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The expression of genes encoding enzymes involved in de novo triglyceride synthesis (lipogenesis) is transcriptionally induced in the liver in response to increased glucose metabolism. The carbohydrate response element-binding protein (ChREBP) is a newly identified basic helix-loop-helix/leucine zipper transcription factor proposed to regulate the expression of the glucose-responsive gene pyruvate kinase. This gene contains a carbohydrate response element (ChoRE) consisting of two E box motifs separated by 5 bp that is necessary and sufficient for glucose regulation. We demonstrate that overexpression of ChREBP in primary rat hepatocytes activates other ChoRE-containing promoters in a manner consistent with their ability to respond to glucose. In vitro binding of ChREBP to ChoRE sequences was not detected. Because E box-binding proteins function as obligate dimers, we performed a yeast two-hybrid screen of a mouse liver cDNA library to identify potential heteromeric partners. Mlx (Max-like protein X) was selected as the only basic helix-loop-helix/leucine zipper interaction partner in this screen. When a plasmid expressing either Mlx or ChREBP was cotransfected with a ChoRE-containing reporter plasmid into human embryonic kidney 293 cells, no increase in promoter activity was observed. However, the expression of both proteins dramatically enhanced promoter activity. This activation was observed with reporters containing ChoREs from several different lipogenic enzyme genes. In contrast, reporters containing non-glucose-responsive E box elements were not activated by ChREBP-Mlx expression. In vitro binding of ChREBP to ChoRE-containing oligonucleotides was observed only in the presence of Mlx. ChREBP-Mlx binding discriminated between E box sites that are glucose-responsive and those that are not. We conclude that Mlx is a functional heteromeric partner of ChREBP in regulating the expression of glucose-responsive genes. The expression of genes encoding enzymes involved in de novo triglyceride synthesis (lipogenesis) is transcriptionally induced in the liver in response to increased glucose metabolism. The carbohydrate response element-binding protein (ChREBP) is a newly identified basic helix-loop-helix/leucine zipper transcription factor proposed to regulate the expression of the glucose-responsive gene pyruvate kinase. This gene contains a carbohydrate response element (ChoRE) consisting of two E box motifs separated by 5 bp that is necessary and sufficient for glucose regulation. We demonstrate that overexpression of ChREBP in primary rat hepatocytes activates other ChoRE-containing promoters in a manner consistent with their ability to respond to glucose. In vitro binding of ChREBP to ChoRE sequences was not detected. Because E box-binding proteins function as obligate dimers, we performed a yeast two-hybrid screen of a mouse liver cDNA library to identify potential heteromeric partners. Mlx (Max-like protein X) was selected as the only basic helix-loop-helix/leucine zipper interaction partner in this screen. When a plasmid expressing either Mlx or ChREBP was cotransfected with a ChoRE-containing reporter plasmid into human embryonic kidney 293 cells, no increase in promoter activity was observed. However, the expression of both proteins dramatically enhanced promoter activity. This activation was observed with reporters containing ChoREs from several different lipogenic enzyme genes. In contrast, reporters containing non-glucose-responsive E box elements were not activated by ChREBP-Mlx expression. In vitro binding of ChREBP to ChoRE-containing oligonucleotides was observed only in the presence of Mlx. ChREBP-Mlx binding discriminated between E box sites that are glucose-responsive and those that are not. We conclude that Mlx is a functional heteromeric partner of ChREBP in regulating the expression of glucose-responsive genes. Triglycerides are the principal energy storage fuel in mammals. The synthesis of triglycerides in the liver is regulated by the nutrition of the animal. For example, when mammals are fed a high carbohydrate/low fat diet, increases in insulin and in glucose uptake and metabolism occur in response to elevated blood glucose levels. These changes are responsible for increasing the production of triglycerides in the liver. The increased production is due to modifications of both the concentration and activity of enzymes involved in the pathway of triglyceride synthesis (lipogenesis). The induction of lipogenic enzyme genes occurs primarily at the transcriptional level. Lipogenic mRNAs that are induced in response to high carbohydrate feeding include pyruvate kinase (PK), 1The abbreviations used are: