The role of proprotein convertases in lipid metabolism

描述（由申请人提供）：脂质代谢紊乱是心血管疾病的几个重要危险因素，心血管疾病仍然是美国发病率和死亡率的主要原因。尽管经过几十年的研究，脂质代谢的许多方面仍未完全了解。原蛋白转化酶被怀疑参与脂质代谢，但直到最近发现两种原蛋白转化酶与人类脂质紊乱有关，人们才充分认识到它们的重要性。pc影响胆固醇代谢的机制尚不清楚。我们的长期目标是描述pc如何切割底物和调节脂质代谢。在本项目中，我们将重点研究pc如何通过血管生成素样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完成。特异性目的1，在细胞培养中，通过使用不同的化合物来研究pc如何影响ANGPTL3的细胞加工。具体目的2，在无细胞系统中，研究pc对ANGPTL3加工的干扰是否对一种名为脂蛋白脂肪酶的酶的活性有任何影响，然后在小鼠中进一步研究它是否也影响动脉粥样硬化小鼠模型中的血脂水平和动脉粥样硬化的形成。具体目的3：在不同的营养状态和小鼠急性炎症下，将研究这一生物事件的生理相关性。这项研究不仅对更好地理解ANGPTL3的生物学过程很重要，而且对描述PCs如何调节脂质代谢也很重要，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了信息。

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.