降胆固醇药物新靶标前蛋白转化酶枯草溶菌素9的研究进展

Proprotein convertase subtilisin/kexin type 9 as a new target of anticholesteremic agent:an update

他汀类药物主要用于降低血低密度脂蛋白胆固醇(LDL-C)以及预防心血管疾病,但其临床疗效和机体的耐受性尚存在不稳定性。人类前蛋白转化酶枯草溶菌素9(PCSK9)属于前蛋白转化酶家族,主要由肝脏产生并分泌入血,可促进肝脏中低密度脂蛋白受体(LDLR)的降解,从而参与调控血LDL-C水平。人群中PCSK9的功能获得型或缺失型基因突变与血LDL-C含量、心血管疾病患病率密切相关。可通过负反馈机制上调PCSK9,促进LDLR的降解,从而降低他汀类药物的疗效。因此,抑制PCSK9活性可望成为治疗高胆固醇血症的一种新的有效方法。本文主要综述PCSK9调节胆固醇代谢及其临床应用的研究进展。

Statins are mainly used to reduce the content of low-density lipoprotein-cholesterol(LDL-C)and to prevent cardiovascular disease,but its clinical efficacy and the tolerance of body are still uncertain.Human proprotein convertase subtilisin/kexin type 9(PCSK9),a member of pre-protein convertase family,is mainly produced in the liver and then released into blood,and plays an important role in regulating plasma LDL-C levels by promoting the degradation of low-density lipoprotein receptor(LDLR)in the liver.Both gain-of-function-and loss-of-function-mutation of PCSK9 have great impact on circulating LDL-C levels and the risk of cardiovascular diseases.Statins can up-regulate the expression of PCSK9 through negative feedback regulation by decreasing hepatic cholesterol.As a result,PCSK9 can reduce the efficiency of statins by promoting the degradation of LDLR;therefore inhibiting PCSK9 is expected to be an effective treatment for hypercholesterolemia.In this paper we reviewed the function of PCSK9 in cholesterol metabolism and its clinical application.