PK, pyruvate kinase; bHLH/LZ, basic helix-loop-helix/leucine zipper; SREBP-1c, sterol regulatory element-binding protein-1c; ChoRF, carbohydrate-responsive factor; ChoRE, carbohydrate response element; ChREBP, carbohydrate response element-binding protein; Mlx, Max-like protein X; EMSA, electrophoretic mobility shift assay; HA, hemagglutinin. fatty-acid synthase, acetyl-CoA carboxylase, S14, and stearoyl-CoA desaturase (for review, see Refs. 1Towle H.C. J. Biol. Chem. 1995; 270: 23235-23238Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar, 2Girard J. Ferre P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (302) Google Scholar, 3Vaulont S. Vasseur-Cognet M. Kahn A. J. Biol. Chem. 2000; 275: 31555-31558Abstract Full Text Full Text PDF PubMed Scopus (226) Google Scholar). The basic helix-loop-helix/leucine zipper (bHLH/LZ) transcription factor sterol regulatory element-binding protein-1c (SREBP-1c) plays a critical role in the insulin-dependent induction of lipogenic genes (for review, see Refs. 4Brown M.S. Goldstein J.L. Cell. 1997; 89: 331-340Abstract Full Text Full Text PDF PubMed Scopus (3004) Google Scholar, 5Horton J.D. Shimomura I. Curr. Opin. Lipidol. 1999; 10: 143-150Crossref PubMed Scopus (274) Google Scholar, 6Osborne T.F. J. Biol. Chem. 2000; 275: 32379-32382Abstract Full Text Full Text PDF PubMed Scopus (441) Google Scholar). SREBP-1c expression is induced by insulin (7Kim J.B. Sarraf P. Wright M. Yao K.M. Mueller E. Solanes G. Lowell B.B. Spiegelman B.M. J. Clin. Invest. 1998; 101: 1-9Crossref PubMed Scopus (612) Google Scholar, 8Foretz M. Pacot C. Dugail I. Lemarchand P. Guichard C. Liepvre X.L. Berthelier-Lubrano C. Spiegelman B. Kim J.B. Ferre P. Foufelle F. Mol. Cell. 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A sequence in the PK promoter has been identified for its ability to support a response to glucose (17Thompson K.S. Towle H.C. J. Biol. Chem. 1991; 266: 8679-8682Abstract Full Text PDF PubMed Google Scholar, 18Liu K.S. Towle H.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, M. Kahn A. PubMed Scopus Google Scholar). This element is a carbohydrate response element (ChoRE) and of two E box motifs separated by 5 ChoREs have been identified in the promoters of the fatty-acid synthase, S14, and acetyl-CoA genes Towle H.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Towle H.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, C. M. M. S.-H. Towle H.C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, S.-H. Y. H.C. Towle H.C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar). In the of both the fatty-acid and sites for the of insulin and glucose have been identified S.-H. Dutcher A.K. Towle H.C. J. Biol. Chem. 2001; 276: 9437-9445Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar, C. M. M. S.-H. Towle H.C. J. Biol. Chem. 2001; 276: Full Text Full Text PDF PubMed Scopus Google Scholar, M.M. S.-H. Towle H.C. Osborne T.F. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). These sites to support the of glucose and a transcription factor has as a for the H. M. M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, M. Y. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus (302) Google Scholar). This carbohydrate response element-binding protein was its ability to the PK ChoRE in H. M. M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). ChREBP as and is a of the of transcription that is to E box sequences in the promoters of genes. ChREBP is in mouse and in the liver H. M. M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, J. 2000; PubMed Scopus Google Scholar). When primary rat hepatocytes are with a ChREBP expression PK promoter activity is increased high not glucose H. M. M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). to ChREBP other lipogenic enzyme gene promoters and it to the regulatory sequences in lipogenic genes. In this we evidence the role of ChREBP in the induction of transcription in glucose-responsive In we that ChREBP not in a heteromeric with the transcription factor Mlx (Max-like protein two to and transcription in a of lipogenic enzyme genes containing the of was by the mouse liver cDNA as and with enzyme and ChREBP was into the expression plasmid Towle H.C. Mol. Cell. Biol. 1995; PubMed Google the Because of its in other this plasmid was in The ChREBP was by ChREBP into the and and to the and M. Y. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). The was at the of both and in the the A. H. Y. 2001; PubMed Scopus Google for and were fed and primary hepatocytes were by the Towle H.