A Combination of HNF-4 and Foxo1 Is Required for Reciprocal Transcriptional Regulation of Glucokinase and Glucose-6-phosphatase Genes in Response to Fasting and Feeding

Abstract

Glucokinase (GK) and glucose-6-phosphatase (G6Pase) regulate rate-limiting reactions in the physiologically opposed metabolic cascades, glycolysis and gluconeogenesis, respectively. Expression of these genes is conversely regulated in the liver in response to fasting and feeding. We explored the mechanism of transcriptional regulation of these genes by nutritional condition and found that reciprocal function of HNF-4 and Foxo1 plays an important role in this process. In the GK gene regulation, Foxo1 represses HNF-4-potentiated transcription of the gene, whereas it synergizes with HNF-4 in activating the G6Pase gene transcription. These opposite actions of Foxo1 concomitantly take place in the cells under no insulin stimulus, and such gene-specific action was promoter context-dependent. Interestingly, HNF-4-binding elements (HBEs) in the GK and G6Pase promoters were required both for the insulin-stimulated GK gene activation and insulin-mediated G6Pase gene repression. Indeed, mouse in vivo imaging showed that mutating the HBEs in the GK and G6Pase promoters significantly impaired their reactivity to the nutritional states, even in the presence of intact Foxo1-binding sites (insulin response sequences). Thus, in the physiological response of the GK and G6Pase genes to fasting/feeding conditions, Foxo1 distinctly decodes the promoter context of these genes and differently modulates the function of HBE, which then leads to opposite outcomes of gene transcription. Glucokinase (GK) and glucose-6-phosphatase (G6Pase) regulate rate-limiting reactions in the physiologically opposed metabolic cascades, glycolysis and gluconeogenesis, respectively. Expression of these genes is conversely regulated in the liver in response to fasting and feeding. We explored the mechanism of transcriptional regulation of these genes by nutritional condition and found that reciprocal function of HNF-4 and Foxo1 plays an important role in this process. In the GK gene regulation, Foxo1 represses HNF-4-potentiated transcription of the gene, whereas it synergizes with HNF-4 in activating the G6Pase gene transcription. These opposite actions of Foxo1 concomitantly take place in the cells under no insulin stimulus, and such gene-specific action was promoter context-dependent. Interestingly, HNF-4-binding elements (HBEs) in the GK and G6Pase promoters were required both for the insulin-stimulated GK gene activation and insulin-mediated G6Pase gene repression. Indeed, mouse in vivo imaging showed that mutating the HBEs in the GK and G6Pase promoters significantly impaired their reactivity to the nutritional states, even in the presence of intact Foxo1-binding sites (insulin response sequences). Thus, in the physiological response of the GK and G6Pase genes to fasting/feeding conditions, Foxo1 distinctly decodes the promoter context of these genes and differently modulates the function of HBE, which then leads to opposite outcomes of gene transcription. The liver plays an important role in maintaining plasma glucose homeostasis by adjusting a delicate balance between hepatic glucose utilization and production via the glycolytic and gluconeogenic pathways. These physiologically opposed cascades are regulated, at least in part, at the transcriptional level of the glucokinase (GK) 2The abbreviations used are: GK, glucokinase; G6Pase, glucose-6-phosphatase; IRS, insulin response sequence; HBE, HNF-4-binding element; qRT-PCR, quantitative reverse transcription-PCR; siRNA, small interfering RNA; ChIP, chromatin immunoprecipitation; WT, wild type; CBP, CREB-binding protein; L-PK, liver-type pyruvate kinase; DMEM, Dulbecco's modified Eagle's medium; hG6Pase, human G6Pase; rGK, rat GK; CMV, cytomegalovirus. and glucose-6-phosphatase (G6Pase) genes, which catalyze the first and last rate-limiting steps in glycolysis and gluconeogenesis, respectively. A number of studies have shown that fasting/feeding (or hormone) controls transcription of these two enzymes in the opposite direction. Fasting is associated with inhibition of GK transcription, whereas feeding or insulin treatment activates its transcription (1Iynedjian P.B. Jotterand D. Nouspikel T. Asfari M. Pilot P.R. J. Biol. Chem. 1989; 264: 21824-21829Abstract Full Text PDF PubMed Google Scholar, 2Iynedjian P.B. Pilot P.R. Nouspikel T. Milburn J.L. Quaade C. Hughes S. Ucla C. Newgard C.B. