Insulin and Sterol-regulatory Element-binding Protein-1c (SREBP-1C) Regulation of Gene Expression in 3T3-L1 Adipocytes

Abstract

We evaluated the hypothesis of sterol-regulatory element-binding protein (SREBP)-1c being a general mediator of the transcriptional effects of insulin, with a focus on adipocytes, in which insulin profoundly influences specific gene expression. Using real time quantitative reverse transcriptase-PCR to monitor changes in the expression of about 50 genes that cover a wide range of adipocyte functions, we have compared the impact of insulin treatment with that of adenoviral overexpression of either dominant positive or dominant negative SREBP-1c mutants in 3T3-L1 adipocytes. As expected, insulin up-regulated, dominant positive stimulated, and dominant negative decreased previously characterized direct SREBP targets (FAS, SCD-1, and low density lipoprotein receptor). We also identified three novel SREBP-1c transcriptional targets in adipocytes, which were confirmed by run-on assays: plasminogen activator inhibitor 1, CCAAT/enhancer-binding protein δ (C/EBPδ), and C/EBPβ. Because most insulin-regulated genes were also modulated by SREBP-1c mutants, our data establish that 1) SREBP-1c is an important mediator of insulin transcriptional effects in adipocytes, and 2) C/EBPβ is under the direct control of SREBP-1c, as demonstrated by the ability of SREBP-1c to activate the transcription from C/EBPβ promoter through canonical SREBP binding sites. Thus, some of the effects of insulin and/or SREBP-1c in mature fat cells might require C/EBPβ or C/EBPδ as transcriptional relays. We evaluated the hypothesis of sterol-regulatory element-binding protein (SREBP)-1c being a general mediator of the transcriptional effects of insulin, with a focus on adipocytes, in which insulin profoundly influences specific gene expression. Using real time quantitative reverse transcriptase-PCR to monitor changes in the expression of about 50 genes that cover a wide range of adipocyte functions, we have compared the impact of insulin treatment with that of adenoviral overexpression of either dominant positive or dominant negative SREBP-1c mutants in 3T3-L1 adipocytes. As expected, insulin up-regulated, dominant positive stimulated, and dominant negative decreased previously characterized direct SREBP targets (FAS, SCD-1, and low density lipoprotein receptor). We also identified three novel SREBP-1c transcriptional targets in adipocytes, which were confirmed by run-on assays: plasminogen activator inhibitor 1, CCAAT/enhancer-binding protein δ (C/EBPδ), and C/EBPβ. Because most insulin-regulated genes were also modulated by SREBP-1c mutants, our data establish that 1) SREBP-1c is an important mediator of insulin transcriptional effects in adipocytes, and 2) C/EBPβ is under the direct control of SREBP-1c, as demonstrated by the ability of SREBP-1c to activate the transcription from C/EBPβ promoter through canonical SREBP binding sites. Thus, some of the effects of insulin and/or SREBP-1c in mature fat cells might require C/EBPβ or C/EBPδ as transcriptional relays. Insulin is the main anabolic hormone in mammals and exerts its effects in liver, adipose tissue, and skeletal and cardiac muscle via the insulin receptor (for a review, see Ref. 1Virkamaki A. Ueki K. Kahn C.R. J. Clin. Invest. 1999; 103: 931-943Crossref PubMed Scopus (715) Google Scholar). The cellular mechanism underlying its action on carbohydrate, lipid, and protein metabolism has been the center of major interest for many years. Active research has led to the identification of the major steps of the insulin signal transduction pathway. These include a family of soluble scaffolding molecules, known as insulin receptor substrates, which initiate downstream signaling cascades involving the phosphatidylinositol 3-kinase/Akt pathway and the mitogen-activated protein kinase pathway (for reviews, see Refs. 1Virkamaki A. Ueki K. Kahn C.R. J. Clin. Invest. 1999; 103: 931-943Crossref PubMed Scopus (715) Google Scholar and 2Whitehead J.P. Clark S.F. Urso B. James D.E. Curr. Opin. Cell Biol. 2000; 12: 222-228Crossref PubMed Scopus (100) Google Scholar). In this cascade, rapid changes in the state of protein phosphorylation ultimately mediate many important actions of insulin (e.g. glucose transport, glycogen synthesis, lipogenesis, and antilipolysis). It is also well known that, alongside these rapid nongenomic effects, important changes in gene expression play critical roles in insulin action in insulin-sensitive tissues (3O'Brien R.M. Granner D.K. Physiol. Rev. 1996; 76: 1109-1161Crossref PubMed Scopus (434) Google Scholar). The transcriptional effects of insulin and the mechanisms by which insulin can relay signal to the nucleus have remained largely unknown until recently. As described (4Flier J.S. Hollenberg A.N. