Suppression of Rho-kinase 1 is responsible for insulin regulation of the AMPK/SREBP-1c pathway in skeletal muscle cells exposed to palmitate
Acta diabetologica(2017)
摘要
Aims Clinical and experimental data suggest that early insulin therapy could reduce lipotoxicity in subjects and animal models with type 2 diabetes mellitus. However, the underlying mechanisms need to be clarified. Sterol regulatory element-binding protein 1c (SREBP-1c), which is negatively regulated by AMP-activated protein kinase (AMPK), plays a critical role in lipotoxicity and insulin resistance in skeletal muscle cells. Here, we investigated the effect and molecular mechanism of insulin intervention on the AMPK/SREBP-1c pathway in skeletal muscle cells with chronic exposure to palmitic acid (PA). Methods Male C57BL/6 mice were fed with a high-fat diet for 12 weeks and were then treated with insulin, AMPK inhibitor, or metformin. L6 myotubes incubated with palmitic acid (PA) were treated with insulin or metformin. Dominant-negative AMPKα2 (DN-AMPKα2) lentivirus, AMPKα2 siRNA, or Rho-kinase 1 (ROCK1) siRNA were transfected into PA-treated L6 myotubes. Results We found that the ability of PA to stimulate SREBP-1c and inhibit AMPK was reversed by insulin in L6 cells. Moreover, DN-AMPKα2 lentivirus and AMPKα2 siRNA were transfected into PA-treated L6 myotubes, and the decrease in SREBP-1c expression caused by insulin was blocked by AMPK inhibition independent of the phosphatidylinositol-4,5-biphosphate-3-kinase (PI3K)/AKT pathway. The serine/threonine kinase Rho-kinase (ROCK) 1, a downstream effector of the small G protein RhoA, was activated by PA. Interestingly, knockdown of ROCK1 by siRNA blocked the downregulation of AMPK phosphorylation under PA-treated L6 myotubes, which indicated that ROCK1 mediated the effect of insulin action on AMPK. Conclusions Our study indicated that insulin reduced lipotoxicity via ROCK1 and then improved AMPK/SREBP-1c signaling in skeletal muscle under PA-induced insulin resistance.
更多查看译文
关键词
Rho-kinase 1,Insulin,AMPK,SREBP-1c,Skeletal muscle
AI 理解论文
溯源树
样例
![](https://originalfileserver.aminer.cn/sys/aminer/pubs/mrt_preview.jpeg)
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要