Effect of SMSr on VLDL metabolism and atherosclerosis

SMSr 对 VLDL 代谢和动脉粥样硬化的影响

• 批准号: 10512745
• 负责人: XIAN-CHENG JIANG
• 金额: --
• 依托单位: VA NEW YORK HARBOR HLTHCARE/SYS/BROOKLYN
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512745
• 关键词: Amino Acids; Animal Model; Animals; Antiatherogenic; Aorta; Apolipoproteins B; Atherosclerosis; Biological Process; Cardiac; Cardiovascular Diseases; Cell Line; Cells; Ceramides; Cholesterol; Circulation; Conserved Sequence; Development; Diet; Diglycerides; Disease; Endoplasmic Reticulum; Event; Family; Fatty acid glycerol esters; Gene Family; Golgi Apparatus; Health; Hepatic; Hepatocyte; Human; Hydrolysis; Hyperlipidemia; Knowledge; Lecithin; Link; Lipids; Lipoprotein (a); Lipoproteins; Liver; Low-Density Lipoproteins; Mediating; Metabolism; Morbidity - disease rate; Mus; Pathway interactions; Phosphatidylethanolamine; Phospholipids; Plasma; Play; Prevention; Process; Production; Proteins; Reaction; Recombinants; Regulation; Research; Role; Site-Directed Mutagenesis; Tertiary Protein Structure; Testing; Time; Tissues; Triglycerides; Tube; Very low density lipoprotein; Veterans; aging population; atherogenesis; feeding; in vivo; insight; member; military veteran; mortality; mutant; novel; novel strategies; particle; phosphatidylcholine-specific phospholipase C; phosphodiester; phosphoethanolamine; prevent; sphingomyelin synthase

Summary Atherosclerosis contributes significantly to cardiac related morbidity and mortality in the aging population of veterans. Plasma low density lipoprotein (LDL) and its precursor very low density lipoprotein (VLDL) are two atherogenic lipoproteins. LDL initiates atherosclerosis through its retention in the subendothelial space of arterial walls. Statin-mediated LDL lowering is now the mainstay of cardiovascular disease treatment. However, despite the efficacy, there are many instances of unresponsiveness and intolerance. There is thus an urgent need for additional approaches for lowering plasma LDL, preferably acting synergistically with statins. Blocking liver VLDL secretion and promoting LDL clearance have long been recognized as an effective LDL lowering strategies. Those are different from the use of statins. It is known for a long time that plasma phosphatidylethanolamine (PE) level is a better predictor for human atherosclerosis. However, how to regulate PE and what is the mechanism linking PE with atherosclerosis are not quite understood. PE is one of the important lipid components on VLDL and LDL, and its level influences the development of atherogenesis in animal models. Thus, study PE regulation may provide an important clue for lowering VLDL and LDL, and for a new treatment of human atherosclerosis. Sphingomyelin synthase (SMS) gene family has three members: SMS1 and SMS2 have SM synthase activity, while SMS-related protein (SMSr) has no SM synthase activity but has ceramide phosphorylethanolamine (CPE) synthase activity in test tubes. Although SMSr is ubiquitously expressed in all tested tissues, the CPE levels in most of mammalian tissues or cells are undetectable under chow or high fat/cholesterol diets. Therefore, SMSr is not a functional CPE synthase in vivo and its real biological function need to be elucidated. From the CPE synthase reaction, we notice that SMSr should have a potential PE-PLC activity, i.e. hydrolyzing PE into diacylglycerol and phosphorylethanolamine, which could be involved in tissue PE steady state regulation. Based on preliminary results of this study, we then hypothesize that SMSr is a functional PE-PLC in vivo. Given the fact that PE levels are involved in VLDL production, LDL clearance, and the development of atherosclerosis, SMSr/PE-PLC should be a novel and promising target for lowering LDL. We have three specific aims: 1. Investigate whether SMSr is a functional PE-PLC. 2. Evaluate the effects of blocking SMSr/PE-PLC on VLDL production and LDL clearance. 3. Examine the role of SMSr/PE-PLC deficiency in the development of atherosclerosis. Insights gained from the proposed studies will allow us to evaluate SMSr/PE-PLC as a target for preventing and treating human atherosclerosis.

概括 动脉粥样硬化对老龄化人口中心脏相关的发病率和死亡率有显着影响 退伍军人。血浆低密度脂蛋白（LDL）及其前体极低密度脂蛋白（VLDL）是两种 致动脉粥样硬化脂蛋白。低密度脂蛋白（LDL）通过其在内皮下空间的滞留引发动脉粥样硬化 动脉壁。他汀类药物介导的低密度脂蛋白降低现在是心血管疾病治疗的支柱。 然而，尽管有功效，但仍有许多反应迟钝和不耐受的情况。因此有 迫切需要其他方法来降低血浆 LDL，最好与 他汀类药物。阻断肝脏 VLDL 分泌和促进 LDL 清除长期以来被认为是 有效的低密度脂蛋白降低策略。这些与他汀类药物的使用不同。长期以来人们都知道 血浆磷脂酰乙醇胺 (PE) 水平是人类动脉粥样硬化的更好预测指标。然而，如何 调节PE以及PE与动脉粥样硬化的联系机制尚不十分清楚。聚乙烯是 VLDL和LDL的重要脂质成分之一，其水平影响着 动物模型中的动脉粥样硬化形成。因此，研究PE调控可能为降低 VLDL和LDL，是人类动脉粥样硬化的新治疗方法。 鞘磷脂合酶 (SMS) 基因家族有 3 个成员：SMS1 和 SMS2 具有 SM SMS 相关蛋白 (SMSr) 没有 SM 合酶活性，但具有神经酰胺 试管中磷酸乙醇胺（CPE）合酶的活性。尽管 SMSr 普遍表达为 在所有测试的组织中，大多数哺乳动物组织或细胞中的 CPE 水平在食物或食物下均检测不到 高脂肪/胆固醇饮食。因此，SMSr并不是体内功能性的CPE合酶，其真正的生物学意义是 功能需要阐明。从 CPE 合酶反应中，我们注意到 SMSr 应该具有 潜在的PE-PLC活性，即将PE水解成二酰基甘油和磷酸乙醇胺，这可以 参与组织PE稳态调节。根据本研究的初步结果，我们 假设 SMSr 是体内功能性 PE-PLC。鉴于 PE 水平与 VLDL 相关 SMSr/PE-PLC 应该是一种新颖且 降低 LDL 的有希望的目标。我们有三个具体目标： 1. 调查 SMSr 是否是一个 功能性PE-PLC。 2. 评估阻断 SMSr/PE-PLC 对 VLDL 产生和 LDL 的影响 清除。 3. 检查 SMSr/PE-PLC 缺陷在动脉粥样硬化发展中的作用。见解 从拟议的研究中获得的成果将使我们能够评估 SMSr/PE-PLC 作为预防和预防的目标 治疗人类动脉粥样硬化。