Targeting RalGAPα1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control
Targeting RalGAPα1 in skeletal muscle to simultaneously improve postprandial glucose and lipid control
复制标题
靶向骨骼肌中的 RalGAPα1，同时改善餐后血糖和血脂控制
DOI：
10.1126/sciadv.aav4116
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发表时间：
2019-04-01
期刊：
影响因子：
13.6
通讯作者：
Chen, Shuai
中科院分区：
文献类型：
--
作者：
Chen, Qiaoli;Rong, Ping;Chen, Shuai
胰岛素如何刺激餐后葡萄糖和长链脂肪酸（LCFAs）进入骨骼肌，以及这些事件在饮食诱导的肥胖中被抑制的机制尚不完全清楚。在这里，我们发现RalGAP α 1是肌肉胰岛素作用的关键调节因子，并控制葡萄糖和脂质稳态。高脂肪饮食增加了RalGAP α 1蛋白，但降低了骨骼肌中胰岛素反应性的Thr(735)-磷酸化。RalGAP α 1（Thr735Ala）突变破坏了胰岛素刺激的肌肉对葡萄糖和LCFAs的同化，并导致小鼠代谢综合征。相反，骨骼肌特异性缺失RalGAP α 1可改善餐后血糖和脂质控制。从机制上讲，这些RalGAP α 1突变通过RalA影响胰岛素反应性葡萄糖转运蛋白GLUT4和脂肪酸转位酶CD36的易位，从而影响葡萄糖和脂质稳态。这些数据表明RalGAP α 1是一个双重靶点，我们为此开发了一种肽阻断剂来改善肌肉胰岛素敏感性。我们的发现对对抗代谢紊乱的药物发现具有启示意义。
How insulin stimulates postprandial uptake of glucose and long-chain fatty acids (LCFAs) into skeletal muscle and the mechanisms by which these events are dampened in diet-induced obesity are incompletely understood. Here, we show that RalGAP alpha 1 is a critical regulator of muscle insulin action and governs both glucose and lipid homeostasis. A high-fat diet increased RalGAP alpha 1 protein but decreased its insulin-responsive Thr(735)-phospho-rylation in skeletal muscle. A RalGAP alpha 1(Thr735Ala) mutation impaired insulin-stimulated muscle assimilation of glucose and LCFAs and caused metabolic syndrome in mice. In contrast, skeletal muscle-specific deletion of RalGAP alpha 1 improved postprandial glucose and lipid control. Mechanistically, these mutations of RalGAP alpha 1 affected translocation of insulin-responsive glucose transporter GLUT4 and fatty acid translocase CD36 via RalA to affect glucose and lipid homeostasis. These data indicated RalGAP alpha 1 as a dual-purpose target, for which we developed a peptide-blockade for improving muscle insulin sensitivity. Our findings have implications for drug discovery to combat metabolic disorders.