Key points are not available for this paper at this time.
Transcription of a number of genes involved in lipogenesis is stimulated by dietary carbohydrate in the mammalian liver. Both insulin and increased glucose metabolism have been proposed to be initiating signals for this process, but the pathways by which these effectors act to alter transcription have not been resolved. We have previously defined by electrophoretic mobility shift assay a factor in nuclear extracts from rat liver, designated the carbohydrate-responsive factor (Cho- RF), that binds to liver-type pyruvate kinase and S14 promoters at sites critical for regulation by carbohydrate. The sterol regulatory element binding protein-1c (SREBP-1c) has also emerged as a major transcription factor involved in this nutritional response. In this study, we examined the relationship between SREBP-1c and ChoRF in lipogenic gene induction. The two factors were found to possess distinct DNA binding specificities both in vitro and in hepatocytes. Reporter constructs containing binding sites for ChoRF were responsive to glucose but not directly to insulin. On the other hand, reporter constructs with an SREBP-1c site responded directly to insulin. The S14 gene possesses binding sites for both ChoRF and SREBP, and both sites were found to be functionally important for the response of this promoter to glucose and insulin in hepatocytes. Consequently, we propose that SREBP-1c and ChoRF are independent transcription factors that mediate signals generated by insulin and glucose, respectively. For many lipogenic enzyme genes, these two factors may provide an integrated signaling system to support the overall nutritional response to dietary carbohydrate. Transcription of a number of genes involved in lipogenesis is stimulated by dietary carbohydrate in the mammalian liver. Both insulin and increased glucose metabolism have been proposed to be initiating signals for this process, but the pathways by which these effectors act to alter transcription have not been resolved. We have previously defined by electrophoretic mobility shift assay a factor in nuclear extracts from rat liver, designated the carbohydrate-responsive factor (Cho- RF), that binds to liver-type pyruvate kinase and S14 promoters at sites critical for regulation by carbohydrate. The sterol regulatory element binding protein-1c (SREBP-1c) has also emerged as a major transcription factor involved in this nutritional response. In this study, we examined the relationship between SREBP-1c and ChoRF in lipogenic gene induction. The two factors were found to possess distinct DNA binding specificities both in vitro and in hepatocytes. Reporter constructs containing binding sites for ChoRF were responsive to glucose but not directly to insulin. On the other hand, reporter constructs with an SREBP-1c site responded directly to insulin. The S14 gene possesses binding sites for both ChoRF and SREBP, and both sites were found to be functionally important for the response of this promoter to glucose and insulin in hepatocytes. Consequently, we propose that SREBP-1c and ChoRF are independent transcription factors that mediate signals generated by insulin and glucose, respectively. For many lipogenic enzyme genes, these two factors may provide an integrated signaling system to support the overall nutritional response to dietary carbohydrate. fatty acid synthase liver-type pyruvate kinase carbohydrate response element carbohydrate-responsive factor sterol regulatory element-binding protein sterol regulatory element electrophoretic mobility shift assay polymerase chain reaction In mammals, the ingestion of carbohydrate in excess of that required to meet immediate energy needs triggers lipogenesis, the conversion of simple carbohydrates into triglycerides. Lipogenesis occurs predominantly in the liver and adipose tissue and its activation by carbohydrate diet is accompanied by the induction of many of the key enzymes involved in this metabolic conversion (for review see Refs.1Hillgartner F.B. Salati L.M. Goodridge A.G. Physiol. Rev. 1995; 75: 47-76Crossref PubMed Scopus (391) Google Scholar, 2Towle H.C. Kaytor E.N. Shih H.