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7838-7842Crossref PubMed Scopus (145) Google Scholar, 3Iynedjian P.B. Gjinovci A. Renold A.E. J. Biol. Chem. 1988; 263: 740-744Abstract Full Text PDF PubMed Google Scholar). Conversely, G6Pase transcription is negatively regulated by insulin or feeding and markedly increased in a fasting state (4Streeper R.S. Svitek C.A. Chapman S. Greenbaum L.E. Taub R. O'Brien R.M. J. Biol. Chem. 1997; 272: 11698-11701Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Previous studies have established that Foxo1, a member of the FOXO family of forkhead transcription factors, is important in mediating the effects of insulin on G6Pase gene expression in cultured cells (5Schmoll D. Walker K.S. Alessi D.R. Grempler R. Burchell A. Guo S. Walther R. Unterman T.G. J. Biol. Chem. 2000; 275: 36324-36333Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 6Vander Kooi B.T. Streeper R.S. Svitek C.A. Oeser J.K. Powell D.R. O'Brien R.M. J. Biol. Chem. 2003; 278: 11782-11793Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). Foxo1 is phosphorylated by protein kinase B (also called Akt) in the presence of insulin signal and then excluded from the nucleus, resulting in inhibition of the expression of target genes (7Biggs III, W.H. Meisenhelder J. Hunter T. Cavenee W.K. Arden K.C. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 7421-7426Crossref PubMed Scopus (942) Google Scholar, 8Tang E.D. Nunez G. Barr F.G. Guan K.L. J. Biol. Chem. 1999; 274: 16741-16746Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, 9Nakae J. Park B.C. Accili D. J. Biol. Chem. 1999; 274: 15982-15985Abstract Full Text Full Text PDF PubMed Scopus (400) Google Scholar, 10Nakae J. Barr V. Accili D. EMBO J. 2000; 19: 989-996Crossref PubMed Scopus (254) Google Scholar). On the other hand, unphosphorylated form of Foxo1 localizes to the nucleus and interacts with insulin response sequences (IRSs) present within the promoter regions of multiple target genes, including the G6Pase gene, and activates their transcription. Recent reports have demonstrated that Foxo1, in some cases, can also be recruited to a promoter through a DNA-binding transcription factor and act as a transcriptional repressor (11Hirota K. Daitoku K. S. T. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Accili D. PubMed Scopus Google Scholar, T. J. III, W.H. Arden K.C. Accili D. J. PubMed Scopus Google Scholar, S. Full Text Full Text PDF PubMed Scopus Google Scholar, D. Barr F.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). is these two and its state as or repressor in The in the and to a as a and activates transcription of genes that are in and PubMed Scopus Google Scholar, T. S. Biol. PubMed Scopus Google Scholar, A. A. M. Biol. PubMed Scopus Google Scholar, G. Biol. PubMed Scopus Google Scholar, M. Proc. Natl. Acad. Sci. U. S. A. 1997; PubMed Scopus Google Scholar). HNF-4 activates the transcription of both GK and G6Pase genes, as are regulated by nutritional U. K. T. J. PubMed Scopus Google Scholar, A. S. G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. A. J. Google Scholar, J. M. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). it HNF-4 is in the nutritional regulation of these HNF-4 as an it is to that nutritional factor the function of the HNF-4 in an opposite in GK and G6Pase gene transcription. have that HNF-4 interacts with Foxo1 (11Hirota K. Daitoku K. S. T. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google which is regulated in its in response to nutritional that Foxo1 is in the regulation of these genes in response to metabolic in that Foxo1 represses the HNF-4-potentiated expression of the GK gene and activation on the transcription of the G6Pase of these effects are by cells with which Foxo1 to the the gene-specific effects of Foxo1 on HNF-4 were promoter of HBEs and on the this regulation in a physiological in vivo imaging and demonstrated that HBEs are in required for the regulation of these two genes in response to fasting and feeding. These that opposite effects of Foxo1 on GK and G6Pase gene expression HNF-4 and that reciprocal action of Foxo1 and HNF-4 is an important of the metabolic the glycolysis or and cells were in a and were by was with was from the of