Acyl-CoA Synthetase Isoforms in Hepatic Lipid Metabolism

描述（申请人提供）：AcyI-CoA合成酶（AcyI-CoA synthetase， ACS）催化脂肪酸与CoA的连接，生成AcyI-CoA，从而完成脂肪酸代谢的第一步。ACS的三种亚型在大鼠肝脏中占主导地位，每种亚型具有不同的亚细胞位置和底物偏好，这表明每种亚型在将脂肪酸分配到不同的代谢途径中具有不同的作用。然而，各异构体在脂肪酸代谢中的作用尚未阐明。此外，多不饱和脂肪酸通过上调过氧化物酶体增殖物激活受体α和下调固醇调节元件结合蛋白lc，诱导脂肪酸氧化相关酶的基因表达，抑制脂肪生成相关基因。相反，acyI-CoAs可以拮抗脂肪酸对基因表达的作用，并上调编码相反途径的基因。因此，我们提出控制脂肪酸向acyI-CoAs的转化及其池大小可能是调节基因表达的关键步骤。由于ACS可以催化这一反应，因此它是调控基因表达的新靶点。本研究将利用RNA干扰确定ACS 1、4和5在肝脏脂肪酸代谢和基因表达中的作用。

DESCRIPTION (provided by applicant): AcyI-CoA synthetase (ACS) catalyzes the ligation of fatty acids to CoA yielding acyI-CoA, thus completing the initial step in fatty acid metabolism. Three isoforms of ACS predominate in rat liver with each isoform having different subcellular locations and substrate preferences, which suggests distinct roles of each isoform in partitioning fatty acids to distinct metabolic pathways. However, the function of each isoform in fatty acid metabolism has not be elucidated. Additionally, polyunsaturated fatty acids induce gene expression of enzymes involved in fatty acid oxidation and suppress genes involved in lipogenesis by upregulating peroxisome proliferators-activated receptor alpha and down-regulating sterol regulatory element binding protein-lc. In contrast, acyI-CoAs antagonize the actions of fatty acids on gene expression and upregulate genes encoding opposing pathways. Thus, we propose that controlling the conversion of fatty acids to acyI-CoAs and their pool size may be a critical step in regulating gene expression. Since ACS catalyzes this reaction, it is a novel target to regulate gene expression. The proposed research will use RNA interference to define the roles of ACS 1, 4 and 5 in hepatic fatty acid metabolism and gene expression.