前蛋白转化酶枯草溶菌素9的研究进展

Research Progress of Proprotein Converting Enzyme Subtilisin 9

前蛋白转化酶枯草溶菌素9(PCSK9)是调节低密度脂蛋白-胆固醇(LDL-C)循环水平的重要蛋白,在低密度脂蛋白受体(LDLR)降解中起关键作用。PCSK9主要通过靶向肝脏中低密度脂蛋白受体(LDLR)的降解来调节胆固醇代谢。PCSK9功能获得突变是常染色体显性高胆固醇血症的遗传原因之一。相反,功能缺失突变与低浓度的LDL胆固醇(LDL-C)和冠心病发病率的降低有关。由于这些缺失功能突变与明显的有害作用无关,抑制PCSK9是降低LDL-C浓度的一种有吸引力的新策略。在抑制PCSK9的各种方法中,人类数据仅可用于抑制PCSK9与LDLR结合的单克隆抗体。此外,也有研究表明,PCSK9可能在神经发生、神经元迁移和凋亡中发挥作用。近年来,降低胆固醇治疗的潜在神经不良反应,特别是PCSK9抑制剂引起了一些关注。该文对PCSK9的功能及其抑制剂的研究进展做一综述。

Proprotein convertase Bacillus subtilis protein convertase 9(PCSK9)is an important protein that regulates the circulating levels of low-density lipoprotein-cholesterol(LDL-C)and plays a key role in the degradation of low-density lipoprotein receptor(LDLR).PCSK9 mainly regulates cholesterol metabolism by targeting the degradation of low-density lipoprotein receptor(LDLR)in the liver.PCSK9 gain-of-function mutation is one of the genetic causes of autosomal dominant hypercholesterolemia.In contrast,loss-of-function mutations are associated with low concentrations of LDL cholesterol(LDL-C)and a decrease in the incidence of coronary heart disease.Since these loss-of-function mutations have nothing to do with obvious harmful effects,inhibiting PCSK9 is an attractive new strategy to reduce the concentration of LDL-C.Among the various methods of inhibiting PCSK9,human data can only be used for monoclonal antibodies that inhibit the binding of PCSK9 to LDLR.In addition,studies have also shown that PCSK9 may play a role in neurogenesis,neuronal migration and apoptosis.In recent years,the potential neurological adverse reaction of cholesterol-lowering treatments,especially PCSK9 inhibitors,have attracted some attention.The article reviews the research progress of PCSK9's function and its inhibitors.