核受体DAF-12调控热敏型脂滴融合的机理研究

Lipid droplet fusion plays an important role in fat metabolism, dysfunction of which may cause metabolic diseases. Our group has discovered a novel lipid droplet fusion process, thermosensitive lipid droplet fusion, in the model animal Caenorhabditis elegans. We also showed that this fusion process is regulated by a novel nuclear hormone receptor pathway, CYP-37A1-EMB-8-Hormone-DAF-12. Based on follow-up experiments, we hypothesized that, as a transcription factor, the nuclear receptor DAF-12 transcribes five of the seven fat genes, which encode desaturases for the synthesis of C20 polyunsaturated fatty acids (PUFAs). The increased expression of fat genes results in an increase of C20 omega-3 PUFAs in phospholipids and an increase of lipid droplet membrane fluidity, leading to thermosensitive lipid droplet fusion. In this research project, we will test this hypothesis using a combination of genetic manipulation, transcription analysis, fatty acid analysis, and lipid droplet imaging.

脂滴融合在脂肪代谢过程中起重要作用，脂滴融合过程紊乱可导致代谢疾病。我们项目组先前在模式动物秀丽线虫里发现了一个新的脂滴融合过程，即热敏型脂滴融合，并发现调控该过程的一条新的核受体信号通路，CYP-37A1-EMB-8-激素-DAF-12。根据后续的研究结果，我们猜想：核受体DAF-12作为转录因子，转录负责合成C20多不饱和脂肪酸（PUFA）的7个fat基因中的5个，导致脂滴磷脂单层膜上的C20 omega-3 PUFA的含量上升、膜流动性升高、热敏型脂滴融合发生。本申请项目将通过遗传操作、转录分析、脂肪酸分析、脂滴成像分析等实验去测试这一猜想。

脂滴融合过程对脂肪代谢起重要调节作用，脂滴融合紊乱可导致脂代谢疾病。我们研究组先前在模式动物秀丽线虫里发现了一种新的脂滴融合过程，即热敏型脂滴融合，并发现调控该过程的一条新的核受体信号通路，CYP-37A1-EMB-8-激素-DAF-12。在本课题的研究中，我们发现核受体DAF-12作为转录因子，上调C20多不饱和脂肪酸（C20 PUFA）的合成酶基因的表达，进而上调C20 PUFA的含量，C20 PUFA被合成进入磷脂，成为脂滴膜的组成成份，升高脂滴磷脂膜的流动性，促进热敏型脂滴融合。