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). a to were in E containing and were used at of reporter and of expression expression containing the gene of were and in the containing either or glucose for were reporter were performed of are as of were protein with as the 293 and embryonic kidney 293 were in with and For reporter were in and from were used at of reporter plasmid and of expression expression containing the gene of were and in with for 293 were and were performed as for electrophoretic mobility shift 293 were in the and of expression For those 293 that were cotransfected with both ChREBP and Mlx, of was the was into of and of was In a was of a and the was to it This was at for and to the 293 The was from the in the from two-hybrid was performed the and a mouse liver cDNA library the The library was from mouse and in the mouse ChREBP were with to the and the other with were in yeast at either or high and were to were the yeast plasmid the library plasmid yeast plasmid were into E. and selected The cDNA in the library plasmid was the of Mlx was into the expression the a yeast two-hybrid screen plasmid as and with or enzyme and was by mouse cDNA and with enzyme and A was to the the were as Towle H.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar). A of and 5 of from 293 The used was of with for at were to a were from For with proteins were with for the with and mouse from were The of protein was with for at of of by ChREBP in with in the ChREBP has been to transcription in the PK promoter high glucose in rat hepatocytes H. M. M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). the role of ChREBP in the glucose of ChoRE-containing we cotransfected ChREBP with reporter containing ChoREs with changes in the between the two E box In ChoREs to a of 5 bp is between the two critical E S.-H. Towle H.C. J. Biol. Chem. 2000; 275: Full Text Full Text PDF PubMed Scopus Google Scholar). with a of bp between the two E box motifs are in their glucose with a not respond to glucose Towle H.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). ChREBP is the carbohydrate-responsive transcription factor, a between its ability to ChoREs and their ability to respond to glucose. hepatocytes were cotransfected with the ChREBP expression and reporter containing the ChoRE and in or high glucose. overexpression of ChREBP not the activity of reporter glucose In the presence of high ChREBP overexpression to an increase in reporter activity in the with ChREBP was to increase promoter activity levels in the However, of ChREBP not increase promoter activity in the ChREBP activation of with their ability to respond to the role of ChREBP in the glucose Mlx with ChREBP in a were with in vitro ChREBP to its binding to ChoRE-containing to ChREBP binding to ChoRE-containing oligonucleotides were Because proteins to as or this that ChREBP a heteromeric with a in the liver to as the A yeast two-hybrid screen was to identify potential liver for a mouse liver cDNA library and a of ChREBP containing the as were Mlx was identified Mlx is a of the and were in the of the other were to Because the screen was performed for the of potential only Mlx was in the to the other proteins are to ChREBP function in ChREBP and Mlx to the PK ChoRE as a ChREBP and Mlx binding to ChoRE-containing we used from 293 that were with expression for When from 293 were with a PK ChoRE in an EMSA, two were observed These E box-binding the to in in different When 293 were with the expression no were of ChREBP to no In contrast, from cotransfected with both and ChREBP a This was with to either the or and the presence of both Mlx and ChREBP in the M. Y. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google evidence that of ChREBP plays an role in kinase of of the ability of a of ChREBP to to an E Also, the expression of a of ChREBP to increased PK promoter activity ChREBP in primary rat hepatocytes with high glucose and When this ChREBP was cotransfected with Mlx into 293 cells, the of the newly was enhanced This was with to either the or and with 293 that the expression of ChREBP and ChREBP was and that their expression not Mlx expression not that the increased binding of the ChREBP was due to and not to an in we the of ChREBP binding of from 293 with ChREBP and Mlx with the of protein to a increase in binding to the This is consistent with the that ChREBP binding in 293 is by an of a protein the PK ChoRE the presence of both Mlx and ChREBP, and binding of ChREBP is by of ChREBP and Mlx of of the ChREBP-Mlx is capable of with ChoRE-containing reporter were in primary of ChREBP and expression no increase in reporter activity that with ChREBP not is in Mlx is at high levels and that of Mlx increase activity. For this were in 293 cells, a that has no Mlx protein C. D.E. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). 