo and in primary cultures of control and hGK-KO hepatocytes. Our results demonstrate that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction of l-PK, ACC, FAS, and Spot 14 gene expression. Indeed, in hGK-KO hepatocytes overexpressing SREBP-1c, the effect of glucose on glycolytic and lipogenic genes is lost because of the impaired ability of these hepatocytes to efficiently metabolize glucose, despite a marked increase in low Km hexokinase activity. Our studies also reveal that the loss of glucose effect observed in hGK-KO hepatocytes is associated with a decreased in the carbohydrate responsive element-binding protein (ChREBP) gene expression, a transcription factor suggested to mediate glucose signaling in liver. Decreased ChREBP gene expression, achieved using small interfering RNA, results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, thereby demonstrating the direct implication of ChREBP in glucose action. Together these results support a model whereby both SREBP-1c and glucose metabolism, acting via ChREBP, are necessary for the dietary induction of glycolytic and lipogenic gene expression in liver. Hepatic glucokinase (GK) 1The abbreviations used are: GK, glucokinase; HK, hexokinase; G6P, glucose 6-phosphate; X5P, xylulose 5-phosphate; SREBP-1c, sterol regulatory element-binding protein-1c; Ad-SREBP-1c, recombinant adenovirus expressing SREBP-1c; Ad-null, adenovirus vector containing no exogenous gene; l-PK, l-pyruvate kinase; FAS, fatty acid synthase; L-CPT I, liver carnitine palmitoyltransferase I; ACC, acetyl-CoA carboxylase; ChREBP, carbohydrate responsive element-binding protein; ChoRE, carbohydrate response element; SRE, sterol regulatory element; RT-PCR, real-time quantitative polymerase chain reaction; HCHO, high carbohydrate diet; siRNA, small interfering RNA; pfu, plaque-forming unit; KO, knockout. 1The abbreviations used are: GK, glucokinase; HK, hexokinase; G6P, glucose 6-phosphate; X5P, xylulose 5-phosphate; SREBP-1c, sterol regulatory element-binding protein-1c; Ad-SREBP-1c, recombinant adenovirus expressing SREBP-1c; Ad-null, adenovirus vector containing no exogenous gene; l-PK, l-pyruvate kinase; FAS, fatty acid synthase; L-CPT I, liver carnitine palmitoyltransferase I; ACC, acetyl-CoA carboxylase; ChREBP, carbohydrate responsive element-binding protein; ChoRE, carbohydrate response element; SRE, sterol regulatory element; RT-PCR, real-time quantitative polymerase chain reaction; HCHO, high carbohydrate diet; siRNA, small interfering RNA; pfu, plaque-forming unit; KO, knockout. catalyzes the phosphorylation of glucose to glucose 6-phosphate (G6P), a key step of glycolysis, glycogen synthesis, and pentose phosphate pathway (1Girard J. Ferré P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (301) Google Scholar). Even small changes in the expression of hepatic GK have a very measurable impact on the blood glucose concentration in transgenic mice (2Hariharan N. Farrelly 1997; PubMed Google J. 1997; PubMed Scopus Google F. J. PubMed Scopus Google Scholar). of GK which an increase in both and glycogen J. J. PubMed Scopus Google Scholar). we have shown that hepatic GK knockout mice and a in liver glycogen and in glucose studies J. J. PubMed Scopus Google Scholar). The major of in liver is to glucose for The of fatty glucose is and has that signaling in response to dietary a in glycolytic kinase and lipogenic gene expression carboxylase (ACC), fatty acid synthase (FAS), and Spot F. Ferré P. J. PubMed Scopus Google Scholar). Indeed, the transcriptional induction of J. PubMed Google ACC, and F. Foufelle F. J. Ferré P. J. 1997; PubMed Scopus Google Foufelle F. J. Ferré P. J. J. PubMed Scopus Google requires both glucose metabolism and and is that the of insulin is to GK gene expression, which is essential for subsequent glucose phosphorylation (1Girard J. Ferré P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (301) Google F. Ferré P. J. PubMed Scopus Google Scholar). the sterol regulatory element-binding protein-1c (SREBP-1c) has emerged as a major mediator of insulin action on hepatic GK Ferré P. Foufelle F. PubMed Scopus Google and lipogenic gene expression F. Ferré P. J. PubMed Scopus Google PubMed Scopus Google Scholar). Indeed, SREBP-1c, which is by insulin in primary cultures of hepatocytes P. Ferré P. Foufelle F. PubMed Scopus Google is to lipogenic genes by its to to the sterol