Clinical trials have unequivocally shown that inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) efficaciously and safely prevents cardiovascular events by lowering levels of LDL cholesterol. PCSK9 in the circulation is derived mainly from the liver, but the protein is also expressed in the pancreas, the kidney, the intestine and the central nervous system. Although PCSK9 modulates cholesterol metabolism by regulating LDL receptor expression in the liver, in vitro and in vivo studies have suggested that PCSK9 is involved in various other physiological processes. Although therapeutic PCSK9 inhibition could theoretically have undesired effects by interfering with these non-cholesterol-related processes, studies of individuals with genetically determined reduced PCSK9 function and clinical trials of PCSK9 inhibitors have not revealed clinically meaningful adverse consequences of almost completely eradicating PCSK9 from the circulation. The clinical implications of PCSK9 functions beyond lipid metabolism in terms of wanted or unwanted effects of therapeutic PCSK9 inhibition therefore appear to be limited. The objective of this Review is to describe the physiological role of PCSK9 beyond the LDL receptor to provide a rational basis for monitoring the effects of PCSK9 inhibition as these drugs gain traction in the clinic.

临床试验明确表明，抑制前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）可通过降低LDL胆固醇水平有效而安全地预防心血管事件。循环中的PCSK9主要来自肝脏，但蛋白质也表达于胰腺，肾脏，肠和中枢神经系统。尽管PCSK9通过调节肝脏中的LDL受体表达来调节胆固醇代谢，但体外和体内研究表明PCSK9参与了其他各种生理过程。尽管理论上通过抑制这些与胆固醇无关的过程，治疗性PCSK9抑制作用可能会产生不良影响，对基因确定的PCSK9功能降低的个体进行的研究以及PCSK9抑制剂的临床试验还没有发现从循环中几乎完全消除PCSK9的临床意义的不良后果。因此，就治疗性PCSK9抑制的想要或不想要的作用而言，PCSK9的功能不仅限于脂质代谢，还具有临床意义。这篇综述的目的是描述PCSK9在LDL受体以外的生理作用，以为监测PCSK9抑制作用提供合理的依据，因为这些药物在临床上越来越受关注。因此，就治疗性PCSK9抑制的想要或不想要的作用而言，PCSK9的功能不仅限于脂质代谢，还具有临床意义。这篇综述的目的是描述PCSK9在LDL受体以外的生理作用，以为监测PCSK9抑制作用提供合理的依据，因为这些药物在临床上越来越受关注。因此，就治疗性PCSK9抑制的想要或不想要的作用而言，PCSK9的功能不仅限于脂质代谢，还具有临床意义。这篇综述的目的是描述PCSK9在LDL受体以外的生理作用，以为监测PCSK9抑制作用提供合理的依据，因为这些药物在临床上越来越受关注。