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的既定风险因素，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不完全清楚。蛋白质前体转化酶（Proprotein convertases，PC）被认为参与脂质代谢，但其重要性尚未得到充分认识，直到最近发现两种PC与人类脂质紊乱有关。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如何切割底物和调节脂质代谢。在这个项目中，我们将重点关注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实现。具体目的1，在细胞培养中，通过使用不同的化合物来检查PC如何影响ANGPTL3的细胞加工。具体目标2，在无细胞系统中，以确定PC对ANGPTL3加工的干扰是否对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检查其是否也影响致动脉粥样硬化小鼠模型中的血浆脂质水平和动脉粥样硬化的形成。具体目标3：将在小鼠的不同营养状态和急性炎症下检查该生物事件的生理相关性。这项研究不仅对更好地了解ANGPTL3的生物学过程非常重要，而且还可以描述PC如何调节脂质代谢，最终提供可能导致开发潜在的新方法来调节脂蛋白代谢和预防心血管疾病的信息。

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.