regulatory in J. PubMed Scopus Google J. 1997; PubMed Google J. PubMed Scopus Google Scholar). a was also in both glycolytic and lipogenic genes J. PubMed Scopus Google J. PubMed Google J. PubMed Scopus Google remains to whether glucose metabolism, which by for the induction of these is necessary for the transcriptional effect of the of a transcription factor ChREBP responsive element-binding PubMed Scopus Google has on the whereby glucose gene transcription and the that glucose a but signaling pathway insulin to glycolytic and lipogenic gene expression in liver. studies to the of the hepatic GK in the control of the transcriptional of glycolytic and lipogenic gene expression by glucose, to whether the effect of SREBP-1c is to glucose metabolism via GK, and to determine the direct implication of ChREBP in glucose signaling in liver. studies in GK knockout mice J. J. PubMed Scopus Google Scholar). adenovirus expressing a form of SREBP-1c was used in vivo and in primary to determine whether glucose metabolism via GK is necessary for the maximal induction of glycolytic and lipogenic gene expression by ChREBP using small interfering in control hepatocytes to determine the direct implication of transcription factor in glucose that hepatic GK is necessary for the of glycolytic and lipogenic gene expression in and that the synergistic action of SREBP-1c and glucose metabolism via GK is necessary for the maximal induction of l-PK, ACC, FAS, and Spot 14 gene expression. also that ChREBP gene expression is decreased in hepatocytes hGK-KO mice and that ChREBP gene in control hepatocytes the glucose effect on l-PK, FAS, and ACC, the direct a that ChREBP glucose signaling on both glycolytic and lipogenic gene expression in liver. control hepatic mice J. J. PubMed Scopus Google a for used for mice in with a to the for the and use of to and of the and mice was for and the was for and for with a high carbohydrate of mice of both in and concentration of insulin was by using a insulin The to the on of of and with the of mice by a of the J. PubMed Scopus Google Scholar). control and hGK-KO mice with glucose, a of using the was was by the and was a of for for concentration in with with of of of and insulin the was by for for in of with plaque-forming of adenovirus adenovirus SREBP-1c in the of was and in for the of the The adenovirus vector containing the transcriptionally active of SREBP-1c was P. Ferré P. Foufelle F. PubMed Scopus Google Scholar). The adenovirus vector containing the with no exogenous gene was used as a control P. Ferré P. Foufelle F. PubMed Scopus Google Scholar). of control and hGK-KO mice with to the the with of in a of of the and and in by for both glucose and insulin and with was using by in the to in and The ChREBP was to the The for ChREBP and for cultures of control hepatocytes with using the by F. PubMed Scopus Google Scholar). the was by for hepatocytes with of ChREBP and in with and in the of was by of and in of to increase the of of the was to the hepatocytes F. J. J. PubMed Scopus Google Scholar). the was and control hepatocytes for in with and was for in the of glucose, and in hepatocytes. in of of in for on with and for by an that the of in the of glucose 6-phosphate in the of glucose and glucose, to GK activity. The and of The glucose is the hexokinase the of glucose the glucose is the glucokinase of the was as the increase in in of concentration was using the using as of and in hepatocytes liver by an PubMed Scopus Google Scholar). the of of the acid was and used for of both and glycogen was used for of in containing of The increased of of was as of as of of liver liver glycogen the was with of concentration in liver was by a using the glucose and results as of of liver in hepatocytes was by an by the of with of for with and of concentration was by the in of of hexokinase glucose was used as as of of in hepatocytes by an F. Foufelle F. J. Ferré P. J. 1997; PubMed Scopus Google Scholar). X5P, the used for and glycogen was in a using in the of to and in the of The decreased of of was as of of and liver by using the P. N. PubMed Scopus Google and hepatocytes using the as J. 1997; PubMed Scopus Google Scholar). of with was by of and using an The GK was a J. PubMed Google Scholar). The was an J. 