-M. Annu. Rev. Nutr. 1997; 17: 405-433Crossref PubMed Scopus (247) Google Scholar, 3Girard J. Ferre P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (301) Google Scholar). Among these are enzymes of glycolysis, such as pyruvate kinase; of fatty acid synthesis, such as acetyl CoA carboxylase and fatty acid synthase (FAS)1; and of fatty acid maturation and packaging, such as stearoyl CoA desaturase. The increased production of these “lipogenic” enzymes results from induction of their specific mRNAs and in most cases correlates with increased transcription of the corresponding genes. Two potential signaling pathways elicited in response to dietary carbohydrate could play a role in lipogenic enzyme induction. Increased insulin secretion by the β cell in response to elevated blood glucose could act as the primary signal. Alternatively, increased glucose metabolism itself might lead to alterations in gene expression. Attempts to sort out the respective roles of these pathways have been most effectively carried out in cultured primary hepatocytes. Treatment of hepatocytes with insulin and high glucose levels mimics the lipogenic response seen in the animal following dietary carbohydrate (4Decaux J.-F. Antoine B. Kahn A. J. Biol. PubMed Google Scholar). is to the response. Treatment of hepatocytes with insulin glucose the of the gene J. Biol. PubMed Google Scholar). of pyruvate kinase gene the other hand, is in glucose is induction of pyruvate kinase occurs in the of insulin B. Kahn A. J. Biol. PubMed Google Scholar). For most of the lipogenic enzyme genes, both insulin and glucose are required for the induction The signaling for the induction of lipogenic gene in response to glucose metabolism (for see 2Towle H.C. Kaytor E.N. Shih H.-M. Annu. Rev. Nutr. 1997; 17: 405-433Crossref PubMed Scopus (247) Google and 3Girard J. Ferre P. Foufelle F. Annu. Rev. Nutr. 1997; 17: 325-352Crossref PubMed Scopus (301) Google Scholar). Two genes, the liver-type pyruvate kinase and S14 genes, have been The S14 gene a nuclear is to play a regulatory role in lipogenesis (for review see PubMed Scopus Google Scholar). of the S14 and promoters in primary hepatocytes to the of a carbohydrate response element that is and for by glucose Kahn A. PubMed Scopus Google Scholar, H.C. J. Biol. PubMed Google Scholar, H.-M. H.C. J. Biol. PubMed Google Scholar, H.-M. H.C. J. Biol. 1995; PubMed Scopus Google Scholar). of two to the H.C. J. Biol. PubMed Scopus Google Scholar). of the the of a protein by that with but not with that to to glucose H.C. J. Biol. PubMed Scopus Google Scholar). The between binding and that this designated might be for signaling the The of the this is The of in the that a of the binds this site to mediate to Among this of SREBP-1c has emerged as a for as a transcription factor that genes enzymes involved in and (for see 1997; PubMed Scopus Google and J. Biol. Scopus Google Scholar). has and to be involved in genes of metabolism 1997; PubMed Scopus Google Scholar). SREBP-1c is in in lipogenesis such as liver and adipose P. Biol. PubMed Scopus Google Scholar, J. 1997; PubMed Scopus Google Scholar). The of SREBP-1c itself found to be increased by dietary carbohydrate in the liver and adipose a role for this factor in lipogenesis P. J. PubMed Scopus Google Scholar, A. PubMed Scopus Google Scholar, P. B. Ferre P. Foufelle F. Biol. PubMed Scopus Google Scholar). The of dietary carbohydrate were to a of insulin in hepatocytes P. B. Ferre P. Foufelle F. Biol. 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We that ChoRF is distinct from SREBP-1c and response lead to a in which both ChoRF activation by glucose and activation by insulin play roles in carbohydrate of gene expression. hepatocytes were from the as previously E.N. Shih H.-M. H.C. J. Biol. 1997; PubMed Scopus Google Scholar). an for were in with and glucose for were cultured in containing glucose for and for For in and were with containing glucose and insulin and cultured with in glucose in the in the of insulin. In these of to the has been to the of the in cultured hepatocytes H.-M. H.C. 1995; Google Scholar). of are as of the S14 and site in to glucose and insulin in hepatocytes. hepatocytes were with the rat S14 that from S14 in the site were cultured in glucose in the in the of insulin for is as the of with the of at glucose with insulin at the of with of from the rat and S14 genes, from these and and the are in containing these were with and sites at the and respectively. and with to a DNA with two in a containing two were into the site of a The is the with a The gene from to that by itself promoter between and Two of were from the E.N. Shih H.-M. H.C. J. Biol. 1997; PubMed Scopus Google with and and into The from the promoter previously H.C. J. Biol. PubMed Scopus Google and into and sites of of for of reporter sites of the are the binding site from the Shih H.-M. H.C. Biol. 1995; PubMed Scopus Google is in The is from the rat S14 E.N. Shih H.-M. H.C. J. Biol. 1997; PubMed Scopus Google and the is from the S14 H.C. J. Biol. PubMed Scopus Google Scholar). in a The sites of the are the binding site from the Shih H.-M. H.C. Biol. 1995; PubMed Scopus Google is in The is from the rat S14 E.N. Shih H.