Acyl-CoA Synthetase: Structure, Function and Regulation

描述（由申请人提供）：从脂肪或碳水化合物中摄入过量的膳食热量会导致脂肪酸（FA）及其活化产物酰基辅酶a的细胞进入或合成增加。酰基辅酶a与三酰基甘油储存和脂蛋白分泌的结合，以及它们进入氧化途径的减少，导致营养相关疾病，如肥胖、脂肪肝和动脉粥样硬化。此外，由于FA和酰基辅酶a都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辅酶a介导的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FA代谢失衡的影响，我们一直在研究长链酰基辅酶a合成酶（ACSL），它促进FA进入细胞并启动几乎所有的FA代谢途径。我们的假设是，每个异构体在将FA引导到特定途径中发挥独立作用，这一假设得到了过表达和敲低研究的支持。我们现在建议研究缺乏一种主要的酰基辅酶a合成酶异构体是如何影响组织和全身代谢的。利用靶向基因破坏，我们已经产生了肝脏和全身敲除ACSL1的小鼠。我们将对这些ACSL1缺失小鼠进行研究，以确定ACSL1缺失对a)脂质代谢和能量平衡的代谢影响，以及b)对FA-和酰基辅酶a介导的基因表达的影响。第三个目标是研究其他ACSL亚型的过表达和敲低对肝细胞和脂肪细胞中FA摄取和代谢的影响。拟议的研究将为酰基辅酶a代谢、不同膳食FA（包括必需FA）的影响以及过量卡路里导致的疾病提供新的见解。它们将使我们了解饮食成分如何影响肝脏、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有关，这表明拟议的研究在治疗人类疾病方面具有实际意义。这项研究涉及肥胖、脂肪肝、糖尿病、脂肪毒性、基因表达的营养调节、癌症和智力低下。

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.