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 14191-14192Crossref PubMed Scopus (34) Google Scholar), new light was shed by the identification of SREBP-1c 1The abbreviations used are: SREBP, sterol-regulatory element-binding protein; Ad, adenovirus; MOI, multiplicity of infection (i.e. plaque-forming units per cell); DN, dominant negative; DP, dominant positive; SRE, sterol-regulatory element; HMG, hydroxymethylglutaryl; PPARγ, peroxisome proliferator-activated receptor γ; C/EBP, CCAAT/enhancer-binding protein; RT-PCR, reverse transcriptase-PCR; LDL, low density lipoprotein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PKB, protein kinase B; GFP, green fluorescent protein; PAI, plasminogen activator inhibitor. 1The abbreviations used are: SREBP, sterol-regulatory element-binding protein; Ad, adenovirus; MOI, multiplicity of infection (i.e. plaque-forming units per cell); DN, dominant negative; DP, dominant positive; SRE, sterol-regulatory element; HMG, hydroxymethylglutaryl; PPARγ, peroxisome proliferator-activated receptor γ; C/EBP, CCAAT/enhancer-binding protein; RT-PCR, reverse transcriptase-PCR; LDL, low density lipoprotein; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; PKB, protein kinase B; GFP, green fluorescent protein; PAI, plasminogen activator inhibitor. as a transcription factor capable of mediating some of the effects of the hormone on previously identified insulin target genes. Indeed, SREBP-1c was shown not only to regulate the expression of key genes of glucose, fatty acid, and triglyceride metabolism in fibroblasts, adipocytes, hepatocytes, and the livers of transgenic mice (5Kim J.B. Spiegelman B.M. Genes Dev. 1996; 10: 1096-1107Crossref PubMed Scopus (824) Google Scholar, 6Shimano H. Horton J.D. Hammer R.E. Shimomura I. Brown M.S. Goldstein J.L. J. Clin. Invest. 1996; 98: 1575-1584Crossref PubMed Scopus (693) Google Scholar, 7Shimomura I. Bashmakov Y. Ikemoto S. Horton J.D. Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 13656-13661Crossref PubMed Scopus (614) Google Scholar) but also to be able to substitute to insulin in inducing transcription of known insulin target genes like glucokinase or FAS in hepatocytes (8Foretz M. Guichard C. Ferre P. Foufelle F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12737-12742Crossref PubMed Scopus (590) Google Scholar). SREBP-1c is particularly in the adipose and the liver, of which insulin-sensitive and a expression compared with the the SREBP that is by a gene M.S. Goldstein J.L. PubMed Scopus Google Scholar). In with expression and SREBP-1c and can also be in by ability to target genes. Indeed, SREBP-1c and functions, being for genes in in Ref. J. Biol. 2000; PubMed Scopus Google Scholar), SREBP-1c actions on and glucose these SREBP-1c as a to be a general mediator of the actions of insulin via the of gene expression. The of the was to this hypothesis with a focus on adipocytes, in which specific gene expression is profoundly by In the of the adipose transcription that play roles ultimately the adipocyte gene expression these is SREBP-1c, known also as P. J.B. Spiegelman B.M. Biol. PubMed Scopus Google a of the family of transcription important adipocyte transcriptional include the fatty receptor peroxisome proliferator-activated receptor and of the family of binding in Ref. P. Spiegelman B.M. Genes Dev. 2000; Google Scholar). In C/EBPβ and by can initiate a transcriptional that in the of and and the of the In this we have used mature 3T3-L1 to the impact of the overexpression of SREBP-1c either dominant positive or dominant on a of 50 genes. The were to cover a of of key fat as glucose transcription and that genes that were by the dominant positive and by dominant negative SREBP-1c were also by insulin, that SREBP-1c is a major factor underlying the transcriptional of we that SREBP-1c insulin action on some adipocyte as and the and δ which were known as insulin-sensitive but previously as SREBP-1c we that SREBP-1c can the C/EBPβ promoter through canonical SREBP binding sites. the insulin of the C/EBPβ Thus, this the of an in and that a transcriptional might be by SREBP-1c to mediate insulin effects on adipocyte gene The the dominant positive of SREBP-1c, DP, was as previously described (8Foretz M. Guichard C. Ferre P. Foufelle F. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 12737-12742Crossref PubMed Scopus (590) Google Scholar) with in the the green fluorescent protein S. J. B. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar). The the dominant negative of SREBP-1c, DN, was described P. Foufelle F. Ferre P. I. J. Biol. PubMed Scopus Google Scholar). and were under control of a The the major promoter with gene was used as The adenoviral were in the by density and until The of infection in 3T3-L1 was by expression a of SREBP target gene expression were also to and from to were were with with insulin with insulin and with 3T3-L1 cells were in and in an of in with glucose, units of per of cells were with a in insulin and from were in with insulin have as by cells were for in a of glucose, fatty in the or in the of insulin and for an of with the was as described S. B. B. J. J. Biol. PubMed Google Scholar). was from of in and reverse The of was either or time quantitative for the genes described in were with 50 of reverse in of with a of and in a of the in an is by to Because we used in of for real time quantitative RT-PCR, was important to that was not by from reverse and/or from with reverse were also on to that a of the was of reverse to were and a was by as a of reverse the of which was used for the of Scholar). were used to for in the of The for as control was of the of the gene and that of the gene in cells and control cells the of Scholar). expression of a control was used as was the as The of insulin was by in the with insulin and that in the with insulin the of by with insulin and the with insulin and the of by with insulin and the with insulin of were in I. In a expression genes be on that were to The were to Ref. of Scholar and were an of as The of expression genes of a family (e.g. for the three was as of and C/EBPδ in the of insulin were and Using the these be as and C/EBPβ as C/EBPβ C/EBPδ It be that the expression of the and C/EBPδ was and of the genes in key of adipose abbreviations of the or and to of the and in a new The abbreviations of the or and to of the and 3T3-L1 cells were with insulin or were with the the SREBP-1c were as previously described Ferre P. I. J. Biol. PubMed Scopus Google Scholar) and were with for were by the of and and was by were for with on were to and was with an promoter of the C/EBPβ in of the in the has been described M. C. Biol. PubMed Google Scholar). this a of was from to to and to to the transcription on sterol-regulatory in the promoter were the as by the The of the were the and for the In the of the was by the by as in the in were the with a of of a promoter of as an and 50 of expression an of the SREBP-1c transcription factor J.B. Spiegelman B.M. Biol. Scopus Google Scholar). The of was in by gene were and data were to 3T3-L1 cells were in and insulin for and by as described previously for mature M. J. Biol. PubMed Scopus Google Scholar). cells in were in the of of promoter and of were in in the or of gene were were from 3T3-L1 as described previously M. J. Biol. PubMed Scopus Google Scholar) and used for with a C/EBPβ of real time for a gene were as from the in the with insulin was by of by In were by of was as the of As a to the impact of changes in SREBP-1c in 3T3-L1 and its with gene expression we the ability of insulin to expression in these In with J.B. P. M. Spiegelman B.M. J. Clin. Invest. PubMed Scopus Google Scholar), we a of insulin on SREBP-1c its by The of insulin was to the SREBP-1c with in or were in livers of I. Bashmakov Y. Ikemoto S. Horton J.D. Brown M.S. Goldstein J.L. Proc. Natl. Acad. Sci. U. S. A. 1999; 96: 13656-13661Crossref PubMed Scopus (614) Google Scholar) and in hepatocytes M. C. I. P. Guichard C. Spiegelman B. J.B. Ferre P. Foufelle F. Biol. 1999; PubMed Scopus Google Scholar). Thus, insulin targets SREBP-1c in adipocytes. It to be the of the hormone in adipose in and in insulin-sensitive tissues (i.e. cardiac and shown that insulin SREBP-1c, we the to expression of SREBP-1c mutants or adenoviral infection of 3T3-L1 adipocytes. DP, which GFP, for transduction