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FAS, ACC, l-PK, and Spot 14 by polymerase chain The used as for FAS, for ACC, for l-PK, for and for was used as control to the for a of by was for in a containing of of and of quantitative was with of RNA, in a of with of using in a in the for an for by of for for and for The used are in was The of the by using the of the was used as an and the for a gene was to the of was by the of and by and in a of and and of control and hGK-KO mice using the and to the and the of control and hGK-KO mice to on a concentration was using the using as a was with a of for of was using the with as and used as to the for and the of hepatocytes with ChREBP the of the with in and with PubMed Scopus Google Scholar). are as The of was using and by in of hGK-KO determine whether the of hepatic GK the acute of glycolytic and lipogenic genes by a high carbohydrate we and studies in control and hGK-KO of control GK, l-PK, ACC, FAS, and Spot 14 low a but increased for l-PK, ACC, FAS, and Spot 14 low in liver of hGK-KO mice in to control l-PK, ACC, FAS, and Spot 14 gene expression in liver of hGK-KO despite a induction in gene expression SREBP-1c is as a form the and its requires a the transcriptionally active of SREBP-1c to the PubMed Scopus Google we and SREBP-1c protein in liver of control and hGK-KO mice used for used an that both and but liver SREBP-1c J. 1997; PubMed Scopus Google we that the in liver of control and hGK-KO mice was to the expression of the of SREBP-1c low in both control and hGK-KO mice a and increased to SREBP-1c, which was in control and hGK-KO was also to in control and hGK-KO mice the of induction of glycolytic and lipogenic genes in liver of hGK-KO mice was to an of insulin in both of mice in the for control for hGK-KO in the for control for hGK-KO in to the of the mice we also of the a gene to and by J. J. PubMed Scopus Google F. J. PubMed Scopus Google Scholar). of control and hGK-KO increased a and demonstrating that both of mice results demonstrate that the of GK in the liver of hGK-KO mice the induction of glycolytic and lipogenic gene expression and that glucose phosphorylation GK is necessary for SREBP-1c gene expression, and for its of SREBP-1c in of and hGK-KO determine whether SREBP-1c, is overexpressed is to glycolytic and lipogenic gene expression in the of GK, we overexpressed the transcriptionally active form of SREBP-1c in of control and hGK-KO mice using an adenovirus the of SREBP-1c adenovirus results in a marked expression of the in liver Ferré P. Foufelle F. PubMed Scopus Google its expression remains in glycolytic and lipogenic gene expression low in of control and hGK-KO mice of SREBP-1c for the expression of GK and in the liver of control also to a marked stimulation of expression to in the liver of hGK-KO despite the of GK and for of SREBP-1c expression of GK was observed the of of for in control mice marked of SREBP-1c in G6P, and glycogen low in control and hGK-KO with in a and was to a in of hGK-KO mice and results to was observed in but by the that SREBP-1c is overexpressed to a direct induction of gene expression in both control and of a increase in hepatic glucose Decreased ChREBP a in of hGK-KO was in hepatocytes as a major mediator of glucose action on gene expression PubMed Scopus Google PubMed Scopus Google Scholar). To determine whether the of induction of glycolytic and lipogenic gene expression in of hGK-KO mice to an in ChREBP gene expression, we by the of ChREBP in of and control and hGK-KO mice liver of control ChREBP low a but increased by of ChREBP low in liver of hGK-KO mice in to control ChREBP gene expression by in of hGK-KO we the of ChREBP in of control and hGK-KO mice for and with the in which glucose metabolism is low and is no in ChREBP gene expression control and hGK-KO mice GK is by SREBP-1c in control mice results that glucose phosphorylation is necessary for ChREBP gene expression in and that SREBP-1c control ChREBP gene expression. in hGK-KO determine whether glucose metabolism a effect on SREBP-1c induction of glycolytic and lipogenic gene expression, we a of using primary cultures of control and hGK-KO hepatocytes. with of and for low high glucose The expression of SREBP-1c in hepatocytes the expression of GK in control hepatocytes as no expression of GK was in hepatocytes hGK-KO mice results glucose also the phosphorylation of glucose to G6P, but GK in of glucose and J. PubMed Scopus Google Scholar). we also to determine whether