293 were cotransfected with a reporter plasmid containing two of the ChoRE to a promoter and an expression containing ChREBP Mlx or The ChoRE is from the rat ChoRE and contains a E box has been to support a response to has binding for the factor and other E box-binding proteins Towle H.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar). When 293 were with an expression for either ChREBP or Mlx, no induction of reporter activity levels was observed In contrast, when expression for both ChREBP and Mlx were was a increase in reporter activity to levels. in reporter activity was observed between with the or of Mlx. These support an role for Mlx in the of and of ChoRE by ChREBP and Mlx with ChREBP and Mlx function in the glucose an was with the of 293 were cotransfected with reporter containing the ChoRE and expression containing ChREBP and The not respond to no increase in reporter activity levels of ChREBP and Mlx The plasmid respond to a induction of ChREBP and Mlx expression the an response to a induction levels when cotransfected with ChREBP and Mlx. the activation of by ChREBP and Mlx the in 293 as the glucose of sequences in binding of ChREBP and Mlx with were performed with oligonucleotides containing E box For this both and enhanced binding to the PK ChoRE, were binding to the with observed from with both and ChREBP a this This was with from with both and the ChREBP the no were observed when were cotransfected with either and ChREBP or and the ChREBP with the 293 This is consistent with the of this sequence to respond to glucose. the the of was observed only when were with and the ChREBP, a of ChREBP-Mlx for this is in its response to glucose. both the binding of ChREBP-Mlx to and the ability of ChREBP-Mlx to transcription in with the potential of sequences to support a glucose ChREBP and Mlx to and in ChoREs from Lipogenic we have that of ChREBP and Mlx to increased promoter activity in containing the PK ChREBP and Mlx function as the ChoRF, to ChoREs from other lipogenic enzyme gene we cotransfected ChREBP and into 293 with a of reporter of the reporter two of a ChoRE of a box promoter from the PK gene to this the ability of ChREBP-Mlx to in the of other transcription When with of the ChoREs from the S14, PK, and acetyl-CoA lipogenic enzyme genes or with the ChoRE, was a increase in reporter activity of ChREBP and Mlx response a binding for was as a This sequence not respond to high glucose in primary rat hepatocytes when to a promoter S.-H. Dutcher A.K. Towle H.C. J. Biol. Chem. 2001; 276: 9437-9445Abstract Full Text Full Text PDF PubMed Scopus (124) Google Scholar). the factor contains an E box sequence to to glucose Towle H.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar). of induction of activity levels of ChREBP and Mlx. was of to the elevated with the factor This sequence a binding for a transcription factor in 293 These demonstrate that ChREBP-Mlx transcription in lipogenic enzyme gene ChoREs and E that support a glucose response from those that not. ChREBP-Mlx to the sequences it were oligonucleotides to those Because of the increased it the ChREBP was used in this When 293 were with the ChREBP and a not in was of the oligonucleotides that function as In contrast, this was not an containing the This is consistent with the in that of ChREBP and Mlx not a reporter with the sterol response element The contains a E box that was for its ability to a of ChREBP and Mlx G. F. A. A. Mol. 2001; 10: PubMed Google Scholar). A was this in with both Mlx and However, this the that the ChoRE This was by to both the and the presence of both Mlx and ChREBP not with this sequence that it not support a response to glucose in primary rat hepatocytes and was not activated by of ChREBP and Mlx in a 293 reporter and H. C. These the ChREBP and Mlx a functional the E box the that is a of ChREBP and Mlx that is not functional in transcriptional The of the has Towle H.C. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, 1999; PubMed Scopus Google Scholar, M. Kahn A. Vasseur-Cognet M. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, M. M. Kahn A. S. J. Biol. Chem. 1997; 272: Full Text Full Text PDF PubMed Scopus (96) Google Scholar). by and H. M. M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google has identified ChREBP as a ChREBP was its ability to to the ChoRE in the PK ChREBP was to a of the transcription factor of this to E box sequences as those in the ChoRE of the PK levels of the for ChREBP are in the this a for the transcription factor responsible for carbohydrate induction of lipogenesis in the liver. in primary rat hepatocytes that overexpression of ChREBP activates transcription of the PK promoter in in high not glucose H. M. M. