Role of PLAB1B in the Development of Hyperlipidemia Associated Atherosclerosis

PLAB1B 在高脂血症相关动脉粥样硬化发展中的作用

• 批准号: 8257380
• 负责人: Norris Isaac Hollie
• 金额: $ 3.35万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8257380
• 关键词: Address; Affect; Animals; Arterial Fatty Streak; Atherosclerosis; Body Weight; Carbohydrates; Cardiac; Cardiovascular Diseases; Cause of Death; Central obesity; Cholesterol; Competence; Coronary heart disease; Development; Diabetes Mellitus; Diet; Dietary Fats; Digestion; Disease; Enzymes; Fatty Acids; Fatty acid glycerol esters; Genes; Genetic; Genetic Polymorphism; Hepatic; Hepatocyte; Human; Hyperlipidemia; In Vitro; Inflammation; Inflammatory; Insulin Resistance; Laboratories; Link; Lipids; Lipoproteins; Low Density Lipoprotein Receptor; Lysophosphatidylcholines; Malabsorption Syndromes; Mediating; Membrane; Membrane Potentials; Metabolism; Mitochondria; Molecular; Mus; Myocardial Infarction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pancreas; Pathology; Pathway interactions; Pb clearance; Permeability; Phospholipase; Phospholipase A2; Phospholipids; Plasma; Population; Prevalence; Production; Research; Resistance; Risk; Risk Factors; Role; Stroke; Testing; Tissues; Triglycerides; United States; Variant; Very low density lipoprotein; Western World; cardiovascular risk factor; cohort; extracellular; fatty acid metabolism; fatty acid oxidation; feeding; in vivo; inhibitor/antagonist; mitochondrial dysfunction; mouse model

DESCRIPTION (provided by applicant): Obesity and diabetes-related disorders have increasingly great prevalence in the western world. Coronary heart disease is the main cause of death among many populations. Due to dietary and genetic causes, atherosclerosis affects over a million people each year with cardiac manifestations. The presence of lysophosphatidylcholine and other inflammatory molecules in the atheroma have led to inquiries regarding the role of phospholipases in the development of atherosclerosis. As the number of phospholipases is large, detailing the contribution of each one is not yet complete. Recent studies have linked human polymorphisms of the group 1B phospholipase A2 gene (PLA2G1B) with increased central adiposity, which is a risk factor for cardiovascular disease. Phospholipase A2 group 1B is a digestive enzyme that aids digestion by selectively catalyzing the conversion of phospholipids in the gut lumen to lysophosphatidylcholine (LPC) and fatty acid. Mice deficient in this enzyme retain the ability to digest dietary lipids due to compensatory enzymes, but do not produce LPC to a similar extent. Furthermore, Pla2g1b-/- mice are resistant to diet-induced obesity, diet-induced type-2 diabetes, and diet-induced hyperlipidemia. The mechanism involves increased fatty acid metabolism, decreased hepatic very-low-density lipoprotein (VLDL) production, and increased post-prandial triglyceride rich lipoprotein clearance. However, the specific subcellular details of how plasma LPC alters hepatocyte metabolism are not known. Furthermore, it is not known whether genetic inhibition of Pla2g1b leads to a decreased risk of atherosclerosis in vivo. This proposal addresses these concerns by testing the ex vivo, in vitro, and in vivo effects of Pla2g1b inhibition and the addition of its enzymatic product, LPC. Mitochondria will be isolated and the effects of LPC upon membrane integrity and potential will be determined. The effect of LPC upon fatty acid metabolism in isolated hepatocytes will also be ascertained. Furthermore, the effect of Pla2g1b competence upon atherosclerosis development and systemic inflammation will be investigated in a mouse model of diet-induced atherosclerosis.

描述（由申请人提供）：肥胖和糖尿病相关疾病在西方世界越来越普遍。冠心病是许多人的主要死因。由于饮食和遗传原因，动脉粥样硬化每年影响超过一百万人的心脏表现。溶血磷脂酰胆碱和其他炎症分子在动脉粥样硬化中的存在导致了磷脂酶在动脉粥样硬化发展中的作用的研究。由于磷脂酶的数量很大，详细说明每一个的贡献还没有完成。最近的研究表明，人类1B组磷脂酶A2基因（PLA 2G 1B）多态性与中心性肥胖增加有关，这是心血管疾病的危险因素。磷脂酶A2 1B组是一种消化酶，通过选择性催化肠腔中的磷脂转化为溶血磷脂酰胆碱（LPC）和脂肪酸来帮助消化。缺乏这种酶的小鼠由于补偿酶而保留消化膳食脂质的能力，但不产生类似程度的LPC。此外，Pla 2g 1b-/-小鼠对饮食诱导的肥胖、饮食诱导的2型糖尿病和饮食诱导的高脂血症具有抗性。其机制涉及脂肪酸代谢增加、肝脏极低密度脂蛋白（VLDL）生成减少和餐后富含甘油三酯的脂蛋白清除增加。然而，血浆LPC如何改变肝细胞代谢的具体亚细胞细节尚不清楚。此外，尚不清楚Pla 2g 1b的遗传抑制是否导致体内动脉粥样硬化风险降低。该提案通过测试Pla 2g 1b抑制的离体、体外和体内效应以及添加其酶产物LPC来解决这些问题。将分离线粒体，并确定LPC对膜完整性和电位的影响。还将确定LPC对分离肝细胞中脂肪酸代谢的影响。此外，将在饮食诱导的动脉粥样硬化的小鼠模型中研究Pla 2g 1b能力对动脉粥样硬化发展和全身炎症的影响。