Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription
Role for sterol regulatory element binding protein-1c activation in mediating skeletal muscle insulin resistance via repression of rat insulin receptor substrate-1 transcription
复制标题
甾醇调节元件结合蛋白-1c 激活通过抑制大鼠胰岛素受体底物-1 转录介导骨骼肌胰岛素抵抗的作用
DOI：
10.1007/s00125-013-3136-1
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发表时间：
2014-03-01
期刊：
影响因子：
8.2
通讯作者：
Zhu, Dalong
中科院分区：
文献类型：
--
作者：
Bi, Yan;Wu, Wenjun;Zhu, Dalong
目的/假设固醇调节元件结合蛋白-1c（SREBP-1c）是脂肪酸合成酶的主要调节因子，控制脂肪生成。IRS-1是骨骼肌中关键的胰岛素信号传导介质。本研究旨在探讨SREBP-1c在骨骼肌细胞IRS-1表达调控中的作用。将表达Srebp-1c（也称为Srebf 1）的腺病毒载体和针对Srebp-1c的小干扰RNA（siRNA）转染到L 6细胞中。通过荧光素酶报告分析，电泳迁移率变动分析和染色质免疫沉淀assay.ResultsWe发现，SREBP-1c的基因和蛋白质表达增加，而在PA处理的L 6细胞IRS-1的表达。SREBP-1c过量表达可剂量依赖性地降低IRS-1 mRNA和IRS-1蛋白的表达，并抑制由此产生的胰岛素信号传导，而Serbp-1csiRNA敲低SERBP-1c可阻断PA诱导的IRS-1表达下调。蛋白质-DNA相互作用研究表明，SREBP-1c能够结合到ratIrs-1启动子区，从而抑制其基因转录。特别重要的是，我们发现二甲双胍治疗downregulatedSREBP-1c启动子活性，降低特异性结合SREBP-1c到Irs-1启动子和upregulatedIrs-1启动子活性在PA培养的L 6 celles.Conclusions/interpretationOur数据表明，第一次，SREBP-1c激活参与骨骼肌胰岛素抵抗通过suppressingIrs-1转录的直接影响。这些发现意味着SREBP-1c可以作为胰岛素抵抗的有吸引力的治疗靶点。
Aims/hypothesisSterol 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.MethodsL6 muscle cells were treated with palmitic acid (PA) or metformin. Adenovirus vectors expressingSrebp-1c(also known asSrebf1) and small interfering RNA (siRNA) againstSrebp-1cwere transfected into the L6 cells. Protein–DNA interactions were assessed by luciferase reporter analysis, electrophoretic mobility shift assay and chromatin immunoprecipitation assay.ResultsWe 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 decreasedIrs-1mRNA and IRS-1 protein expression in a dose-dependent manner, and suppressed the resultant insulin signalling, whereas SERBP-1c knockdown bySerbp-1csiRNA blocked the downregulation of IRS-1 induced by PA. Protein–DNA interaction studies demonstrated that SREBP-1c was able to bind to the ratIrs-1promoter region, thereby repressing its gene transcription. Of particular importance, we found that metformin treatment downregulatedSrebp-1cpromoter activity, decreased the specific binding of SREBP-1c toIrs-1promoter and upregulatedIrs-1promoter activity in PA-cultured L6 cells.Conclusions/interpretationOur data indicate for the first time that SREBP-1c activation participates in skeletal muscle insulin resistance through a direct effect of suppressingIrs-1transcription. These findings imply that SREBP-1c could serve as an attractive therapeutic target for insulin resistance.