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar). However, this activation is at only induction by the In ChREBP overexpression to an increase in PK promoter activity in H. J. Biol. Chem. 2002; 277: Full Text Full Text PDF PubMed Scopus Google Scholar). functional evidence that ChREBP is the is with the PK to ChREBP the other lipogenic enzyme promoters that are induced in response to a high carbohydrate In this we evidence that ChREBP activates transcription in several other glucose-responsive sequences in to For example, the of to have to the of induction by ChREBP it is the this functional activity with to ChREBP ChoRE-containing oligonucleotides in an were was in an with in vitro ChREBP, that it not as a with ChREBP was not to with in a yeast two-hybrid interaction G. F. A. A. Mol. 2001; 10: PubMed Google Scholar). of ChREBP binding to E box sequences that were with a of ChREBP the M. Y. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google Scholar, G. F. A. A. Mol. 2001; 10: PubMed Google Scholar). is that sequences at the of ChREBP are to its binding to as a A was for a heteromeric partner for We were in a liver-specific heteromeric partner For this a yeast two-hybrid was with the of ChREBP as In a mouse liver cDNA Mlx was identified as the only interaction this screen was not the of Mlx that Mlx is the ChREBP partner in liver. Mlx has been to with ChREBP in other G. F. A. A. Mol. 2001; 10: PubMed Google Scholar). Mlx was identified as a protein by yeast two-hybrid screen C. D.E. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). to Mlx was proposed to a partner of a transcription factor In to ChREBP, Mlx is to with and no genes for interaction have been identified C. D.E. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar, G. S. G. S. A. A. 2000; 19: PubMed Scopus Google Scholar). Mlx is a of the of transcription ChREBP and Mlx a heteromeric and to oligonucleotides containing a ChoRE, were with sequences from the PK in the presence of both Mlx and ChREBP was a the PK binding of this was enhanced when a of ChREBP was used in of This has two for protein kinase by and M. Y. Proc. Natl. Acad. Sci. U. S. A. 2001; PubMed Scopus Google have that two sites are in regulating the ability of ChREBP to the and to to with we have observed an increase in ChREBP-Mlx binding when from 293 expressing ChREBP and Mlx were with protein ChREBP and Mlx in to a functional to a increase in the reporter activity of containing a ChoRE in hepatocytes cotransfected with both ChREBP and Mlx. However, this increase was not observed. is that high levels of proteins in the induced are sufficient to the glucose Therefore, were in 293 cells, in the Mlx expression is C. D.E. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). In 293 cells, of either ChREBP or Mlx not induce transcription of ChoRE-containing reporter of ChREBP and Mlx to a induction in containing glucose-responsive not in those containing E that not respond to glucose. binding with functional we to ChREBP and Mlx a heteromeric that oligonucleotides containing functional ChoREs from lipogenic enzyme gene We that a of ChREBP and Mlx to sequences that respond to glucose and not to sequences that not respond to glucose. the of this evidence that ChREBP and Mlx the functional ChoRF, to and activates ChoREs in the promoters of lipogenic enzyme genes. In to G. F. A. A. 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PubMed Scopus (302) Google has proposed a role for in the activation of high glucose increased glucose metabolism in the to of was to a protein of is the to of ChREBP to the of the ability of ChREBP to to in the glucose activates protein kinase to of and of ChREBP to the this protein has been to the kinase activity of the enzyme M. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). This in increased levels and elevated of the of glucose at the of enzyme activation and gene transcription that is by this is activation by ChREBP and Mlx occurs in the 293 These are not as the critical that of glucose metabolism in the to to blood glucose levels. the it that a of the ChREBP in the in 293 due to levels of and protein kinase A activity. However, the binding observed with the or of ChREBP, in 293 cells, a of the ChREBP to in a and We have the ChREBP for its ability to in The of the is that this in hepatocytes in glucose. However, we that the ChREBP not ChoRE-containing it was capable of levels in the presence of high to and H. C. with we have that hepatocytes glucose with no not induce ChoRE-containing promoters Towle H.C. J. Biol. Chem. Full Text PDF PubMed Google Scholar, Towle H.C. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar). levels and it is that protein kinase A in to of protein kinase to to ChREBP Mlx high glucose We G. for with and for with the yeast two-hybrid
Stoeckman et al. (Thu,) studied this question.