Functional Endoproteolysis Laboratory, Montreal Clinical Research Institute, Montreal, H2W 1R7 QC, Canada.
Biochem Cell Biol. 2022 Jun 1;100(3):189-198. doi: 10.1139/bcb-2021-0540. Epub 2022 Mar 9.
Proprotein Convertase Subtilisin/Kexin-type 9 (PCSK9) is a circulating negative regulator of hepatic low-density lipoprotein receptor (LDLR), which clears cholesterol from blood. Gain-of-function genetic mutations that amplify PCSK9 activity have been found to cause potentially lethal familial hypercholesterolemia. Inversely, reduction of its activity through loss-of-function genetics or with pharmaceuticals was shown to increase hepatic LDLR, to lower blood cholesterol, and to protect against cardiovascular diseases. New epidemiological and experimental evidence suggests that this reduction could also attenuate inflammation, reinforce cancer immunity, provide resistance to infections, and protect against liver pathologies. In this review, we question the relevance of this protein under normal physiology. We propose that PCSK9 is an important, but nonessential, modulator of cholesterol metabolism and immunity, and that its pathogenicity results from its chronic overexpression.
前蛋白转化酶枯草溶菌素 9（PCSK9）是一种循环的肝脏低密度脂蛋白受体（LDLR）负调节剂，可清除血液中的胆固醇。已经发现，功能获得性遗传突变会放大 PCSK9 的活性，从而导致潜在致命的家族性高胆固醇血症。相反，通过功能丧失遗传学或药物降低其活性可增加肝脏 LDLR，降低血液胆固醇，并预防心血管疾病。新的流行病学和实验证据表明，这种减少还可以减轻炎症、增强癌症免疫力、抵抗感染并预防肝脏病变。在这篇综述中，我们质疑了这种蛋白在正常生理条件下的相关性。我们提出 PCSK9 是胆固醇代谢和免疫的重要但非必需的调节剂，其致病性源于其慢性过表达。
