A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.
A MED13-dependent skeletal muscle gene program controls systemic glucose homeostasis and hepatic metabolism.
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DOI：
10.1101/gad.273128.115
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发表时间：
2016-02-15
影响因子：
10.5
通讯作者：
Olson EN
中科院分区：
文献类型：
--
作者：
Amoasii L;Holland W;Sanchez-Ortiz E;Baskin KK;Pearson M;Burgess SC;Nelson BR;Bassel-Duby R;Olson EN
Amoasii等人发现，小鼠中Mediator亚基MED13的骨骼肌特异性缺失通过激活增强肌肉葡萄糖摄取和储存为糖原的代谢基因程序来赋予对肝脂肪变性的抗性。MED13通过抑制核受体METRR1和MEF2转录因子抑制参与骨骼肌葡萄糖摄取和代谢的基因表达。介体复合体通过连接上游信号通路和基础转录机制来控制基因表达。然而，如何个别调解员亚基可能在不同的组织功能仍有待研究。通过骨骼肌特异性缺失小鼠的Mediator亚基MED13，我们发现了骨骼肌调节肝脏对高脂饮食反应的基因调控机制。小鼠骨骼肌特异性MED13缺失通过激活代谢基因程序增强肌肉葡萄糖摄取和储存为糖原而赋予对肝脂肪变性的抵抗力。骨骼肌内的胰岛素增敏作用降低了全身葡萄糖和胰岛素水平，与体重增加和肥胖无关，并防止了肝脏脂质蓄积。MED13通过抑制核受体METR1和MEF2转录因子抑制参与骨骼肌葡萄糖摄取和代谢的基因的表达。这些发现揭示了骨骼肌控制葡萄糖代谢和控制肝脏脂质积聚的基本分子机制。有趣的是，MED13在骨骼肌和心脏中发挥相反的代谢作用，突出了Mediator复合物的定制组织特异性功能。
Amoasii et al. found that skeletal muscle-specific deletion of the Mediator subunit MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. MED13 suppressed expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. The Mediator complex governs gene expression by linking upstream signaling pathways with the basal transcriptional machinery. However, how individual Mediator subunits may function in different tissues remains to be investigated. Through skeletal muscle-specific deletion of the Mediator subunit MED13 in mice, we discovered a gene regulatory mechanism by which skeletal muscle modulates the response of the liver to a high-fat diet. Skeletal muscle-specific deletion of MED13 in mice conferred resistance to hepatic steatosis by activating a metabolic gene program that enhances muscle glucose uptake and storage as glycogen. The consequent insulin-sensitizing effect within skeletal muscle lowered systemic glucose and insulin levels independently of weight gain and adiposity and prevented hepatic lipid accumulation. MED13 suppressed the expression of genes involved in glucose uptake and metabolism in skeletal muscle by inhibiting the nuclear receptor NURR1 and the MEF2 transcription factor. These findings reveal a fundamental molecular mechanism for the governance of glucose metabolism and the control of hepatic lipid accumulation by skeletal muscle. Intriguingly, MED13 exerts opposing metabolic actions in skeletal muscle and the heart, highlighting the customized, tissue-specific functions of the Mediator complex.