or cells was and with G6Pase mouse glucokinase mouse J. T. S. T. S. T. R. M. S. K. A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google and G. V. 1999; PubMed Scopus Google were used as and The for human G6Pase was by and reverse the between Foxo1 and HNF-4 in the G6Pase promoter cells were with with Foxo1 or Foxo1 expression in the or presence of HNF-4 expression cells were in with for and then for in the presence or of G6Pase in cells were by of was by The were with and the the of and cells were in with for and then for in the presence or of of HNF-4 and Foxo1 to the G6Pase promoter was by with chromatin from liver in and a chromatin was with was by with was were to in the and G6Pase in cells were by cells were with for or cells were with as was and were by G6Pase were to are for was from cells with to the was reverse and to the was in reactions the and gene expression was by the G6Pase were to the and were used for for were from of cells at were with to the cells were with protein were from The were used as and and were at of Expression of HNF-4 were by and G6Pase expression were by and and cells were cultured in Dulbecco's modified Eagle's with cells were cultured in Dulbecco's modified Eagle's with and were or of or was in to for were to was with an and for in the and were in liver from a mouse was in and in of A The were in a The was through a and the was at for at The was used as hepatic were as by the with some between transcription and chromatin was by to hepatic for for were and with with (11Hirota K. Daitoku K. S. T. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google or with and for at were with a for with and then at for for reverse was and to the quantitative the G6Pase promoter the were and the GK promoter the were and The quantitative was in the with as an for at by of at and at of and in was under for expression as G. V. 1999; PubMed Scopus Google Scholar, C.B. V. 2003; PubMed Scopus Google Scholar). to were a of or with and in in a of The was used as an to for were by and a of in were for with a imaging were by were by were with in of and were for with a imaging were by GK, the first of was to and the of was to a for were then an of and glucose and insulin were from imaging with a imaging were to a of and G6Pase, the first of was to and the of was to a for were a of imaging with a imaging were to or to a for were an of and and glucose in and insulin in from the were were in a from the of the of and in with the for at and for of and in under the of the of and were by was are as the WT, WT, and were (11Hirota K. Daitoku K. S. T. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, M. S. T. M. T. A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The in the of and Foxo1 were by The was with the the human and rat glucokinase promoters from to and from to to the transcription were to and an to the gene promoter was The and were within the context of The sequences were the The sequences the A was used to an to from GK a to of the human G6Pase was of the A was used to an to from used for were as HNF-4 HNF-4 in first the GK and G6Pase in the liver of under of fasting and feeding. from (1Iynedjian P.B. Jotterand D. Nouspikel T. Asfari M. Pilot P.R. J. Biol. Chem. 1989; 264: 21824-21829Abstract Full Text PDF PubMed Google Scholar, 2Iynedjian P.B. Pilot P.R. Nouspikel T. Milburn J.L. Quaade C. Hughes S. Ucla C. Newgard C.B. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7838-7842Crossref PubMed Scopus (145) Google Scholar, 3Iynedjian P.B. Gjinovci A. Renold A.E. J. Biol. Chem. 1988; 263: 740-744Abstract Full Text PDF PubMed Google Scholar, R.S. Svitek C.A. Chapman S. Greenbaum L.E. Taub R. O'Brien R.M. J. Biol. Chem. 1997; 272: 11698-11701Abstract Full Text Full Text PDF PubMed Scopus (131) Google the G6Pase level was in the fasting state and in the feeding On the other hand, GK level was in the fasting state and in the feeding state These that of these two enzymes is conversely by nutritional at least in at the gene expression Expression of HNF-4 and Foxo1 were A and it is established that HNF-4 and activates the rat GK promoter U. K. Unterman T.G. T. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google an in the human GK promoter at the of the rat gene We an of HNF-4 on the transcriptional of GK and G6Pase HNF-4 the promoter of these two genes U. K. T. J. PubMed Scopus Google Scholar, K. A. J. Google Scholar, J. M. