The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol.
The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol.
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DOI：
10.2147/dddt.s36984
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
Mayer G
中科院分区：
文献类型：
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作者：
Poirier S;Mayer G
前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型 (PCSK9) 直接与低密度脂蛋白受体的表皮生长因子样重复 A 结构域结合并诱导其降解，从而控制循环低密度脂蛋白胆固醇 (LDL-C) 浓度。 PCSK9 杂合功能丧失突变可降低 LDL-C 的终生水平，从而使冠心病的发病率降低高达 88%。此外，两个等位基因均带有 PCSK9 功能丧失突变（导致功能性 PCSK9 完全缺失）的两名受试者的循环 LDL-C 水平极低，没有其他明显异常。因此，PCSK9 可以代表一个安全有效的药理学靶点，以增加 LDL-C 的清除率并降低冠心病的风险。最近的临床试验显示，使用阻断 PCSK9:低密度脂蛋白受体相互作用的抗 PCSK9 单克隆抗体，单独使用时可显着降低 LDL-C 水平高达 65%，在已经接受他汀类药物治疗的患者中可显着降低高达 72%。在这篇综述中，我们将讨论 PCSK9 细胞生物学的重大科学突破如何导致新型和即将推出的 LDL-C 降低药物的开发。
Proprotein convertase subtilisin/kexin type 9 (PCSK9) directly binds to the epidermal growth factor-like repeat A domain of low-density lipoprotein receptor and induces its degradation, thereby controlling circulating low-density lipoprotein cholesterol (LDL-C) concentration. Heterozygous loss-of-function mutations in PCSK9 can decrease the incidence of coronary heart disease by up to 88%, owing to lifelong reduction of LDL-C. Moreover, two subjects with PCSK9 loss-of-function mutations on both alleles, resulting in a total absence of functional PCSK9, were found to have extremely low circulating LDL-C levels without other apparent abnormalities. Accordingly, PCSK9 could represent a safe and effective pharmacological target to increase clearance of LDL-C and to reduce the risk of coronary heart disease. Recent clinical trials using anti-PCSK9 monoclonal antibodies that block the PCSK9:low-density lipoprotein receptor interaction were shown to considerably reduce LDL-C levels by up to 65% when given alone and by up to 72% in patients already receiving statin therapy. In this review, we will discuss how major scientific breakthroughs in PCSK9 cell biology have led to the development of new and forthcoming LDL-C-lowering pharmacological agents.