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: 10252097
• 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/10252097
• 关键词: Amino Acids; Animal Model; Animals; Antiatherogenic; Aorta; Apolipoproteins B; Atherosclerosis; Attenuated; Biological Process; Blood Circulation; Cardiac; Cardiovascular Diseases; Cell Line; Cells; Ceramides; Cholesterol; Conserved Sequence; Development; Diet; Diglycerides; Disease; Endoplasmic Reticulum; Event; Family; Fatty acid glycerol esters; Gene Family; Golgi Apparatus; Health; Hepatic; Hepatocyte; Human; Hydrolysis; Hyperlipidemia; Italy; 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; Triad Acrylic Resin; Triglycerides; Tube; Very low density lipoprotein; Veterans; aging population; atherogenesis; base; 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 动脉粥样硬化对心脏相关的发病率和死亡率显着贡献 退伍军人。血浆低密度脂蛋白（LDL）及其前体非常低密度脂蛋白（VLDL）为两个 动脉粥样硬化脂蛋白。 LDL通过其在下皮下空间中的保留来启动动脉粥样硬化 动脉墙。他汀类药物介导的LDL降低现在是心血管疾病治疗的主要手段。 但是，尽管有疗效，但有很多无反应和不宽容的情况。因此 迫切需要降低血浆LDL的其他方法，最好与 他汀类药物。肝脏VLDL分泌和促进LDL清除长期以来一直被认为是一种被认为是一种 有效的LDL降低策略。这些与他汀类药物的使用不同。很长一段时间以来 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。但是，如何 为了调节PE以及将PE与动脉粥样硬化联系起来的机制是什么。 PE是 VLDL和LDL的重要脂质成分之一及其水平影响 动物模型中的动脉粥样硬化。因此，研究PE调节可能提供降低的重要线索 VLDL和LDL，以及对人动脉粥样硬化的新治疗。 鞘磷脂合酶（SMS）基因家族有三个成员：SMS1和SMS2具有SM 合成酶活性，而SMS相关蛋白（SMSR）没有SM合酶活性，但具有神经酰胺 测试管中的磷酸甲醇胺（CPE）合酶活性。尽管SMSR无处不在 所有测试的组织，大多数哺乳动物组织或细胞中的CPE水平在Chow或 高脂肪/胆固醇饮食。因此，SMSR不是体内功能性CPE合酶及其实际生物学 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水解为二酰基甘油和磷酸乙醇胺，这可能 参与组织PE稳态调节。基于这项研究的初步结果，我们然后 假设SMSR是体内功能性PE-PLC。鉴于PE水平与VLDL有关 生产，LDL清除和动脉粥样硬化的发展，SMSR/PE-PLC应该是新颖的，并且 降低LDL的有希望的目标。我们有三个具体的目标：1。调查SMSR是否是一个 功能性PE-PLC。 2。评估阻断SMSR/PE-PLC对VLDL生产和LDL的影响 清除。 3。检查SMSR/PE-PLC缺乏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将使我们能够评估SMSR/PE-PLC作为预防和 治疗人动脉粥样硬化。