Proteolytic cleavage of the low density lipoprotein (LDL) receptor: a novel regulator of plasma LDL cholesterol?

低密度脂蛋白 (LDL) 受体的蛋白水解裂解：血浆 LDL 胆固醇的新型调节剂？

• 批准号: MR/L009625/1
• 负责人: Nigel Hooper
• 金额: $ 50.34万
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL009625%2F1
• 关键词: Proteolytic; cleavage; low; density; lipoprotein

Cardiovascular disease, a term that generally refers to conditions that involve narrowed or blocked blood vessels that can lead to a heart attack, chest pain (angina) or stroke, kills one in three people in the UK. One of the most significant risk factors for cardiovascular disease is elevated levels of low-density lipoprotein (LDL) cholesterol - often referred to as 'bad cholesterol' - in the blood. The amount of LDL-cholesterol in the blood is controlled by its uptake into liver cells. On the surface of the liver cells is a specific protein, the LDL receptor, that binds the LDL-cholesterol. The number of active LDL receptors on the surface of liver cells is the single most important factor in regulating the amount of LDL-cholesterol in the blood. Through a series of molecular and cell-based studies we have identified that the LDL receptor is cut by the enzyme BMP1. This cleavage of the receptor by BMP1 reduces the ability of the receptor to take up the LDL-cholesterol into the cells. From these observations we hypothesise that proteolytic cleavage of the human LDL receptor by BMP1 regulates LDL-cholesterol uptake and hence the blood level of LDL-cholesterol. The overall aim of this project is to test the hypothesis that proteolytic cleavage of the human LDL receptor by BMP1 regulates LDL receptor function and hence plasma LDL cholesterol in vivo, and investigate the molecular and cellular mechanisms underpinning this. This will include utilizing mouse models to determine whether regulation of the activity of BMP1 may be a novel mechanism to lower the concentration of LDL-cholesterol in the blood. The findings from this research will be of great importance, both in terms of understanding the increasingly complex processes underlying the regulation of LDL-cholesterol, as well as potentially providing a new mechanism that could be a target for novel cholesterol-lowering drugs.

心血管疾病是一个术语，通常指的是涉及血管狭窄或堵塞的疾病，这些疾病可能导致心脏病发作、胸痛(心绞痛)或中风，在英国，三分之一的人死于心血管疾病。心血管疾病最重要的风险因素之一是血液中低密度脂蛋白(LDL)胆固醇--通常被称为“坏胆固醇”--水平升高。低密度脂蛋白-胆固醇在血液中的含量受其在肝细胞中的吸收控制。肝细胞表面有一种特殊的蛋白质，即低密度脂蛋白受体，它与低密度脂蛋白-胆固醇结合在一起。肝细胞表面活跃的低密度脂蛋白受体的数量是调节血液中低密度脂蛋白胆固醇含量的最重要因素。通过一系列基于分子和细胞的研究，我们已经确定低密度脂蛋白受体被BMP1酶切割。BMP1对受体的这种切割降低了受体将低密度脂蛋白-胆固醇吸收到细胞中的能力。根据这些观察，我们假设BMP1对人低密度脂蛋白受体的蛋白水解性切割调节低密度脂蛋白胆固醇的摄取，从而调节低密度脂蛋白胆固醇的血液水平。该项目的总体目标是验证BMP1对人低密度脂蛋白受体的蛋白水解性切割调节体内低密度脂蛋白受体功能从而调节血浆低密度脂蛋白胆固醇的假设，并探讨支持这一假说的分子和细胞机制。这将包括利用小鼠模型来确定BMP1活性的调节是否可能是降低血液中低密度脂蛋白-胆固醇浓度的新机制。这项研究的发现将具有非常重要的意义，无论是在理解调节低密度脂蛋白-胆固醇的日益复杂的过程方面，还是在潜在地提供一种可能成为新型降胆固醇药物靶点的新机制方面。

项目成果

VEGF-A isoforms program differential VEGFR2 signal transduction, trafficking and proteolysis.

• DOI: 10.1242/bio.017434
• 发表时间: 2016-05-15
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Fearnley GW;Smith GA;Abdul-Zani I;Yuldasheva N;Mughal NA;Homer-Vanniasinkam S;Kearney MT;Zachary IC;Tomlinson DC;Harrison MA;Wheatcroft SB;Ponnambalam S
• 通讯作者: Ponnambalam S