RTN3调控脂肪细胞内脂滴大小和甘油三酯代谢的研究

Recent evidence has emerged for an association between lipid droplets (LDs) and the development of obesity. However, the mechanism of the regulation of LDs expansion remains to be fully elucidated. Our preliminary research revealed that the high expression of RTN3 (reticulon-3) correlated with obesity in mouse; In mature white adipocytes, RTN3 translocated from endoplasmic reticulum to the surface of mature LDs. RTN3-RNAi leaded to the decrease of the LDs size; After intervention with ox-LDL, the LDs size in macrophage with stable high expression of RTN3 changed significantly compared to the control group; The RTN3 also participated in the regulation of LDs size in Caenorhabditis elegans. Meanwhile，we found that RTN3 combined with Atlastin1 in adipose tissue. It has been recently reported that Atlastin1 is closely related to LDs and the metabolism of triglyceride through its activity to promote endoplasmic reticulum(ER) membranes fusion. Therefore, we hypothesized that RTN3 may induce LDs expansion by interacting with atlastin1. In this study, we will focus to verify the effect of RTN3 regulating adipocyte LDs size and triglyceride metabolism and to explore the potential mechanism. This study is expected to provide a new strategy for the prevention and treatment of obesity.

脂滴是与肥胖发生关系最密切的亚细胞结构，但其调控机制亟待研究。申请者前期研究发现：RTN3（内质网蛋白3）在小鼠中的高表达促进肥胖的发生；在成熟白色脂肪细胞中, 内质网定位蛋白RTN3可转移至脂滴表面，RTN3-RNA干扰后脂滴体积明显减小；RTN3稳定高表达的巨噬细胞荷脂后，细胞内脂滴大小较对照组有显著变化；线虫中，RTN3也调控大脂滴的形成。同时，申请者发现RTN3与Atlastin1在脂肪组织中存在相互作用。而新近研究表明Atlastin1通过介导内质网膜同型融合促进脂滴增大和甘油三酯蓄积。由此推测：RTN3可能通过与Atlastin1相互作用,调控内质网膜融合，从而促进脂滴增大、影响脂肪细胞甘油三酯代谢。本项目拟从分子、细胞和线虫水平，明确RTN3对脂肪细胞脂滴大小和甘油三酯代谢的调控及其可能机制。本项目将揭示RTN3新的生物学功能,同时也可能为肥胖的防治提供新的治疗靶点。

肥胖状态下脂肪细胞脂滴明显增大，脂滴是与肥胖发生关系最密切的亚细胞结构。申请者研究发现：RTN3（内质网蛋白3）在小鼠中的高表达促进肥胖的发生；在成熟白色脂肪细胞中, 内质网定位蛋白RTN3可转移至脂滴表面，RTN3-RNA干扰后脂滴体积明显减小；RTN3稳定高表达的巨噬细胞荷脂后，细胞内脂滴大小较对照组有显著变化；线虫中，RTN3也调控大脂滴的形成。同时，我们发现RTN3与热休克蛋白家族A膜蛋白5 (HSPA5)在脂肪组织中存在相互作用。而新近研究表明HSPA5 通过介导内质网膜同型融合促进脂滴增大和甘油三酯蓄积。进一步研究发现：RTN3通过与HSPA5 相互作用, 增强固醇调节元件结合蛋白1c (SREBP1c)，从而促进脂滴增大、影响脂肪细胞甘油三酯代谢。本项目从分子、细胞和线虫水平，明确RTN3对脂肪细胞脂滴大小和甘油三酯代谢的调控及其可能机制。本项目将揭示RTN3新的生物学功能,同时也可能为肥胖的防治提供新的治疗靶点。