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[Effects of transcription factor sterol regulatory element binding protein-1c in palmitate acid-induced L6 cells insulin resistance and its mechanism].

AbstractOBJECTIVE:
Sterol regulatory element binding protein-1c (SREBP-1c) is a master regulator of fatty acid synthase and controls lipogenesis. And insulin receptor substrate-1 (IRS-1) is a key insulin signaling mediator in skeletal muscle. The present study was conducted to explore the mechanism of SREBP-1c in the regulation of IRS-1 in skeletal muscle cells and elucidate the role of SREBP-1c in high fat-induced skeletal muscle insulin resistance.
METHODS:
L6 cells differentiated into myotubes in differentiation medium with 2%FBS. An in vitro insulin resistant model in L6 myotubes was established by 500 µmol/L of palmitate acid (PA). SREBP-1c, p-IRS-1(Tyr608/612), IRS-1, p-AKT (Ser473) and AKT were detected by Western blot after incubating L6 myobutes with 500 µmol/L of PA for 0.5, 1, 3, 6, 12, 18 or 24 h.SREBP-1c, FAS and molecules related to insulin signaling pathway were detected by Western blot when L6 myotubes over-expressed SREBP-1c or after a treatment of liver X receptor (LXR) agonist (TO901317, 5 µmol/L). The regulatory effects of transcription factor SREBP-1c on promoter region of IRS-1 were assessed by dual-luciferase reporter assay.
RESULTS:
SREBP-1c protein expression increased significantly after 1-hour exposure to PA. The protein levels of p-IRS-1(Tyr608/612),IRS-1 and p-AKt (Ser473) decreased significantly after a 6-hour incubation of PA. However AKT protein levels were unaffected. The protein expressions of SREBP-1c and FAS were up-regulated by LXR agonist treatment versus controls. By contrast, LXR agonist treatment led to decreased expressions of IRS-1, p-IRS-1(Tyr608/612) and p-AKt (Ser473)/AKT proteins versus controls. The expressions of related proteins were similar to the observations made with LXR agonist intervention. The results of dual-luciferase reporter assay indicated that IRS-1 promoter activity was repressed significantly by SREBP-1c over-expression or TO901317 treatment whereas the dominant negative form of SREBP-1c (a mutant of Tyr320Ala lacking the ability of binding DNA) had no effect.
CONCLUSION:
SREBP-1c may suppress IRS-1 expression and the subsequent insulin signaling pathway. And it plays a key role in PA-induced insulin resistance of skeletal muscle.
AuthorsWenjun Wu, Yan Bi, Yinyan Tangsun, Wenwen Yin, Yingying Chen, Dalong Zhu
JournalZhonghua yi xue za zhi (Zhonghua Yi Xue Za Zhi) Vol. 95 Issue 8 Pg. 611-5 (Mar 03 2015) ISSN: 0376-2491 [Print] China
PMID25917039 (Publication Type: Journal Article)
Chemical References
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Palmitates
  • Sterol Regulatory Element Binding Protein 1
Topics
  • Cell Line
  • Insulin
  • Insulin Receptor Substrate Proteins
  • Insulin Resistance
  • Liver X Receptors
  • Orphan Nuclear Receptors
  • Palmitates
  • Promoter Regions, Genetic
  • Signal Transduction
  • Sterol Regulatory Element Binding Protein 1
  • Up-Regulation

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