the expression of of these was increased by SREBP-1c real-time quantitative that gene expression was increased by of SREBP-1c in hepatocytes control and hGK-KO mice marked induction is of the glucose concentration was in hepatocytes in glucose SREBP-1c no effect on gene expression The of SREBP-1c also control hepatocytes glucose, GK increased in with GK gene expression the of SREBP-1c no GK was in hepatocytes. SREBP-1c increased to in hGK-KO in control hepatocytes increase with a increase in to the of caused by the of GK in these hepatocytes results glucose The increase in in hGK-KO hepatocytes was to protein which was to in both control and hGK-KO the results that to the in hGK-KO hepatocytes. is to glycolysis, to use by the an of glucose metabolism J. PubMed Scopus Google Scholar). To determine the of SREBP-1c on glucose metabolism, G6P, and glycogen was in with and of SREBP-1c in control hepatocytes in glucose a increase in increase was glucose control hepatocytes glucose increase in in control hepatocytes was with the increase in GK gene expression and GK and the of GK in hepatocytes a effect on ability to both glucose and for of SREBP-1c Indeed, a small increase in concentration was in hGK-KO hepatocytes the of the glucose and no effect of glucose was observed was increased in the in control that low Km is to for the of GK in hGK-KO hepatocytes. was low in both control and hGK-KO hepatocytes glucose increased in a in control hepatocytes glucose of glycogen was in hGK-KO hepatocytes with glucose, the of the SREBP-1c was overexpressed to glycogen in response to of glucose was decreased by in hGK-KO hepatocytes results the of hepatic GK in glucose metabolism, and glycogen in liver. of and in and hGK-KO the of the synergistic action of SREBP-1c and glucose phosphorylation on glycolytic and lipogenic gene we the expression of genes in hepatocytes. control hepatocytes glucose, SREBP-1c the expression of l-PK, FAS, ACC, and Spot 14 of SREBP-1c to in hGK-KO in glucose to of the FAS, ACC, and Spot 14 gene expression to FAS, ACC, and Spot a small induction of gene expression by SREBP-1c was observed in hGK-KO hepatocytes in The of the in control hepatocytes glucose The induction of and Spot 14 is in the of glucose in hepatocytes thereby that both glucose and SREBP-1c, acting in have a synergistic effect on the expression of these genes. in hGK-KO is no effect of glucose on l-PK, FAS, ACC, and Spot 14 gene expression high glucose demonstrating that the signaling of glucose is lost in of GK in these hepatocytes. ChREBP and Decreased in hGK-KO determine whether the loss of the glucose effect observed on the expression of l-PK, FAS, ACC, and Spot 14 in hGK-KO hepatocytes was to an in ChREBP expression we by the of ChREBP in control and hGK-KO hepatocytes in glucose of ChREBP was decreased by in hGK-KO hepatocytes with with a high glucose concentration ChREBP gene expression by in control hepatocytes GK is by SREBP-1c in the of GK no effect of glucose was observed in hGK-KO hepatocytes in the of glucose and ChREBP was in control hepatocytes both glucose results that glucose metabolism via GK is for the and of ChREBP gene expression in hepatocytes has suggested that is the glucose signaling necessary for ChREBP and for the induction of glycolytic and lipogenic gene expression in liver PubMed Scopus Google was in control and hGK-KO hepatocytes SREBP-1c a increase in in control hepatocytes both and glucose a increase in was in hGK-KO hepatocytes on PubMed Scopus Google results that the of of ChREBP by in hGK-KO hepatocytes the loss of the glucose effect observed high glucose of ChREBP by and by in determine the direct implication of ChREBP in glucose action on endogenous glycolytic and lipogenic gene expression, we a of using to ChREBP gene expression in primary cultures of control hepatocytes. hepatocytes with of ChREBP and for low glucose concentration insulin in the of insulin SREBP-1c in to a ChREBP gene hepatocytes for in the of glucose with insulin with high glucose concentration and insulin ChREBP gene expression by glucose low glucose insulin no effect on ChREBP gene expression results as observed that glucose metabolism is necessary for the induction of ChREBP gene expression in hepatocytes. ChREBP gene induction by high glucose and insulin concentration was by control hepatocytes with ChREBP the effect of glucose was no