二甲双胍通过激活 AMPK 改善线粒体呼吸活动。,Cell Reports

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二甲双胍通过激活 AMPK 改善线粒体呼吸活动。
Cell Reports ( IF 7.5 ) Pub Date : 2019-11-05 , DOI: 10.1016/j.celrep.2019.09.070
Yu Wang ₁ , Hongying An ₂ , Ting Liu ₃ , Caolitao Qin ₂ , Hiromi Sesaki ₄ , Shaodong Guo ₅ , Sally Radovick ₆ , Mehboob Hussain ₇ , Akhil Maheshwari ₁ , Fredric E Wondisford ₆ , Brian O'Rourke ₃ , Ling He ₈

Affiliation

线粒体呼吸活动受损会导致 2 型糖尿病患者出现胰岛素抵抗。二甲双胍是一线抗糖尿病药物，其作用主要是改善患者的高血糖和胰岛素抵抗。然而，其作用机制仍不清楚。我们在此表明，药理学二甲双胍浓度会增加肝细胞中的线粒体呼吸、膜电位和 ATP 水平，临床相关的二甲双胍剂量会增加肝线粒体密度和复合物 1 活性，同时改善高脂饮食 (HFD) 喂养小鼠的高血糖。二甲双胍通过 5' AMP 激活蛋白激酶 (AMPK) 发挥作用，促进线粒体裂变，从而改善线粒体呼吸并恢复线粒体生命周期。此外，肝脏特异性敲除 AMPKα1/2 亚基的高脂饮食小鼠在接受二甲双胍治疗时表现出更高的血糖水平。我们的结果表明，二甲双胍激活 AMPK 可改善肥胖患者的线粒体呼吸和高血糖。我们还发现，超药理学浓度的二甲双胍会减少腺嘌呤核苷酸，导致线粒体呼吸停止。这些发现揭示了二甲双胍抗肿瘤作用的机制。

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Metformin Improves Mitochondrial Respiratory Activity through Activation of AMPK.

Impaired mitochondrial respiratory activity contributes to the development of insulin resistance in type 2 diabetes. Metformin, a first-line antidiabetic drug, functions mainly by improving patients' hyperglycemia and insulin resistance. However, its mechanism of action is still not well understood. We show here that pharmacological metformin concentration increases mitochondrial respiration, membrane potential, and ATP levels in hepatocytes and a clinically relevant metformin dose increases liver mitochondrial density and complex 1 activity along with improved hyperglycemia in high-fat- diet (HFD)-fed mice. Metformin, functioning through 5' AMP-activated protein kinase (AMPK), promotes mitochondrial fission to improve mitochondrial respiration and restore the mitochondrial life cycle. Furthermore, HFD-fed-mice with liver-specific knockout of AMPKα1/2 subunits exhibit higher blood glucose levels when treated with metformin. Our results demonstrate that activation of AMPK by metformin improves mitochondrial respiration and hyperglycemia in obesity. We also found that supra-pharmacological metformin concentrations reduce adenine nucleotides, resulting in the halt of mitochondrial respiration. These findings suggest a mechanism for metformin's anti-tumor effects.

更新日期：2019-11-05

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