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google the function of HNF-4 with to nutritional of these two regulated genes We explored HNF-4 plays role in these HNF-4-potentiated GK by Foxo1 in to showed that hepatic expression of Foxo1 in was to GK gene expression S. Guo S. Powell D.R. J. A. R. R. M. Unterman T.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). A with of Foxo1 in also that Foxo1 GK expression in the liver insulin is M. A. Accili D. Full Text Full Text PDF PubMed Scopus Google Scholar). it Foxo1 is in a of the GK gene On the other hand, have by an promoter of HBEs the that Foxo1 HNF-4-potentiated transcriptional and this was by the cells with insulin (11Hirota K. Daitoku K. S. T. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). Foxo1 of the transcriptional also place in the GK promoter In the HNF-4 the GK of insulin Foxo1 was with HNF-4 in the of GK promoter was no was in the of HNF-4 insulin significantly the of GK promoter in the presence of Foxo1 of the in which sites and were by and B and We that the Foxo1 was Foxo1 the the to the as the that Foxo1 in the nucleus, that the Foxo1 and are in the to the of Foxo1 to the GK promoter in that the of the GK promoter on hepatic from and The by that HNF-4 to the in the or On the other hand, Foxo1 is recruited to the on GK promoter in the liver of in of these that Foxo1 is recruited to the of the GK promoter through the to HNF-4 and represses its transcriptional whereas feeding or insulin signal in the of Foxo1 from the through the of Foxo1, to of the transcriptional These that between HNF-4 and Foxo1 plays a role in the insulin response of GK gene Foxo1 with HNF-4 on the G6Pase explored the of between Foxo1 and HNF-4 on the G6Pase gene transcription. Previous studies in cells have shown that Foxo1 activates the G6Pase promoter through the (5Schmoll D. Walker K.S. Alessi D.R. Grempler R. Burchell A. Guo S. Walther R. Unterman T.G. J. Biol. Chem. 2000; 275: 36324-36333Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, 6Vander Kooi B.T. Streeper R.S. Svitek C.A. Oeser J.K. Powell D.R. O'Brien R.M. J. Biol. Chem. 2003; 278: 11782-11793Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar). We found in and cells that the G6Pase was by Foxo1, in with cells These to that an important for transcriptional activation is from and with an HNF-4 an in cells in or cells at HNF-4 is for level G6Pase promoter Foxo1 and HNF-4 or cells and found that the G6Pase was in with of Foxo1 The level activation by Foxo1 was of or which and activates the G6Pase promoter C. S. C. V. J. Biol. Chem. 1999; 274: Full Text Full Text PDF PubMed Scopus Google Scholar, 1997; PubMed Scopus Google Scholar, A. G. 19: PubMed Scopus Google or no in the G6Pase transcriptional A and In the of the form of HNF-4 S. T. PubMed Scopus Google which with on the transcriptional of Foxo1 and found that the of the a of G6Pase promoter and with these of HNF-4 by significantly the expression of the G6Pase gene in conditions, which of Foxo1 and these that HNF-4 is an of the G6Pase promoter the between Foxo1 and HNF-4 in G6Pase the of insulin on the transcriptional between HNF-4 and Foxo1 in the G6Pase promoter In cells under no insulin the G6Pase was by Foxo1 and HNF-4 treatment of the cells significantly the G6Pase promoter activation by Foxo1 by the Foxo1 We HNF-4 and Foxo1 also the G6Pase gene, in a in the chromatin cells were with HNF-4 with Foxo1 or expression and G6Pase gene expression was by of Foxo1 WT, or Foxo1 or no in G6Pase G6Pase was HNF-4 and Foxo1 or Foxo1 expression were insulin treatment of the cells significantly the activation of the G6Pase gene by HNF-4 and Foxo1 activation by HNF-4 and Foxo1 was by insulin These that Foxo1 and HNF-4 both and G6Pase gene We this the of Foxo1 and HNF-4 to and respectively. We the in cells or Foxo1 in which two that are for and were by and resulting in a of E.D. Nunez G. Barr F.G. Guan K.L. J. Biol. Chem. 1999; 274: 16741-16746Abstract Full Text Full Text PDF PubMed Scopus (662) Google Scholar, R. R. PubMed Scopus Google Scholar). The showed that no activation was or Foxo1 was These showed that the of both Foxo1 and HNF-4 to the G6Pase gene is for the to the of HNF-4 and Foxo1 to the and the of the G6Pase promoter in were mouse HNF-4 was recruited to the on the G6Pase promoter in both the liver of fasting and Foxo1 to the under the fasting condition These that under the fasting conditions, both HNF-4 and Foxo1 and the on the G6Pase gene transcription. On the other hand, insulin signal or feeding the by Foxo1 that between HNF-4 and Foxo1 a role in the regulation of G6Pase gene expression in response to fasting/feeding to the of in the is a that as a in M. G. T. D. Full Text Full Text PDF PubMed Scopus Google Scholar). We have that to both HNF-4 and Foxo1 M. S. T. M. T. A. