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The function of the fatty acyl-CoA synthetase ACSL3 in the dynamic metabolism of lipid droplets

脂酰辅酶A合成酶ACSL3在脂滴动态代谢中的作用

基本信息

批准号：
239761035
负责人：
Professor Dr. Joachim Füllekrug
金额：
--
依托单位：
Klinik für Gastroenterologie, Infektionskrankheiten, Vergiftungen
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2013
资助国家：
德国
起止时间：
2012-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/239761035?language=en
关键词：
function fatty acyl CoA synthetase

项目摘要

Lipid droplets are intracellular storage organelles highly relevant for lipid homeostasis and the pathophysiology of metabolic diseases. They adapt dynamically to nutrient supply, growing and shrinking accordingly. There are many open questions about the mechanisms involved, and which molecular players are required. Enzymes of the fatty acyl-CoA synthetase family are essential for the synthesis of the neutral lipids in the lipid droplet core, and for the phospholipids of the surrounding membrane.Recently, we investigated the association of the acyl-CoA synthetase ACSL3 with lipid droplet membranes. ACSL3 translocated from the endoplasmic reticulum to emerging lipid droplets when neutral lipid synthesis was induced, suggesting an important role in the formation and growth of lipid droplets. Preliminary data indicate that cells lacking ACSL3 are greatly impaired in neutral lipid synthesis and the formation of lipid droplets.This proposal now asks for the function of ACSL3 in the dynamic storage of lipids in mammalian cells. The overall hypothesis is: Lipid droplet localized ACSL3 contributes significantly to the efficient storage and mobilization of neutral lipids. This may be achieved by providing fatty acids specifically for the growth of lipid droplets, and by regulating the triglyceride-fatty acid cycle between biosynthesis and lipolysis. The main experimental strategy is to analyze cells depleted for ACSL3.The specific aims are:1. to elucidate if ACSL3 contributes to the growth of lipid droplets by the local biosynthesis of surface phospholipids and core triglycerides. Lipid droplets will be assessed for their biosynthetic capacities and their lipid composition. Fatty acid and lysolipid supplementation in vivo will show the physiological relevance of ACSL3.2. to reveal a role of ACSL3 in the regulation of the triglyceride-fatty acid cycle. Basal and hormone stimulated lipolysis will be compared between ACSL3-RNAi and control cells by using metabolic labeling and microscopy quantification of lipid droplets.3. to assess the putative unique function of ACSL3 on lipid droplets. Other acyl-CoA synthetases and an ACSL3 variant which cannot translocate to lipid droplets will be used for rescue experiments of the ACSL3 depleted cells.Investigating the function of ACSL3 will yield novel insights into lipid droplet biology, which will improve our understanding of metabolic diseases in molecular detail.

脂滴是细胞内储存细胞器，与脂质稳态和代谢性疾病的病理生理密切相关。它们动态地适应养分供应，相应地生长和缩小。关于所涉及的机制，以及需要哪些分子参与者，还有许多悬而未决的问题。脂肪酰基辅酶a合成酶家族的酶对于脂滴核心中的中性脂的合成以及周围膜的磷脂是必不可少的。最近，我们研究了酰基辅酶a合成酶ACSL3与脂滴膜的关系。诱导中性脂合成时，ACSL3从内质网转移到新出现的脂滴，提示在脂滴形成和生长中起重要作用。初步数据表明，缺乏ACSL3的细胞在中性脂合成和脂滴形成方面受到严重损害。这个提议现在要求ACSL3在哺乳动物细胞中脂质动态储存中的功能。总体假设是：脂滴定位的ACSL3对中性脂的有效储存和动员有重要作用。这可以通过提供专门用于脂滴生长的脂肪酸，以及通过调节生物合成和脂解之间的甘油三酯-脂肪酸循环来实现。主要的实验策略是分析ACSL3耗尽的细胞。具体目标是：1。以阐明ACSL3是否通过表面磷脂和核心甘油三酯的局部生物合成来促进脂滴的生长。脂滴的生物合成能力和脂质组成将被评估。体内脂肪酸和溶脂的补充将显示ACSL3.2的生理相关性。揭示ACSL3在调节甘油三酯-脂肪酸循环中的作用。通过脂滴的代谢标记和显微镜定量，比较ACSL3-RNAi和对照细胞之间的基础和激素刺激的脂肪分解。以评估ACSL3对脂滴的独特功能。其他酰基辅酶a合成酶和不能转移到脂滴的ACSL3变体将用于ACSL3耗尽细胞的拯救实验。研究ACSL3的功能将对脂滴生物学产生新的见解，这将提高我们对代谢疾病分子细节的理解。