ORP8调控脂滴自噬的作用和机制研究

脂滴是细胞内结构独特的动态细胞器，其合成和分解在细胞脂质运输和能量代谢中扮演关键角色。脂滴自噬是脂滴分解代谢的重要方式，但其发生过程和调控机制尚不明确。前期研究中我们发现，氧化固醇结合相关蛋白ORP8能定位脂滴，其表达与脂滴形态和数量以及细胞的甘油三酯水平密切相关；ORP8还能特异与自噬蛋白LC3相互作用并被细胞能量感受蛋白激酶AMPK磷酸化。这些结果强烈提示ORP8作为选择性自噬受体介导脂滴自噬调控细胞脂质代谢的可能性。本项目拟在前期结果的基础上，重点开展三方面内容研究：（1）ORP8在脂质代谢过程中的亚细胞定位及其动态变化；（2）ORP8在脂滴自噬中的作用及作用机制；（3）ORP8介导脂滴自噬活性的调控机理。通过鉴定ORP8是脂滴自噬的受体，揭示其作用和调控机制，本研究的发现将促进我们对细胞脂质和能量代谢以及相关疾病的认识。

Lipid droplets are dynamic organelles with unique structure in cells. The synthesis and decomposition of lipid droplets play a key role in cell lipid transport and energy metabolism. Lipophagy is an important pathway of lipid droplet catabolism, but its process and regulation are unclear. Recently, we found that the oxidized sterol binding protein ORP8 can localize to lipid droplets, and its expression is closely related to the number and morphology of lipid droplets. In addition, ORP8 can specifically interact with autophagy-related protein LC3 and be phosphorylated by cell energy sensor AMPK. These results strongly suggest that ORP8 may function as a selective autophagy receptor in mediating lipophagy. Based on these preliminary results, we plan to investigate in this study: (1) the subcellular localization of ORP8 and dynamic changes in lipid metabolism; (2) the role and mechanism of ORP8 in lipophagy; (3) the regulatory mechanism of ORP8 activity in mediating lipophagy. Through the identification of ORP8 as a lipophagy receptor protein and its mechanism of action and regulation, our findings will promote the understanding of cell lipid and energy metabolism and related diseases.