Biogenesis and Catabolism of Atherogenic Lipoproteins

总结/摘要-总体而言：死于心血管疾病（CVD）的人数比任何 世界范围内的其他疾病。我们的建议集中在致动脉粥样硬化apoB的生物发生和代谢上， 含有脂蛋白（apoB-Lps），这是心血管疾病的主要危险因素。ApoB-Lp包含胆固醇和 和甘油三酯（TG）。虽然降低胆固醇可以减少动脉粥样硬化，但它仍然存在。 为了令人信服地确定降低TG或携带TG的apoB-Lp水平是否会降低 CVD。阻断肝脏分泌apoB-Lps会降低富含胆固醇的apoB-Lps（如LDL和LDL）的水平。 其富含TG的前体VLDL。不幸的是，这种方法导致脂肪肝。但人类 基因突变和动物研究表明，减少肝脏分泌的TG并不总是导致 脂肪变性通过表征调节肝脏apoB-Lp产生的新因子和途径， 脂肪分解，脂肪TG的保留和动员，我们将确定独特的目标，以减少循环载脂蛋白B- 脂多糖及其对动脉壁的浸润与动脉粥样硬化。我们将定义细胞和 新的啮齿动物模型，然后将我们的发现与人类数据相关联，强调翻译和 积极的方法。我们的总体目标是：1）确定调节循环TG的新过程和因素 和FA水平，2）研究apoB在肝细胞中的脂化和细胞内转运，以及3）研究 不同的apoB-Lp与细胞相互作用并最终催化动脉粥样硬化形成。该应用程序包括三个 项目（P1-P3）整合了三位已建立的apoB-Lp代谢研究者的工作， 动脉粥样硬化P1将研究脂肪MTP和FIT 2在调节脂肪脂解、循环中的作用。 脂质、肝脏apoB-Lp产生和动脉粥样硬化。P2将研究两种特征不佳的蛋白质， 肝脏、KLHL 12和FIT 2，它们控制肝脏apoB-Lp脂质负载和分泌，以及 致动脉粥样硬化的载脂蛋白B脂蛋白P3将研究富含TG的apoB-LPS如何与血管壁相互作用， 确定apoB的N-末端区域对血管内皮细胞的脂质摄取和apoB-Lps的转胞吞作用的作用。 内皮细胞及其与动脉粥样硬化的关系。方案规划小组有一个行政核心和三个科学核心（C1-C3）。 行政核心将监督总体的项目编制小组职能和财务。为了协助P1-P3，C1将提供 生物统计学和生物信息学支持，C2将对apoB-LPS和组织进行脂质组学和蛋白质组学研究， 提供人体样本，C3将进行最先进的动脉粥样硬化检测。我们的研究将产生 新的小鼠模型对于了解调节脂质代谢和动脉粥样硬化的因素是非常宝贵的， 确定新的治疗靶点，并更好地确定动脉粥样硬化性载脂蛋白B-脂蛋白和其他 因素有助于动脉粥样硬化形成。解剖调节apoB的产生和致动脉粥样硬化性的途径- LPS有望揭示减少CVD的新方法。这就需要我们三个方面的研究相结合， 项目，因为每个项目的试验都需要其他项目和核心资源的援助。

SUMMARY/ABSTRACT – OVERALL: More people die of cardiovascular disease (CVD) than any other disease worldwide. Our proposal focuses on the biogenesis and catabolism of atherogenic apoB- containing lipoproteins (apoB-Lps), which are major risk factors for CVD. ApoB-Lps comprise both cholesterol and triglycerides (TGs). Whereas reducing cholesterol is well established to reduce atherosclerosis, it remains to be convincingly determined whether decreasing levels of TGs or the apoB-Lps that carry TGs will decrease CVD. Blocking secretion of apoB-Lps by the liver reduces levels of cholesterol-rich apoB-Lps, such as LDL and its TG-rich precursor VLDL. Unfortunately, such approaches have led to hepatosteatosis. However, human genetic mutation and animal studies demonstrate that reduced liver secretion of TGs does not invariably cause steatosis. By characterizing novel factors and pathways regulating liver apoB-Lp production, intravascular lipolysis, and adipose TG retention and mobilization, we will identify unique targets to reduce circulating apoB- Lps, their infiltration into the artery wall, and atherosclerosis. We will define basic mechanisms in cells and in new rodent models and then correlate our discoveries with human data, emphasizing a translational and transfomative approach. Our overall goals are to: 1) identify new processes and factors regulating circulating TG and FA levels, 2) investigate the lipidation and intracellular transport of apoB in hepatocytes, and 3) study how different apoB-Lps interact with cells and ultimately catalyze atherogenesis. This application comprises three projects (P1–P3) that have integrated work from three established investigators of apoB-Lp metabolism and atherosclerosis. P1 will investigate the role of adipose MTP and FIT2 in regulating adipose lipolysis, circulating lipids, hepatic apoB-Lp production, and atherosclerosis. P2 will study two poorly characterized proteins in the liver, KLHL12 and FIT2, which control hepatic apoB-Lp lipid-loading and secretion, and the composition of atherogenic apoB-Lps. P3 will study how TG-rich apoB-Lps interact with the vascular wall, and specifically determine the role of the N-terminal region of apoB on lipid uptake and transcytosis of apoB-Lps by vascular ECs and their links to atherosclerosis. The PPG has an administrative core and three scientific cores (C1–C3). The Administrative Core will oversee the overall PPG function and finances. To assist P1–P3, C1 will provide biostatistics and bioinformatics support, C2 will perform lipidomics and proteomics on apoB-Lps and tissues and provide human samples, and C3 will perform state-of-the-art atherosclerosis assays. Our studies will generate novel mouse models invaluable to understand the factors that regulate lipid metabolism and atherosclerosis, identify new therapeutic targets, and better define how high circulating levels of atherogenic apoB-Lps and other factors contribute to atherogenesis. Dissecting pathways that regulate the production and atherogenicity of apoB- Lps promises to reveal novel approaches to reduce CVD. This requires the integration of reseach in our three projects, as experiments in each require assistance from the others and core resources.