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar, S. M. M. T. K. A. 1997; PubMed Scopus Google Scholar). to the of in the and the of shown in of significantly the by Foxo1 and HNF-4 in a whereas it showed effects on the HNF-4 or Foxo1 was and the of to with Foxo1 and HNF-4 in the regulation of G6Pase transcription. Expression of found to be under the fasting state and to gluconeogenic enzymes by HNF-4 J. M. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google Scholar). of the transcriptional of HNF-4 and Foxo1 and These that and are for the activation of the G6Pase gene by HNF-4 and Foxo1 The or of on the the of the mechanism by which Foxo1 modulates transcriptional The G6Pase promoter two HBEs and Kooi B.T. Streeper R.S. Svitek C.A. Oeser J.K. Powell D.R. O'Brien R.M. J. Biol. Chem. 2003; 278: 11782-11793Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, K. A. J. Google Scholar). A on the G6Pase promoter is required for the activation of the gene the GK gene the HBEs in the these to a in which Foxo1 synergizes with the HNF-4 on the promoters both and HNF-4-binding sites G6Pase whereas it promoters no in GK this in which were from the G6Pase and their in Foxo1 and HNF-4 the G6Pase as shown in G6Pase in On the other hand, a HBEs was significantly by an of Foxo1 in the presence of HNF-4 in and a in which were the GK and its Foxo1 the on the GK as shown in GK in whereas Foxo1 increased the on the GK both an and in These that the presence or of the on the promoter the genes to be or by Foxo1 and that HBEs are for both of genes for the regulation by The HNF-4-binding for of GK and G6Pase in in a that Foxo1 is an important of insulin action on both GK and G6Pase gene regulation, and its effects transcriptional the physiological of these in vivo imaging by a imaging that insulin action of GK and G6Pase gene expression HNF-4 in the of HBEs on gene leads to a response to nutritional in the expression of these were with the GK promoter and to fasting and then and then were insulin level was in the in the with the transcriptional of the GK gene (1Iynedjian P.B. Jotterand D. Nouspikel T. Asfari M. Pilot P.R. J. Biol. Chem. 1989; 264: 21824-21829Abstract Full Text PDF PubMed Google Scholar, 2Iynedjian P.B. Pilot P.R. Nouspikel T. Milburn J.L. Quaade C. Hughes S. Ucla C. Newgard C.B. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 7838-7842Crossref PubMed Scopus (145) Google Scholar, 3Iynedjian P.B. Gjinovci A. Renold A.E. J. Biol. Chem. 1988; 263: 740-744Abstract Full Text PDF PubMed Google the level of the was in the state and increased in the this in transcriptional of the in in We then the in which HBEs from the The level in the state was in the in with that in the In the the level was increased in the the of the was with that in the that the HBEs are required for the regulation of GK gene expression in response to nutritional in also that is a of insulin action on GK gene expression in We the in vivo role of the HBEs in the G6Pase promoter level in the in between was with transcriptional of the G6Pase gene and of the from the in in the state and no transcriptional in response to in and that are for G6Pase gene activation in the We then HBEs in the G6Pase promoter are required for transcriptional activation of this gene in the of the in in the G6Pase promoter in the the mouse of the promoter the presence of intact in and Previous studies have shown that Foxo1 the G6Pase promoter in the of insulin (5Schmoll D. Walker K.S. Alessi D.R. Grempler R. Burchell A. Guo S. Walther R. Unterman T.G. J. Biol. Chem. 2000; 275: 36324-36333Abstract Full Text Full Text PDF PubMed Scopus (296) Google Scholar, K. A. J. Google Scholar). that to the fasting state on the G6Pase gene promoter in to this and shown in A and HNF-4 is to be an of the G6Pase gene activation in We that between HNF-4 and Foxo1 on the G6Pase gene promoter is for the transcriptional response of this gene to