-M. H.C. J. Biol. 1997; PubMed Scopus Google and the is from the S14 H.C. J. Biol. PubMed Scopus Google Scholar). The site of the rat S14 gene generated by as previously H.C. J. Biol. PubMed Scopus Google Scholar). a site and to the rat were at the enzyme by and into in an at to of the S14 constructs were and rat S14 were with to into the The rat S14 from to were from the rat S14 the that a in the E.N. Shih H.-M. H.C. J. Biol. 1997; PubMed Scopus Google and into the site of the site rat The SREBP-1c Shih H.-M. H.C. Biol. 1995; PubMed Scopus Google into the J. Biol. PubMed Google for in primary hepatocytes. The the the with SREBP-1c containing of the site from and and into The the PubMed Scopus Google into site of for in primary hepatocytes. constructs were by DNA nuclear extracts were from that been a high carbohydrate diet for as previously H.-M. H.C. J. Biol. PubMed Google Scholar). The that between and for nuclear extracts from containing nuclear SREBP-1c were as by P. 17: PubMed Scopus Google Scholar). For this were with for and cultured for an to as previously H.C. J. Biol. PubMed Scopus Google Scholar). reaction of with of the from liver nuclear extracts of cell nuclear were of and of for with liver nuclear extracts and of with cell nuclear at for were to a and to to from and to nuclear for at to the of For a excess of with into the to the of SREBP-1c as the transcription factor for the nutritional response of lipogenic genes to carbohydrate SREBP-1c has been to to insulin a between insulin signaling pathways and P. J. PubMed Scopus Google Scholar, P. B. Ferre P. Foufelle F. Biol. PubMed Scopus Google Scholar). induction of most lipogenic enzyme genes both insulin and elevated glucose metabolism in the and of glucose have been found in hepatocytes Ferre P. Foufelle F. A. PubMed Scopus Google Scholar, Ferre P. Foufelle F. J. PubMed Scopus Google Scholar). the that potential might be by glucose, as by Ferre P. Foufelle F. A. PubMed Scopus Google the following reporter containing two of a to a promoter from the pyruvate kinase gene into primary hepatocytes with a for the nuclear of rat SREBP-1c were with high glucose for are to for glucose induction of S14 promoters in hepatocytes. of SREBP-1c in induction of from the reporter both in and high glucose, as in the of induction were between from and high glucose that the potential of SREBP-1c is not in the of high of the that might with the binding of the an a SREBP-1c in which its with the for this protein into hepatocytes with a promoter containing of the of the protein promoter but were found between and high glucose the that SREBP-1c is by signals generated by glucose metabolism in primary hepatocytes. We by that a of but not a protein designated with rat liver nuclear H.C. J. Biol. PubMed Scopus Google Scholar). Consequently, ChoRF to be for of glucose genes containing the such as S14 and Among the in that a a binding site for that ChoRF is not with the this In this liver nuclear were with a from the and the of to for the binding of the ChoRF were and with were to for ChoRF binding with with the of as a excess of On the other hand, an containing the to with ChoRF binding the of that the ChoRF is not to the SREBP-1c that SREBP-1c might be a of a ChoRF with other the of an to to the of ChoRF a the binding of SREBP-1c to an Attempts to SREBP-1c binding nuclear extracts were of its as by J. Biol. PubMed Google Scholar). this extracts were from that were with a the nuclear of the nuclear of a specific with the of the between SREBP-1c and the and to the of a the of the ChoRF the in the of SREBP-1c is not to be a of the ChoRF this we were in with with binding to its DNA the binding of to a the itself could for the binding of SREBP-1c to were to the SREBP-1c with the is that the rat S14 to with SREBP-1c for The rat S14 a binding site for factors Shih H.-M. H.C. Biol. 1995; PubMed Scopus Google Scholar). that the of the could lead to for the major promoter which also a but is for the site could for the SREBP-1c binding with to a to rat S14 not Consequently, the to for SREBP-1c binding not with the of containing to support a glucose response. a role for SREBP-1c in the glucose regulation of important to the of the in vitro binding in the of the For this the of SREBP-1c to constructs by a the reporter containing two of the of this into hepatocytes a of that with the of a a nuclear of SREBP-1c in a in reporter induction of by SREBP-1c by of and a induction of with of in by of In to the results seen with a of reporter SREBP-1c with constructs containing two of the induction of by to of SREBP-1c that SREBP-1c has a for the for the is that the by the not by