Ragulator-AXIN复合体在Metformin-AMPK通路中的作用

Metformin is the most widely used drug for treating type 2 diabetes. Cancer incidence is reported to be much reduced among diabetic patients using the drug. The master energy sensor AMPK is activated during metformin treatment and is critical for pharmaceutical effects of the drug. However, how AMPK is activated by metformin remains elusive. We have reported that Ragulator (a pentamer of LAMTOR1-5) and AXIN are required for AMPK activation under energy stress. In this process, Ragulator triggers the formation of Ragulator-AXIN/LKB1-AMPK complex on lysosome and the complex formation is a prerequisite of AMPK activation. Our unpublished results further show that in AXIN- or LAMTOR1-deficient MEFs or mice livers, metformin fails to activate AMPK. In addition, metformin elicits lysosomal translocation of AXIN, leading to the accumulation of the Ragulator-AXIN/LKB1-AMPK complex on the surface of lysosome. These results indicate that metformin relies on the Ragulator-AXIN/LKB1-AMPK axis. Based on the preliminary data, we propose to investigate the roles of Ragulator and AXIN played in AMPK activation upon metformin treatment, and to explore the physiological significance of deficiency of AXIN or Ragulator with relation to metformin treatment. The proposed work will depict the panoramic and detailed pathway of metformin-AMPK, and make a major contribution to the understanding of the mechanisms for the pharmacological action of metformin, ultimately providing new therapeutic avenues for the prevention and treatment of type 2 diabetes.

Metformin（二甲双胍）是使用最为广泛的治疗II型糖尿病的药物，并可以降低病人的肿瘤发病风险。Metformin能够激活AMPK，后者是其发挥药效的关键因子。然而，该过程的机制还不明确。我们之前发现，Ragulator（由LAMTOR1-5组成）和AXIN是能量胁迫条件下AMPK激活的必需因子；Ragulator-AXIN/LKB1-AMPK复合体在溶酶体上的组装的过程是该条件下AMPK激活的必要条件。我们前期的研究发现，Metformin不能在缺失了AXIN或者LAMTOR1的MEFs和小鼠肝脏中激活AMPK。同时，Metformin能引起Ragulator-AXIN/LKB1-AMPK复合体的形成。在此基础上，我们将继续研究Ragulator和AXIN在Metformin-AMPK信号通路中的作用和生理意义，从而加深我们对该药物药理作用的理解，为其更加深入而广泛的应用作出贡献。

二甲双胍（metformin）是使用最为广泛的治疗II型糖尿病的药物，并可以降低病人脂肪肝病症乃至肿瘤的发病风险。二甲双胍能够激活AMPK，后者是其发挥药效的关键因子。然而，该过程的机制还不明确。通过本项目的研究我们发现，激活AMPK的溶酶体途径是二甲双胍激活AMPK所必需，并进一步鉴定了其中的分子机制：二甲双胍通过抑制溶酶体上的v-ATPase，引起了和其相互作用的Ragulator复合体（由LAMTOR1-5组成）的变构，进一步引起了架构蛋白AXIN和与之结合的AMPK上游激酶LKB1向溶酶体的迁移，并在此处激活AMPK。我们进一步发现，二甲双胍降低脂肪肝水平也需要通过溶酶体途径。同时，在患有II型糖尿病的重度脂肪肝患者的肝脏中，AXIN和LAMTOR1的表达量下降，并和二甲双胍的不敏感性有联系。在此基础上，我们的研究揭示了溶酶体途径介导二甲双胍激活AMPK的机制，并分析了该过程的生理意义，从而加深我们对二甲双胍药理作用的理解，为其更加深入而广泛的应用作出贡献。