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

心血管疾病通常指的是血管变窄或阻塞，可导致心脏病发作、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危险因素之一是血液中低密度脂蛋白（LDL）胆固醇水平升高——通常被称为“坏胆固醇”。血液中低密度脂蛋白胆固醇的含量是由肝细胞对其的吸收来控制的。肝细胞表面有一种特殊的蛋白质，LDL受体，它与LDL-胆固醇结合。肝细胞表面活性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。通过一系列分子和细胞研究，我们已经确定低密度脂蛋白受体是由酶BMP1切割的。BMP1对受体的切割降低了受体吸收低密度脂蛋白胆固醇进入细胞的能力。根据这些观察，我们假设BMP1对人类LDL受体的蛋白水解裂解调节LDL-胆固醇的摄取，从而调节血液中LDL-胆固醇的水平。本项目的总体目标是验证BMP1对人体低密度脂蛋白受体的蛋白水解裂解在体内调节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，并研究支撑这一假设的分子和细胞机制。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ldl -胆固醇浓度的新机制。这项研究的发现将是非常重要的，无论是在理解日益复杂的低密度脂蛋白胆固醇的调节过程，以及潜在地提供一个新的机制，可能是新的降胆固醇药物的目标。

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.