nutritional in The expression of GK and G6Pase genes is regulated in response to it is that HNF-4 promoter of these genes U. K. T. J. PubMed Scopus Google Scholar, A. S. G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, K. A. J. Google Scholar, J. M. Proc. Natl. Acad. Sci. U. S. A. 2003; PubMed Scopus Google it established HNF-4 is in the regulation of these genes by nutritional the mechanism of these genes by on the between HNF-4 and showed that Foxo1 represses HNF-4-potentiated transcription of the GK gene and that it synergizes with HNF-4 in G6Pase gene transcription and and and and These reciprocal by Foxo1, place and insulin treatment of the cells both These to that HNF-4 plays in the reciprocal regulation of GK and G6Pase genes in that Foxo1 the insulin in response to two opposite transcriptional outcomes these genes are by in is a that is on In the of insulin Foxo1 localizes to the nucleus, it represses of the GK promoter as a Foxo1 and HNF-4 the G6Pase gene by the with and These the balance between glycolysis and the in the cells are by insulin Foxo1 is phosphorylated and excluded from the nucleus, resulting in its from the HNF-4 (11Hirota K. Daitoku K. S. T. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar). HNF-4 can the GK gene promoter through HBE, whereas the G6Pase gene promoter is by HNF-4 Thus, insulin the metabolic balance in of by G6Pase gene expression and activating GK gene In this Foxo1 plays a role in between glycolysis and gluconeogenesis, and HNF-4 is an of this to the reports (11Hirota K. Daitoku K. S. T. A. J. Biol. Chem. 2003; 278: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Accili D. PubMed Scopus Google Scholar, T. J. III, W.H. Arden K.C. Accili D. J. PubMed Scopus Google Scholar, S. Full Text Full Text PDF PubMed Scopus Google Scholar, D. Barr F.G. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Foxo1 as transcriptional in some and repressor in the of Foxo1 in In this showed that Foxo1 or transcriptional on HNF-4-potentiated gene in a promoter Foxo1 by HNF-4 in promoters that GK and with HNF-4 in activating promoters sites for both HNF-4 and Foxo1 G6Pase with this the from the G6Pase promoter and the of Foxo1 from the to the We that or of sites in a promoter transcription gene transcription, and the are a of this of the response to the nutritional in the G6Pase promoter was also in the were from the G6Pase promoter in the signal in to be that in and the was These the that are for G6Pase gene activation in the fasting state also in the of Foxo1 as an or A. A. M. Biol. PubMed Scopus Google have shown that promoter of the liver-type pyruvate kinase gene, an important in the glycolytic and no was to this gene, Foxo1 the HNF-4-potentiated transcriptional of the gene and response on Indeed, M. A. PubMed Scopus Google have the response in the gene, and this the with that Foxo1 represses the HNF-4-potentiated of the gene in the fasting and the is in the feeding On the other hand, a was found in the promoter of the gene, which is a in the regulation of through the gluconeogenic Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). Interestingly, found that Foxo1 also activation with HNF-4 on the promoter in the Thus, a of and be found in the promoter of important enzymes in the a role in transcription of the genes in response to nutritional and a of G6Pase gene expression is found in and it is regulated nutritional C. S. J. G. PubMed Scopus Google Scholar). Previous studies have shown that Foxo1 transcriptional of the G6Pase gene in response to the insulin on gene expression J. T. Accili D. J. PubMed Scopus Google Scholar). Foxo1 is S. Cavenee W.K. Arden K.C. PubMed Scopus Google Scholar, T. T. J. 2000; PubMed Scopus Google it a to Foxo1 on the that HNF-4 as a of G6Pase gene transcription. HNF-4 expression is to the and which with the of In of HNF-4 is an of the Foxo1 in activating G6Pase transcription in the In HNF-4 is transcriptional of the G6Pase gene be Foxo1 to in the G6Pase is with the that of the HBEs in the G6Pase promoter transcription of the gene in the fasting the presence of intact and Thus, it is that a of Foxo1 and HNF-4 transcription is for and G6Pase promoter the of gene expression to a number of transcriptional it is in by a of the of which is a that the of two even the opposite in transcription with the promoter We for the and for We and for and of the for and with