Aida调控脂代谢稳态的分子机制

Organisms possess extraordinary ability to maintain homeostasis of fat absorption, consumption, storage and secretion. Deregulated fat metabolism can cause a wide range of diseases, including cardiovascular diseases, obesity, and diabetes. Although we have uncovered many genes that are implicated development of obesity and have learned they participate in numerous molecular networks, it is still unclear as to how obesity occurs as a result of dysfunction of the individual genes. In the course of identifying factors that interact with Axin, we identified a novel interactor and termed it as Aida for Axin interaction partner, dorsalization associated for its morpholino-based knockdown caused dorsalization during zebrafish embryo development. Our preliminary work has shown knockout of Aida caused severe obesity in mice, along with hepatic steatosis and hyperglycemia. We also found that Aida forms complex with components of the endoplasmic reticulum unfolded protein response (ER stress response) pathway. It has been increasingly appreciated that the UPR pathway is linked to various metabolic disorders. Based on our new findings and our established former Axin work, we aim to investigate the interplay between Aida, Axin, and the UPR pathway, and the mechanisms underlying the obesity/steatosis phenotypes associated with Aida knockout, which will contribute to the overall understanding of molecular mechanism for development of obesity, insulin sensitivity and metabolism as a whole.

机体具有平衡脂肪吸收、代谢、储存和分泌的功能，脂稳态的维持关系到人类的多种疾病，包括心血管病、糖尿病等。细胞维持脂稳态依赖于复杂的分子网络协同作用，但是其分子机制的研究还处于起步阶段。本课题的中心分子是一种被称为Aida的蛋白，是我们在探索Axin相互作用蛋白中首先克隆的一个新基因。在前期研究中，我们建立了Aida缺失的小鼠，并发现其表现出明显的肥胖，同时呈现肝脏脂肪累积和高血糖等代谢紊乱表型。我们的初步实验数据表明，Aida这一在哺乳动物中尚未有任何功能性报道的蛋白可能参与内质网胁迫反应。结合之前我们长期研究的与Aida有相互作用的蛋白Axin参与包括葡萄糖转运、细胞自噬和细胞能量代谢调控等维持机体脂稳态的关键细胞进程的线索，我们拟进一步研究Aida是如何参与内质网胁迫反应、细胞自噬和葡萄糖转运等进程，阐明Aida及其相互作用蛋白调控体脂稳态的分子机制，并为肥胖及其相关的代谢性疾病的预防

机体具有平衡脂肪吸收、代谢、储存和分泌的功能，脂稳态的维持关系到人类的多种疾病，包括心血管病、糖尿病等。细胞维持脂稳态依赖于复杂的分子网络协同作用，但是其分子机制的研究还处于起步阶段。在本项目执行期间，我们阐明了AIDA通过抑制肠道对膳食脂肪的过度吸收而抑制肥胖发生的作用和机制：发现了AIDA蛋白在哺乳动物中作为“浪费基因”的生理功能，揭示了内质网降解途径在膳食脂肪吸收过程中的重要功能，还首次提供了肠道脂肪吸收效率的上升会导致肥胖发生的实例。我们还揭示了TIP60通过乙酰化脂肪合成途径的代谢酶lipin-1并促进其向内质网转运，从而提高脂肪合成速率而导致体脂累积的机制；揭示细胞通过代谢调控核心激酶AMPK活化相关蛋白感应葡萄糖水平并调控代谢的分子机制。这些成果发表于Nature、Cell Metabolism、Cell Research和Nature Communications等杂志，部分理论成果的后续应用型研究已申请专利，为认识脂肪合成途径的调控机制、肥胖症及其相关代谢紊乱的发生机制提供了新思路，为研发治疗肥胖症、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。项目资助的9篇论文迄今已被包括Nature Review系列大型综述等引用300余次，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”，2017年“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。负责人于2015年获“福建省科学技术重大贡献奖”，以“细胞感知营养物质与能量的分子机制”获2018年福建省自然科学奖一等奖。

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