because ChREBP in ChREBP hepatocytes both glucose with insulin ChREBP gene expression was by high glucose and insulin concentration in hepatocytes with the expression of genes by the induction of and was in hepatocytes with glucose and insulin with in the of glucose in ChREBP hepatocytes glucose a effect of glucose on and gene expression was Indeed, of these genes to in control hepatocytes glucose with The effect of ChREBP was to l-PK, FAS, and because and GK by insulin in ChREBP of the glucose both and of SREBP-1c protein in ChREBP hepatocytes with both control and hepatocytes demonstrating that the loss of glucose effect observed is to ChREBP gene we whether the of ChREBP gene expression by in of for in the of glucose insulin to in hepatocytes results with ChREBP in the of glucose in hepatocytes. was in ChREBP hepatocytes glucose insulin demonstrate that the decreased in ChREBP gene expression in control hepatocytes in the of high glucose results demonstrate the direct implication of ChREBP in glucose action on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression in hepatocytes. SREBP-1c has emerged in the as a major mediator of insulin action on glycolytic and lipogenic gene expression F. Ferré P. J. PubMed Scopus Google the extent to which glucose metabolism to its transcriptional effect has use of hepatic mice J. J. PubMed Scopus Google we have shown that glucose metabolism via GK is of primary for the maximal induction of glycolytic and lipogenic gene expression in liver. Indeed, in the of GK, glycolytic and lipogenic genes are in of hGK-KO in the of of SREBP-1c of of SREBP-1c on GK and overexpressing a form of SREBP-1c in control and hGK-KO hepatocytes glucose, we to the of glucose metabolism to SREBP-1c action. as in studies Ferré P. Foufelle F. PubMed Scopus Google Ferré P. Foufelle F. PubMed Scopus Google that expression of a form of SREBP-1c GK gene expression and both in vivo and in hepatocytes control we also that of SREBP-1c the expression of in hepatocytes control and hGK-KO but the of studies also the stimulation of gene expression by SREBP-1c in J. Foufelle F. Ferré P. PubMed Scopus Google and PubMed Scopus Google but to is the of an effect on hepatic gene expression. The that have on the of the gene J. PubMed Scopus Google is in with but with the of J. PubMed Scopus Google in which transgenic mice overexpressing but SREBP-1c, of in liver. caused by the that is a transcriptional SREBP-1c J. 1997; PubMed Scopus Google and is overexpressed to with genes that are its Our with the of J. PubMed Scopus Google that the of have an in expression of in liver. in hGK-KO have shown that GK is for the increased of and glycogen in response to glucose and SREBP-1c is hGK-KO hepatocytes in the of glucose, a marked in ability to glycogen is increased to in control hepatocytes. studies have that of GK, but of has a effect on glycogen in primary hepatocytes J. J. PubMed Scopus Google J. J. PubMed Scopus Google and that by overexpressed GK is because the of glycogen is studies that the low Km the of GK for the of and glycogen in response to high glucose the ability of the hepatocytes to efficiently and glycogen is on GK and on activity. are with studies in which hepatic GK was overexpressed in transgenic mice (2Hariharan N. Farrelly 1997; PubMed Google J. 1997; PubMed Scopus Google F. J. PubMed Scopus Google and support a key for hepatic GK in glucose the that of hepatic GK glucose and increase hepatic glucose J. J. PubMed Scopus Google that GK has a high control on hepatic glucose metabolism PubMed Scopus Google Scholar). of via GK and SREBP-1c on has as a major mediator of insulin action on lipogenic gene expression as by knockout and transgenic studies F. Ferré P. J. PubMed Scopus Google Scholar). Indeed, SREBP-1c knockout mice have an impaired ability to lipogenic gene expression a J. J. PubMed Scopus Google and in transgenic mice that SREBP-1c in the of as well as the of lipogenic gene expression J. 1997; PubMed Scopus Google J. PubMed Scopus Google Scholar). The that SREBP-1c, is to ACC, FAS, Spot 14 to in control and hGK-KO hepatocytes in glucose in the liver of control and hGK-KO a direct action of a on an the direct action of SREBP-1c in the of glucose metabolism, is by to glycolytic and lipogenic gene expression. Indeed, the effect of SREBP-1c on l-PK, FAS, ACC, and Spot 14 gene expression is by glucose but in