Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex.
Metformin Inhibits Hepatic mTORC1 Signaling via Dose-Dependent Mechanisms Involving AMPK and the TSC Complex.
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DOI：
10.1016/j.cmet.2016.12.009
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发表时间：
2017-02-07
期刊：
影响因子：
29
通讯作者：
Manning BD
中科院分区：
文献类型：
--
作者：
Howell JJ;Hellberg K;Turner M;Talbott G;Kolar MJ;Ross DS;Hoxhaj G;Saghatelian A;Shaw RJ;Manning BD
二甲双胍是治疗2型糖尿病处方最广泛的药物。然而，对于二甲双胍在其主要靶组织——肝脏中的生化途径和过程的全面影响的了解是有限的。二甲双胍的一个已确定的作用是降低细胞能量水平。腺苷酸活化蛋白激酶（AMPK）和雷帕霉素靶蛋白（mTOR）复合物1（mTORC1）是代谢的关键调节因子，它们在对细胞能量耗竭的急性反应中分别被激活和抑制。在此我们表明，二甲双胍强烈抑制小鼠肝脏组织和原代肝细胞中的mTORC1。通过小鼠遗传学研究，我们发现，在抑制肝脏mTORC1信号传导的最低二甲双胍浓度下，这种抑制依赖于AMPK和结节性硬化复合物（TSC）蛋白复合物（TSC复合物）。最后，我们表明二甲双胍在很大程度上以依赖其抑制mTORC1信号传导能力的方式深刻抑制肝细胞蛋白质合成。
Metformin is the most widely prescribed drug for the treatment of type-2 diabetes. However, knowledge of the full effects of metformin on biochemical pathways and processes in its primary target tissue, the liver, is limited. One established effect of metformin is to decrease cellular energy levels. The AMP-activated protein kinase (AMPK) and mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) are key regulators of metabolism that are respectively activated and inhibited in acute response to cellular energy depletion. Here we show that metformin robustly inhibits mTORC1 in mouse liver tissue and primary hepatocytes. Using mouse genetics, we find that at the lowest concentrations of metformin that inhibit hepatic mTORC1 signaling, this inhibition is dependent on AMPK and the tuberous sclerosis complex (TSC) protein complex (TSC complex). Finally, we show that metformin profoundly inhibits hepatocyte protein synthesis in a manner that is largely dependent on its ability to suppress mTORC1 signaling.