LAMTOR1在糖异生调控中的作用机制研究

Gluconeogenesis is a metabolic pathway that generates glucose from non-carbohydrate carbon substrates. It is a major mechanism used by humans and many other animals to maintain blood glucose levels, avoiding hypoglycemia. Gluconeogenesis is often upregulated in type 2 diabetic patients and this rise in glucose output plays a major role in diabetes. Increasing evidence suggests that the signaling pathway mediated by LKB1 and SIK (originally defined as a salt-inducible kinase) plays a critical role in regulating gluconeogenesis in the liver; however, the molecular mechanism that governs this pathway is still unclear. We previously elucidated several key steps leading to the activation of AMPK, with which SIK shares the same family. We showed that AXIN is the scaffold of LKB1 and AMPK, and upon energy starvation, AXIN-LKB1 is recruited to the lysosomal membrane through a protein known as LAMTOR1. Our preliminary data demonstrate that the mice with liver specific knockout of LAMTOR1 (LAMTOR1-LKO) exhibit significantly higher blood glucose than the wild type mice, and the activity of gluconeogenesis is increased in these mice. Elevated glucose production is also observed in the LAMTOR1-deficient primary hepatocytes, which is dependent on the LKB1-SIK pathway. Based on our current preliminary data and our established systems for the work on AXIN/LKB1-LAMTOR1-dependent activation of AMPK, we aim to investigate the role of LAMTOR1 in the LKB1-SIK pathway, and the mechanisms underlying the phenotypes in the LAMTOR1 knockout mice pertaining to dysregulated blood glucose levels. The proposed work will make a major contribution to the understanding of the molecular mechanisms for the regulation of the LKB1-SIK pathway, regulation of gluconeogenesis as well as the molecular mechanism for the development of diabetes, ultimately providing new therapeutic avenues for the prevention and treatment of diabetes.

糖异生作用是机体将非糖物质转化为葡萄糖的生化途径，其异常升高是2型糖尿病患者体内持续维持高血糖并导致一系列并发症的重要原因。有遗传学证据显示LKB1-SIK途径是调节糖异生途径最为重要的方面。然而，LKB1在体内激活SIK的具体分子机理还不清楚。我们的前期研究发现，LAMTOR1肝脏特异性敲除的小鼠血糖升高，糖异生能力显著高于野生型小鼠。LAMTOR1缺失的肝细胞也具有更强的产生葡萄糖的能力，且该作用依赖于LKB1-SIK途径。结合我们之前发现的LAMTOR1作为溶酶体膜上的铆钉将结合在AXIN上的LKB1定位到溶酶体上继而激活AMPK的关键作用，我们推测LAMTOR1对LKB1-SIK通路起重要的调节作用。我们将应用分子生物学、生化重组和细胞生物学方法，结合小鼠模型和病理样本，研究LAMTOR1调控LKB1-SIK途径的分子机制，为开发更有效的糖尿病药物和治疗方法做出贡献。

血糖的稳态调控机制是2型糖尿病患病机制研究及设计治疗性药物的关键。我们的前期工作发现Lamtor1、Tip60和Aida基因敲除小鼠的血糖水平异常，可能涉及血糖稳态调控的新机制，因此我们针对这些蛋白在血糖稳态调节的功能和机制上开展了研究。项目执行四年来，我们发现了治疗糖尿病的一线药物二甲双胍能通过LAMTOR1/AXIN激活AMPK这一糖脂稳态调控枢纽蛋白质，揭示了基于LAMTOR/AXIN-AMPK途径的葡萄糖感应机制，揭示了AIDA通过介导内质网降解途径对脂肪合成途径代谢酶的降解而抵御肥胖乃至高血糖的功能和机制，并揭示了TIP60通过乙酰化脂肪合成途径的代谢酶lipin 1而提高脂肪合成导致肥胖和高血糖的机制。这些成果发表于Nature、Cell Metabolism和Nature Communications杂志，为认识血糖稳态调控的机制、二甲双胍作用机制、机体对葡萄糖感应机制和脂肪合成调控机制提供了新思路，为研发治疗糖尿病及其他代谢相关疾病的药物提供了新的潜在靶点和策略。目前项目资助的四篇论文被包括Nature Review系列大型综述等引用173次，被国际权威评论机构Faculty 1000推荐，获2017年度“中国生命科学十大进展”，“中国糖尿病十大研究”，2018年度“邹承鲁杰出研究论文奖”，被科技日报等传统媒体和多个学术公众号报道。负责人及团队成员之一分别于2018年和2019年获基金委优秀青年基金资助，项目组中三人以“细胞感知营养物质与能量的分子机制”项目参与者身份获2018年福建省自然科学奖一等奖。