of SREBP-1c in primary which is with in in Kahn A. Google Scholar). In the induction of by SREBP-1c correlates with SREBP-1c binding examined in in which SREBP-1c the for the rat S14 and the for the rat The constructs that were for their activation by SREBP-1c were for their to to glucose in primary hepatocytes. in constructs were at by high The induction by high The of high glucose are directly with the of SREBP-1c in B. between the induction by glucose with that by is that SREBP-1c is the factor that and glucose signaling in hepatocytes. The the distinct of ChoRF and to that both factors may both be involved in the of carbohydrate lipogenic gene induction. We that is involved in insulin and ChoRF in the of this we reporter constructs that binding sites for ChoRF for their to glucose insulin. two of the rat S14 to a The other a of the rat promoter between and to the of the gene has been to to and with two sites to mediate to the of insulin and glucose H.C. J. Biol. PubMed Scopus Google Scholar). into primary and were in glucose with insulin. in the responded to a in glucose between and in the of insulin in the that in these in the cell following of hepatocytes from to support this glucose response. this to insulin glucose levels were at that insulin is not required as a for the carbohydrate response the The promoter of the in high glucose insulin that in the of both high glucose and insulin. is to be by insulin and critical for glucose the of might in the response to glucose insulin is a with the reporter the of reporter gene at glucose in the of insulin of also increased reporter gene at glucose is in the in an by the regulatory protein 1997; PubMed Scopus Google Scholar). The of the of regulatory and the excess to the glucose for and promoter from the not seen at glucose, is results support the that the is a The results with the site in are In this insulin promoter at glucose at glucose is glucose has in the of insulin and a in its of in insulin the of the to to the site in the promoter to be predominantly an that glucose and insulin may distinct transcription factors to mediate their following carbohydrate We previously that in the between and of the rat S14 gene promoter the of this promoter to support a response to glucose in cultured in the of insulin E.N. Shih H.-M. H.C. J. Biol. 1997; PubMed Scopus Google Scholar). J. Biol. PubMed Scopus Google the of an site in the S14 promoter between and and that this site for the of by fatty the that both of these binding sites might be important for the regulation of S14 gene by carbohydrate S14 been to to increased glucose levels in primary J. Biol. 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The ChoRF with a of and that glucose in but not with of these that were Consequently, we proposed that ChoRF for the induction of and are a high carbohydrate diet and that might also mediate the induction of many other lipogenic enzyme genes following the nutritional In this the role of insulin to be in of elevated glucose In is insulin and its is critical for the of the to to elevated glucose levels J. Biol. PubMed Google Scholar, Kahn A. J. PubMed Scopus Google Scholar). with this SREBP-1c emerged as a major factor production of lipogenic SREBP-1c gene found to in response to insulin in hepatocytes Ferre P. Foufelle F. A. PubMed Scopus Google Scholar, Ferre P. Foufelle F. J. PubMed Scopus Google Scholar). In sites were the promoter of a number of lipogenic genes, and J. Biol. PubMed Scopus Google Scholar, J. J. Biol. 1997; PubMed Scopus Google Scholar, J. Biol. PubMed Scopus Google Scholar). SREBP-1c in liver elevated lipogenesis and the of lipogenic enzyme with carbohydrate J. Biol. PubMed Scopus Google Scholar). a of the gene were in their nutritional response to high carbohydrate diet F. J. Biol. PubMed Scopus Google Scholar). these results that is a major transcription factor lipogenic genes in response to carbohydrate and the that ChoRF might be to Consequently, we the to this The from the support a in which ChoRF and SREBP-1c are transcription factors that both play a role in the induction of lipogenic enzyme genes and are for signals generated by glucose and respectively. both to the the binding of the two factors are ChoRF binding not by a and binding not by most ChoRF binding two to the H.C. J. Biol. PubMed Scopus Google Scholar). two are found in an with a with and the has been to be critical to ChoRF binding and H.-M. H.C. J. Biol. 1995; PubMed Scopus Google Scholar). ChoRF not directly to with a in which the sites are in an between to the in Shih H.-M. H.C. 