hepatocytes in which GK expression increased of glucose metabolism and glycogen results are in with the that for FAS, ACC, and Spot 14 for SREBP-1c J. PubMed Scopus Google J. PubMed Scopus Google J. PubMed Scopus Google and for a carbohydrate responsive factor J. PubMed Scopus Google J. PubMed Scopus Google J. PubMed Scopus Google have these studies that the effect of SREBP-1c on genes its as a mediator of insulin action a in the glucose signaling to to a extent to and Spot SREBP-1c a induction in gene expression in hGK-KO hepatocytes in of glucose that the induction of l-PK, as observed by and J. PubMed Scopus Google in hepatocytes overexpressing SREBP-1c, is on glucose metabolism on SREBP-1c Indeed, of the in primary hepatocytes to the of a that an glucose response N. PubMed Scopus Google J. PubMed Scopus Google Scholar). glucose metabolism via GK and SREBP-1c, in a synergistic effect on the expression of glycolytic and lipogenic genes. SREBP-1c is in the of GK Ferré P. Foufelle F. PubMed Scopus Google the impaired glucose response of the glycolytic and lipogenic genes in liver of both mice J. J. PubMed Scopus Google N. J. F. N. J. PubMed Scopus Google and protein mice PubMed Scopus Google the in GK expression the direct in in liver of these glycolytic and lipogenic genes are in the liver of hGK-KO mice despite of SREBP-1c of in the of that SREBP-1c is to for the maximal effect of glycolytic and lipogenic genes expression, the of the of glucose in The is the of a transcription factor that mediate the glucose and in with The and of ChREBP, on its to to the of the PubMed Scopus Google has on the whereby glucose gene have whether the induction of glycolytic and lipogenic gene expression in for by the effect of SREBP-1c and of endogenous ChREBP expression. that glucose the expression of ChREBP in control hepatocytes in vivo and in as also in J. PubMed Scopus Google and in J. PubMed Scopus Google Scholar). Our results the direct that GK, and glucose metabolism, are necessary for the expression of ChREBP in hepatocytes. decreased ChREBP gene expression in control hepatocytes using small interfering results in a loss of glucose effect on endogenous glycolytic (l-PK) and lipogenic (FAS, ACC) gene expression, demonstrating the direct implication of ChREBP in gene induction by results are in with studies PubMed Scopus Google PubMed Scopus Google J. PubMed Scopus Google in which ChREBP was as essential for gene demonstrate for the the direct implication of ChREBP in glucose effect on endogenous lipogenic genes as and in hepatocytes and in the of Our the that ChREBP a in carbohydrate metabolism and The of ChREBP and its in glucose action the of the signaling pathway that is for its by has that the of ChREBP requires a of which is by the of protein by PubMed Scopus Google Scholar). have shown that increased glucose metabolism via GK is necessary for the of Indeed, the of glucose metabolism and in hGK-KO hepatocytes glucose the loss of glucose effect observed on glycolytic and lipogenic gene expression caused by the of ChREBP SREBP-1c and ChREBP for the results support the model in which these a in the dietary induction of glycolytic and lipogenic genes Annu. Rev. Nutr. 1997; 17: PubMed Scopus Google Scholar). as shown by P. Ferré P. Foufelle F. PubMed Scopus Google PubMed Scopus Google we have observed that glucose the of SREBP-1c and increase its the that glucose a in the of SREBP-1c has N. J. F. N. J. PubMed Scopus Google have shown that the of and of SREBP-1c protein are by high glucose in the but whether glucose SREBP-1c in liver has Ferré P. Foufelle F. J. PubMed Scopus Google Scholar). The that the of SREBP-1c protein is in control and hGK-KO mice support a of glucose of glucose metabolism, in the of results support a for insulin in SREBP-1c gene expression. of SREBP-1c expression and are by insulin signaling is an that requires we have that glucose metabolism via GK is necessary for the transcriptional effect of SREBP-1c on l-PK, FAS, ACC, and Spot 14 gene expression, the key of hepatic GK in induction we have that ChREBP an essential in the of but also of genes in metabolism as and support the that glycolytic and lipogenic gene expression is by SREBP-1c and glucose acting via for adenovirus for in N. and for of the for the insulin and the of used in in an with the of the
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