乙酰辅酶A合成酶ACS-1调控脂滴和内质网稳态的作用机制研究

Maintenance of lipid homeostasis is crucial for normal activity of life. The endoplasmic reticulum (ER) and lipid droplets (LDs) are important intracellular for lipid biosynthesis and storage. However, less is known how ER and LD coordinately regulate lipid homeostasis. Our preliminary works showed that RNAi knockdown of acs-1, encoding an acetyl-Coa synthetase, led to not only reduced lipid droplet size and fat content, but also abnormal morphology of endoplasmic reticulum. Therefore, we here proposed several approaches to explore: 1) the roles of ACS-1 in the biosynthesis of fatty acids and triacylglycerol (TAG); 2) the underlying mechanisms of ACS-1 regulating the ER homeostasis by what lipids, unsaturated fatty acids, phospholipids or sphingolipids; 3) and how ACS-1 regulates lipid droplets biogenesis and enlarged. The results of this study will clarify the relationship between lipid droplets biogenesis and endoplasmic reticulum, as well as provide new insights for treatments of metabolic disorders.

脂质代谢平衡是维持细胞或者有机体正常生命活动的关键。内质网和脂滴分别是脂类合成和储存的重要场所，但它们之间如何协同调控脂质代谢平衡目前很多未知。我们前期工作筛选同时影响内质网和脂代谢的基因时发现，RNAi干扰抑制乙酰辅酶A合成酶ACS-1不仅阻碍脂滴的增大、降低脂肪的积累，而且导致内质网形态异常。在此基础上，我们提出本项目研究：1）ACS-1在脂肪酸合成中的作用机制；2）ACS-1影响内质网形态和功能的作用机制研究；3）ACS-1调控脂滴增大和脂肪储存的作用机制研究。本项目的研究将对揭示内质网与脂滴的增长甚至起源的相互关系，以及为内质网或者脂代谢异常疾病的预防提供新的思路。

在真核细胞中，脂滴是动态调节细胞能量稳态的关键细胞器。脂滴起源于内质网，并且在生长过程中不断接触内质网。内质网对脂滴增长的影响目前还不清楚。本项目研究中，我们发现RNAi敲除acs-1，编码酰基辅酶A合成酶，参与合成单甲基支链脂肪酸C15iso和C17iso，显著抑制了秀丽隐杆线虫的脂滴的生长。外源添加C17iso或含有C17iso的复合脂质，包括磷脂酰胆碱、磷脂酰乙醇胺和三酰基甘油，恢复acs-1RNAi中脂滴的生长。C17iso可以并入磷脂，以确保内质网的完整性，维持内质网驻留酶如SCD/硬脂酰辅酶A去饱和酶和DGAT2/二酰基甘油酰基转移酶的正常功能，用于脂质合成和脂滴生长。总的来说，我们的工作揭示了一个独特的脂肪酸，C17iso，作为磷脂的侧链，决定秀丽线虫中内质网稳态和脂滴的增大。