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PubMed Scopus Google Scholar). these that ChoRF is a distinct from this we propose the following for the induction of lipogenic genes by high carbohydrate diet blood glucose levels following a secretion of insulin from the β the insulin and to the induction of SREBP-1c and binds to the promoter of many lipogenic enzyme genes to increased glucose levels following a carbohydrate lead to elevated in the is in by the of the high which in the to be increased with glucose is by SREBP-1c Ferre P. Foufelle F. A. PubMed Scopus Google the two pathways are to Increased glucose metabolism in the results in the of an that the ChoRF binds to a distinct site from SREBP-1c the promoter of many lipogenic enzyme genes to their expression. In many ChoRF may with to transcription of lipogenic enzyme genes and lipogenesis in the liver. In support of this we have that the S14 gene is directly by in to its by by in which were to possess levels of S14 insulin its A. PubMed Scopus Google Scholar). is to of insulin from of glucose metabolism in such We have in this that S14 gene is and by glucose and insulin. Two regulatory the at and an site at are required for the activation of The critical roles of these two sites were by that both the S14 promoter with both sites is of to glucose insulin. of the site in a in the of the S14 promoter to to with the role of in insulin a that an site from the promoter also responded to insulin. The site of the S14 promoter the to to glucose, but the overall of this with the the roles of insulin in of glucose metabolism as as its of the site of the S14 the other hand, are in their to to glucose but most of the insulin that ChoRF is a glucose signal. The of the two to to glucose in the of insulin also this the glucose could for this the S14 promoter might of to a glucose response. 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We found that this a site for binding of ChoRF and that this site is in a response to and may be in a to S14 a activation by both ChoRF and this may also be for other lipogenic genes is by the of these are with to their to to carbohydrate most of the lipogenic genes a of induction in the of F. J. Biol. PubMed Scopus Google Scholar). For is in the S14 levels that factor in to is of nutritional to carbohydrate proposed by P. B. Ferre P. Foufelle F. Biol. PubMed Scopus Google Scholar, Ferre P. Foufelle F. A. PubMed Scopus Google that SREBP-1c is by insulin at the of transcription and by glucose to mediate carbohydrate induction of lipogenic genes. the that an for the nuclear of SREBP-1c of effectively in cultured in high glucose in in alterations in SREBP-1c protein levels were found in hepatocytes to glucose levels Ferre P. Foufelle F. A. PubMed Scopus Google Scholar, Ferre P. Foufelle F. J. PubMed Scopus Google Scholar). in glucose not the potential of reporter this of might for the between these in a by Ferre P. Foufelle F. A. PubMed Scopus Google were levels from genes. and ChoRF as by the levels could be for by the regulation of these gene by and ChoRF stimulated by the high glucose from the that glucose not to transcription but also to levels for many lipogenic enzyme genes H.C. Kaytor E.N. Shih H.-M. Annu. Rev. Nutr. 1997; 17: 405-433Crossref PubMed Scopus (247) Google Scholar). in levels in their study, Ferre P. Foufelle F. A. PubMed Scopus Google could have been the of of transcription and glucose of In the at the of not be a of the gene an response to a carbohydrate diet in the induction of of lipogenic enzyme gene a role of in the nutritional induction F. J. Biol. 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PubMed Scopus Google Scholar). support a role for in the nutritional of lipogenic enzyme genes. the that of could gene and increased glucose metabolism be In as in of in hepatocytes in elevated promoter from a containing a site at glucose the of a role of in regulation of lipogenic enzyme gene by carbohydrate the of a site that the of the promoter to to insulin most of the lipogenic enzyme genes are by both ChoRF and to S14 and might be the for this is that this that lipogenesis is not in the liver both signals from insulin and glucose metabolism are in is that this system to provide regulation the levels of gene and their by effectors of the lipogenic In this is to that fatty which to lipogenesis, mediate their by of nuclear SREBP-1c J. Biol. PubMed Scopus Google Scholar, J. J. Biol. PubMed Scopus Google Scholar, F. J. Biol. PubMed Scopus Google Scholar). On the other hand, of lipogenic enzyme gene production occurs at in by of and of the ChoRF these two factors are to in levels of production for the of lipogenic enzyme genes. We of for the of and for the containing SREBP-1c
Koo et al. (Thu,) studied this question.