Acyl-CoA Synthetase: Structure, Function and Regulation

描述(由申请人提供)：从脂肪或碳水化合物摄入过多的饮食卡路里会导致细胞进入或脂肪酸(FA)及其活性产物酰基-COAs的合成增加。酰基-COA结合到三酰甘油储存库和脂蛋白分泌，以及它们进入氧化途径的减少，有助于营养相关的疾病，如肥胖、脂肪肝和动脉粥样硬化。此外，由于FA和酰基-COA都被认为是几种核转录因子的配体，饮食过量可能会改变脂肪酸和酰基-CoA对多种细胞过程的调节，包括细胞增殖和神经元功能。为了了解脂肪酸失衡对代谢的影响，我们一直在研究长链酰辅酶A合成酶(ACSL)，它促进细胞对FA的摄取，几乎启动了FA代谢的每条途径。我们的假设是，每一种异构体在将FA引导到特定途径中发挥着独立的作用，这一假说得到了过度表达和基因敲除研究的支持。我们现在建议调查缺乏一个主要的酰辅酶A合成酶亚型如何影响组织和全身的代谢。利用有针对性的基因破坏，我们已经培育出肝脏和全身ACSL1基因敲除的小鼠。我们将对这些ACSL1缺失的小鼠进行研究，以确定ACSL1缺失对脂代谢和能量平衡的代谢影响，以及对脂肪酸和酰辅酶A介导的基因表达的影响。第三个目标是研究其他ACSL亚型的过度表达和敲除对肝细胞和脂肪细胞中FA摄取和代谢的影响。这项拟议的研究将为酰辅酶A代谢、不同膳食脂肪酸(包括必需脂肪酸)的影响以及由过量热量引起的疾病提供新的见解。它们将使我们能够了解饮食组成如何影响肝脏、脂肪组织和心脏中FA代谢的特定途径，从而控制代谢途径。ACSL亚型不仅是控制肥胖的潜在靶点，而且它们与结肠癌和遗传性智力低下的关系表明，拟议的研究在人类疾病的治疗中具有实际意义。这项研究与肥胖、脂肪肝、糖尿病、脂肪毒性、营养调节基因表达、癌症和智力低下有关。

DESCRIPTION (provided by applicant): Excess dietary caloric intake from either fat or carbohydrate results in increased cell entry or synthesis of fatty acids (FA) and their activated products, acyl-CoAs. The incorporation of acyl-CoAs into triacylglycerol stores and lipoprotein secretion and their diminished entry into oxidation pathways contribute to nutrition- related disorders such as obesity, fatty liver, and atherosclerosis. Further, because both FA and acyl-CoAs are purported ligands for several nuclear transcription factors, dietary excess may alter fatty acid- and acyl- CoA-mediated regulation of a wide variety of cellular processes, including cell proliferation and neuronal function. In order to understand the effects of FA imbalance oh metabolism, we have been studying the long-chain acyl-CoA synthetases (ACSL) which promote FA uptake into cells and initiate virtually every pathway of FA metabolism. Our hypothesis that each isoform plays an independent role in channeling FA to specific pathways is supported by over-expression and knockdown studies. We now propose to investigate how the lack of one of the major acyl-CoA synthetase isoforms affects tissue and whole body metabolism. Using targeted gene disruption we have produced mice with liver and total body knockouts of ACSL1. We will study these ACSL1 null mice to determine the metabolic effects of ACSL1 lack a) on lipid metabolism and energy balance, and b) on FA- and acyl-CoA-mediated gene expression. A third objective will be to study the effects of overexpression and knockdown of other ACSL isoforms on FA uptake and metabolism in hepatocytes and adipocytes. The proposed studies will provide new insights into acyl-CoA metabolism, the effects of different dietary FA including essential FA, and disorders resulting from excess calories. They will enable us to understand how diet composition influences specific pathways of FA metabolism in liver, adipose tissue and heart to control metabolic pathways. Not only are the ACSL isoforms potential targets for the control of obesity, but their involvement in colon cancer and in genetic mental retardation shows that the proposed studies have practical relevance in the treatment of human disease. This research is relevant to obesity, fatty liver, diabetes, lipotoxicity, nutrient regulation of gene expression, cancer, and mental retardation.