of 3T3-L1 with were of was with an of the state of were by real time to target SREBP-1c, or expression as well as or of see for was used as control and effects on gene the that the infection of with of of SREBP-1c dominant negative or as expected, a in expression in adipocytes. Because we that the of and SREBP-1c were not by or the in infection was for by an in the expression of the As shown in expression by in cells with the of and was to a the of was confirmed by with an that a in SREBP protein in from cells with not that transcriptional was in with the the or SREBP-1c mutants, we the state of known SREBP target genes as FAS (5Kim J.B. Spiegelman B.M. Genes Dev. 1996; 10: 1096-1107Crossref PubMed Scopus (824) Google Scholar, P. Foufelle F. Ferre P. I. J. Biol. PubMed Scopus Google J. Biol. PubMed Scopus Google Scholar), D.E. J.B. Spiegelman B.M. J. Biol. PubMed Scopus Google Scholar), and receptor C. J. Goldstein J. Brown M.S. PubMed Scopus Google Scholar). that of the expression of SCD-1, and receptor genes The of SCD-1, and receptor gene expression plaque-forming and a was the plaque-forming being The FAS and were with to that of the which was only well with the ability of SREBP-1c to in to in J.D. Shimomura I. Brown M.S. Hammer R.E. Goldstein J.L. H. J. Clin. Invest. PubMed Google Scholar, Brown M.S. Goldstein J.L. J. Biol. PubMed Scopus Google Scholar) in Ref. J. Biol. 2000; PubMed Scopus Google Scholar). In cells were with of We as expected, a in the state of SCD-1, and receptor The changes in cells were of in cells the the dominant negative SREBP-1c transcriptional by SREBP-1c (5Kim J.B. Spiegelman B.M. Genes Dev. 1996; 10: 1096-1107Crossref PubMed Scopus (824) Google Scholar), is that expression might not to transcriptional of these genes in to SREBP transcription as or D.E. J.B. Spiegelman B.M. J. Biol. PubMed Scopus Google Scholar, Proc. Natl. Acad. Sci. U. S. 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H. PubMed Scopus Google Scholar) and the transcription on the we identified for SREBP binding in the promoter to the transcription and the These the identified in the that might be in SREBP-1c of the C/EBPβ 50 of these we also a binding the of which was shown to be for transcriptional by SREBP-1c J. Biol. 2000; PubMed Scopus Google Scholar). that the identified on the C/EBPβ promoter might be the of in which in these have been The of the the ability of SREBP-1c to the C/EBPβ the the of the promoter was the was In in a a of and by SREBP-1c be demonstrated that SREBP-1c of the C/EBPβ promoter on the of identified and a of the establish the direct control of C/EBPβ promoter by SREBP-1c and by insulin, we the of the of the in C/EBPβ we used and 3T3-L1 and we in that the promoter to the of insulin in the by a of the We that the insulin was but of low not a with the of run-on also that the of insulin is cells were with promoter in or of the binding sites. that these for the insulin of the C/EBPβ these establish that SREBP-1c is able to the C/EBPβ promoter through canonical binding that with the of the C/EBPβ as a new direct transcriptional target of SREBP-1c and that the of insulin on C/EBPβ gene expression was through a direct transcriptional control of SREBP-1c the promoter we SREBP-1c and insulin C/EBPβ the of of C/EBPβ protein in from 3T3-L1 to insulin for or with the protein from the C/EBPβ a and a dominant negative that the of the In with the of P. 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Biol. PubMed Scopus Google Scholar) in that on the of the gene in the SREBP-1c was in that has not been by the data in to that C/EBPβ might be an important relay for the transcriptional effects of Thus, a main in this is the of a direct SREBP-1c and C/EBPβ. a by J. Biol. PubMed Scopus Google Scholar) for the of a demonstrated that the of C/EBPβ the on for that C/EBPβ might be in the of by the of The been for SREBP-1c by J.B. M. Spiegelman B.M. Proc. Natl. Acad. Sci. U. S. A. PubMed Scopus Google Scholar), that control the adipocyte of In this the which that C/EBPβ expression is by SREBP-1c, might SREBP-1c and C/EBPβ a ability to activate in the mature SREBP-1c can our that some mechanisms might a transcriptional relay through C/EBPβ. might be particularly in mediating the effects of insulin and in on the of the insulin-sensitive state that the adipocyte We Foufelle for the SREBP-1c and and for the and used in run-on