中国药理学通报Issue(1)：55-59,5.DOI:10.3969/j.issn.1001-1978.2016.01.012
二甲双胍抑制 SREBP-1c 改善高脂诱导的骨骼肌胰岛素抵抗
Metformin ameliorates PA-induced skeletal muscle insulin resistance by suppressing SREBP-1c
摘要
Abstract
Aim Metformin has been the first-line oral agent for the treatment of type 2 diabetes. The results from preliminary studies suggested that sterol regulatory element binding protein-1c( SREBP-1c) inhibited the transcription of insulin receptor substrate-1 ( IRS-1), which plays a key role in PA-induced skeletal muscle insulin resistance. In the current study, we investiga-ted the role and mechanism of SREBP-1c in metformin ameliorating PA-induced skeletal muscle insulin resist-ance. Methods L6 cells were treated with metformin (1,10 mmol·L - 1 ) for 24h in 500 μmol·L - 1 PA-in-duced insulin-resistant state and then harvested for pro-tein and glucose uptake assay. Glucose uptake was performed by 2-NBDG method. The protein expression of SREBP-1c, FAS, p-IRS-1 ( Tyr608 / 612), IRS-1, p-AKT ( Ser473 ) and AKT was detected by western blot. The effects of metformin on SREBP-1c and IRS-1 gene transcription were assessed by a dual-luciferase reporter assay. CHIP assay was performed to examine the binding of SREBP-1c protein to the IRS-1 promoter region by metformin treatment. Results PA treatment decreased glucose uptake in L6 myotubes. The protein expression of SREBP-1c and its downstream molecule FAS was increased significantly after exposure to PA. By contrast, the proteins related to insulin signaling pathway including IRS-1, p-IRS-1( Tyr608 / 612) and p-AKT ( Ser473) / AKT were decreased significantly. Metformin increased glucose uptake in a dose-depend-ent manner compared to PA-cultured L6 cells. The SREBP-1c and FAS protein levels were decreased by metformin treatment. Correspondingly, p-IRS-1 (Tyr608 / 612), IRS-1, p-AKT(Ser473) / AKT protein levels were increased significantly. The results from dual-luciferase reporter assay indicated metformin sup-pressed SREBP-1c promoter activity and enhanced IRS-1 promoter. The results from CHIP assay showed that metformin decreased binding of SREBP-1c protein to the IRS-1 promoter region (about 30% ). Conclu-sion Metformin can improve PA-induced muscular in-sulin resistance by suppressing SREBP-1c.关键词
二甲双胍/固醇调节元件结合蛋白-1c/胰岛素受体底物-1/棕榈酸/骨骼肌细胞/胰岛素抵抗Key words
metformin/SREBP-1c/IRS-1/palmitate acid/skeletal muscle cell/insulin resistance分类
医药卫生引用本文复制引用
吴文君,汤孙寅炎,时俊锋,尹雯雯,曹殊,朱大龙,毕艳..二甲双胍抑制 SREBP-1c 改善高脂诱导的骨骼肌胰岛素抵抗[J].中国药理学通报,2016,(1):55-59,5.基金项目
国家自然科学基金资助项目(No 8127090681500630) （No 8127090681500630）
南京医科大学科技发展基金(No 2013NJMU155) （No 2013NJMU155）
