FGF21调控脂滴自噬的分子机制

Lipid droplet is a dynamic organelle in eukaryotic cells to store cellular energy, including triglyceride and cholesterol. The dysregulation of lipid droplet homeostasis is a central feature of metabolic disorders, such as obesity, diabetes, non-alcoholic fatty liver disease and atherosclerosis. Recently, it was reported that autophagy, an evolutionarily conserved process for protein quality control and organelle recycling, promotes the degradation of lipid droplet as lipophagy. However, it is unclear how lipophagy is regulated in response to various environmental cues in mammals. In this study, we will use cutting-edge techniques to investigate how a fasting induced hormone fibroblast growth factor 21 (FGF21), functioning in glucose and lipid metabolism, bone loss and life span extension, regulates the homeostasis of lipid droplet via autophagy. Therefore, results from this study will provide not only new insights to the intrinsic mechanisms among fasting induced hormone FGF21, nutrition controlled autophagy and lipid metabolism modulated by lipid droplet homeostasis, but also therapeutic targets for lipid metabolism disorders.

脂滴是真核细胞中用以储存甘油三酯和胆固醇等能量分子的高度动态的细胞器。脂滴动态平衡失调是肥胖、糖尿病、非酒精性脂肪肝与动脉粥样硬化等代谢性疾病的一个重要特征。细胞自噬是进化上保守的进行蛋白质质量控制和细胞器重新利用的代谢过程。最近的研究表明细胞自噬促进了脂滴的降解，即脂滴自噬,然而脂滴自噬在哺乳动物中是如何响应环境中各种因素而发生动态变化的还不甚清楚。激素FGF21在糖脂代谢、骨质流失和寿命延长中起了重要的作用,研究发现，长时间空腹饥饿时，哺乳动物会产生FGF21。在本课题中，我们将使用各种先进的技术手段来深入探讨FGF21通过自噬调节脂滴稳态的分子机制。本课题的研究将不仅有助于我们理解空腹饥饿诱导的激素信号FGF21、营养状态相关的自噬与脂滴稳态调控的脂代谢三者之间的内在联系，而且有利于发现新的脂代谢紊乱相关疾病的治疗靶点。

溶酶体是哺乳动物适应饥饿条件下营养物质感应和循环的中心。通过营养物质感应调控溶酶体稳态已有报道，但是激素调控溶酶体功能的具体机制仍不清楚。我们发现饥饿诱导的激素FGF21在调控溶酶体稳态中的重要作用及其分子机制。TFEB是调控溶酶体新生和自噬的一个重要转录因子，FGF21通过增强TFEB的活性进而促进溶酶体依赖的脂自噬。FGF21诱导内质网中钙离子的释放，从而激活转录抑制因子DREAM的表达，进而抑制E3泛素化连接酶MID1的表达。MID1的抑制增加了TFEB磷酸酶PP2A的累积，促进了TFEB的去磷酸化和核转录活性，从而上调与溶酶体新生、自噬和脂代谢相关基因的表达。综上，我们在生理水平上阐述了FGF21通过FGF21-TFEB信号通路调控溶酶体稳态进而影响脂代谢的分子机制，对理解脂代谢相关疾病的发生发展有重要的指导意义。