Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders
Central role of E3 ubiquitin ligase MG53 in insulin resistance and metabolic disorders
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DOI：
10.1038/nature11834
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发表时间：
2013-02-21
期刊：
影响因子：
64.8
通讯作者：
Xiao, Rui-Ping
中科院分区：
文献类型：
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作者：
Song, Ruisheng;Peng, Wei;Xiao, Rui-Ping
胰岛素抵抗是各种代谢紊乱（包括肥胖和2型糖尿病）中存在的基本致病因素（1）。尽管骨骼肌占胰岛素刺激的葡萄糖处置的70-90%（2，3），但对肌肉胰岛素抵抗的机制知之甚少。在这里，我们在小鼠中显示，肌肉特异性Mitsugumin 53（MG 53;也称为TRIM 72）介导胰岛素受体和胰岛素受体底物1（IRS 1）的降解;当上调时，会导致代谢综合征，包括胰岛素抵抗，肥胖，高血压和血脂异常。MG 53表达在胰岛素抵抗模型中显著升高，并且MG 53过表达足以依次触发肌肉胰岛素抵抗和代谢综合征。相反，MG 53的消融通过保留胰岛素受体、IRS 1和胰岛素信号传导的完整性来预防饮食诱导的代谢综合征。从机制上讲，MG 53作为E3连接酶靶向胰岛素受体和IRS 1进行泛素依赖性降解，包括控制骨骼肌中胰岛素信号强度的中枢机制。这些发现将MG 53定义为治疗代谢紊乱和相关心血管并发症的新型治疗靶点。
Insulin resistance is a fundamental pathogenic factor present in various metabolic disorders including obesity and type 2 diabetes(1). Although skeletal muscle accounts for 70-90% of insulin-stimulated glucose disposal(2,3), the mechanism underlying muscle insulin resistance is poorly understood. Here we show in mice that muscle-specific mitsugumin 53 (MG53; also called TRIM72) mediates the degradation of the insulin receptor and insulin receptor substrate 1 (IRS1); and when upregulated, causes metabolic syndrome featuring insulin resistance, obesity, hypertension and dyslipidaemia. MG53 expression is markedly elevated in models of insulin resistance, and MG53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of MG53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, IRS1 and insulin signalling integrity. Mechanistically, MG53 acts as an E3 ligase targeting the insulin receptor and IRS1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. These findings define MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.