Acyl-CoA Synthetase: Structure, Function and Regulation

描述（由申请人提供）：饮食中摄入过量的脂肪或碳水化合物会导致三酰甘油（TAG）的合成和储存增加。参与TAG合成的长链脂肪酸（FA）必须首先通过长链酰基辅酶a合成酶（ACSL）转化为酰基辅酶a。由于酰基辅酶a位于储存和线粒体氧化的分支点，形成的酰基辅酶a的命运可能有助于或抵消营养失调

DESCRIPTION (provided by applicant): Dietary intake of excess fat or carbohydrate results in increased synthesis and storage of triacylglycerol (TAG). The long-chain fatty acids (FA) that contribute to TAG synthesis must be first converted to acyl-CoAs by long-chain acyl-CoA synthetase (ACSL). Because acyl-CoAs lie at a branch-point of storage and mitochondrial ¿-oxidation, the fate of the acyl-CoAs formed may contribute to, or counteract, nutritional disorders related to increased TAG storage like obesity, fatty liver, atherosclerosis, and diabetes. We hypothesize that 1) ACSL1 is able to direct FA towards ¿-oxidation in highly oxidative tissues because the enzyme interacts with carnitine acyltranferase to hand off its acyl-CoA product; 2) that the function of ACSL1 differs in liver because at least 50% of the protein is present on the endoplasmic reticulum where it interacts with glycerolipid acyltransferases; and 3) that the mechanism for these differences lies both in the membrane association and phosphorylation status of ACSL1. Further, we propose that tissue use of glucose rather than FA as a fuel source is not without cost, and that the metabolic and functional problems arising from this use may be dangerous for organ function and insulin signaling. We further hypothesize, in keeping with the proposition that each ACSL directs FA towards a specific fate, that the ACSL4 isoform functions to regulate the entry of arachidonate into pathways of phospholipid synthesis versus eicosanoid formation. Our studies will address critical gaps in our knowledge about the metabolic fates of FA as substrates for complex lipid formation, as metabolic fuels, as precursors for eicosanoid signaling, as regulators of insulin action, and as transcription factor ligands. PUBLIC HEALTH RELEVANCE: This project will enhance our understanding of insulin resistance, the metabolic syndrome, and cardiac and skeletal muscle fuel metabolism by determining the functions of two of the long-chain acyl-CoA synthetase isoforms in different tissues, by examining how they direct fatty acids towards different downstream pathways, and by investigating how abnormalities in ACSL function alters insulin signaling in cardiac and skeletal muscle.