The role of proprotein convertases in lipid metabolism

描述(申请人提供)：脂代谢紊乱是导致心血管疾病的几个重要的既定危险因素，在美国，心血管疾病仍然是发病率和死亡率的主要原因。尽管经过了几十年的研究，但人们对脂类代谢的许多方面仍不完全了解。原蛋白转换酶(PC)被怀疑与脂质代谢有关，但其重要性直到最近发现两个PC与人类的脂质紊乱有关时才被充分认识。PC影响胆固醇代谢的机制尚不清楚。我们的长期目标是描绘PC如何裂解底物和调节脂质代谢。在这个项目中，我们将重点研究PC如何通过血管生成素样蛋白3(Angptl3)影响脂质代谢。这将通过针对三个具体目标进行实验来实现。具体目标1，在细胞培养中检测PC如何通过使用不同的化合物影响Angptl3的细胞加工。具体目的2，在无细胞系统中，了解PC对Angptl3加工的干扰是否对一种名为脂蛋白脂酶的酶的活性有影响，然后在小鼠身上进一步检查它是否也影响致动脉粥样硬化小鼠模型的血脂水平和动脉粥样硬化的形成。具体目标3：将在不同的营养状态和小鼠的急性炎症情况下检查这一生物事件的生理学相关性。这项研究不仅对更好地了解Angptl3的生物过程具有重要意义，而且还将描述PC如何调节脂代谢，最终为开发潜在的调节脂蛋白代谢和预防心血管疾病的新方法提供信息。

DESCRIPTION (provided by applicant): Disorders of lipid metabolism are responsible for several important established risk factors for cardiovascular disease, which continues to be the leading cause of morbidity and mortality in the United States. Despite of decades of research, many aspects of lipid metabolism are incompletely understood. Proprotein convertases (PCs) were suspected to be involved in lipid metabolism, but their importance has not been fully appreciated until the recent discoveries that two PCs were found to be associated with lipid disorders in humans. The mechanisms by which PCs influence cholesterol metabolism remain unclear. Our long-term goal is to delineate how PCs cleave substrates and regulate lipid metabolism. In this project, we will focus on how PCs influence lipid metabolism through angiopoietin-like 3 (ANGPTL3). This will be accomplished by conducting experiments addressing three Specific Aims. Specific Aim 1, in cell culture to examine how PCs influence the cellular processing of ANGPTL3 by using different compounds. Specific Aim 2, in a cell-free system to find out whether the interference of ANGPTL3 processing by PCs has any effects on activity of an enzyme named lipoprotein lipase, then to further examine in mice whether it also affects plasma lipid levels and formation of atherosclerosis in an atherogenic mouse model. Specific Aim 3: The physiological relevance of this biological event will be examined under different nutritional states and acute inflammation in mice. This study will be not only important to better understand the biologic processing of ANGPTL3, but also to delineate how PCs regulate lipid metabolism, ultimately, provides information that could lead to the development of potential novel approaches for regulating lipoprotein metabolism and preventing cardiovascular diseases.