Department of Vascular Medicine, Academisch Medisch Centrum, Amsterdam, Netherlands.
Inserm UMR 1188 DéTROI, Université de La Réunion, Saint-Denis de La Réunion, France.
Nat Rev Endocrinol. 2018 Dec;15(1):52-62. doi: 10.1038/s41574-018-0110-5.
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，通过降低 LDL 胆固醇水平，抑制前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）可有效且安全地预防心血管事件。循环中的 PCSK9 主要来源于肝脏，但该蛋白也在胰腺、肾脏、肠道和中枢神经系统中表达。虽然 PCSK9 通过调节肝脏中 LDL 受体的表达来调节胆固醇代谢，但体外和体内研究表明，PCSK9 还参与了各种其他生理过程。虽然理论上通过干扰这些与胆固醇无关的过程，治疗性 PCSK9 抑制可能会产生不良影响，但具有遗传决定的 PCSK9 功能降低的个体研究和 PCSK9 抑制剂的临床试验并未显示出从循环中几乎完全消除 PCSK9 会带来临床上有意义的不良后果。因此，治疗性 PCSK9 抑制的除脂质代谢以外的 PCSK9 功能的临床意义，在药物治疗的预期或非预期效果方面似乎是有限的。本综述的目的是描述 PCSK9 除 LDL 受体以外的生理作用，为监测 PCSK9 抑制的效果提供合理依据，因为这些药物在临床上逐渐得到应用。
