title: Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription.
abstract: OBJECTIVE
  Sterol regulatory element binding protein-1c (SREBP-1c) is a master regulator of fatty acid synthase and controls lipogenesis. IRS-1 is the key insulin signalling mediator in skeletal muscle. In the present study, we investigated the role of SREBP-1c in the regulation of IRS-1 in skeletal muscle cells.
  
  
  METHODS
  L6 muscle cells were treated with palmitic acid (PA) or metformin. Adenovirus vectors expressing Srebp-1c (also known as Srebf1) and small interfering RNA (siRNA) against Srebp-1c were transfected into the L6 cells. Protein-DNA interactions were assessed by luciferase reporter analysis, electrophoretic mobility shift assay and chromatin immunoprecipitation assay.
  
  
  RESULTS
  We found that both gene and protein expression of SREBP-1c was increased in contrast to IRS-1 expression in PA-treated L6 cells. SREBP-1c overproduction decreased Irs-1 mRNA and IRS-1 protein expression in a dose-dependent manner, and suppressed the resultant insulin signalling, whereas SERBP-1c knockdown by Serbp-1c siRNA blocked the downregulation of IRS-1 induced by PA. Protein-DNA interaction studies demonstrated that SREBP-1c was able to bind to the rat Irs-1 promoter region, thereby repressing its gene transcription. Of particular importance, we found that metformin treatment downregulated Srebp-1c promoter activity, decreased the specific binding of SREBP-1c to Irs-1 promoter and upregulated Irs-1 promoter activity in PA-cultured L6 cells.
  
  
  CONCLUSIONS
  Our data indicate for the first time that SREBP-1c activation participates in skeletal muscle insulin resistance through a direct effect of suppressing Irs-1 transcription. These findings imply that SREBP-1c could serve as an attractive therapeutic target for insulin resistance.
authors.affiliation: Department of Endocrinology, Drum Tower hospital affiliated to Nanjing University Medical School, No321 Zhongshan Road, Nanjing, 210008, People's Republic of China, biyan@nju.edu.cn.
authors.forename: Yan
authors.initials: Y
authors.lastname: Bi
authors.forename: Wenjun
authors.initials: W
authors.lastname: Wu
authors.forename: Junfeng
authors.initials: J
authors.lastname: Shi
authors.forename: Hua
authors.initials: H
authors.lastname: Liang
authors.forename: Wenwen
authors.initials: W
authors.lastname: Yin
authors.forename: Yingying
authors.initials: Y
authors.lastname: Chen
authors.forename: Sunyinyan
authors.initials: S
authors.lastname: Tang
authors.forename: Shu
authors.initials: S
authors.lastname: Cao
authors.forename: Mengyin
authors.initials: M
authors.lastname: Cai
authors.forename: Shanmei
authors.initials: S
authors.lastname: Shen
authors.forename: Qian
authors.initials: Q
authors.lastname: Gao
authors.forename: Jianping
authors.initials: J
authors.lastname: Weng
authors.forename: Dalong
authors.initials: D
authors.lastname: Zhu
mesh_terms: D000256:Adenoviridae; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D059305:Diet, High-Fat; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism*; D007333:Insulin Resistance; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008687:Metformin / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000187:drug effects / Q000378:metabolism*; D015533:Transcriptional Activation
chemical_list: D007004:Hypoglycemic Agents; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; D051780:Sterol Regulatory Element Binding Protein 1; D008687:Metformin