Department of Medicine, McMaster University, The Research Institute of St. Joe's Hamilton and Hamilton Centre for Kidney Research, Hamilton, Ontario, Canada.
Laboratory of Functional Endoproteolysis, Clinical Research Institute of Montreal, affiliated with the University of Montreal, Montreal, Quebec, Canada.
J Clin Invest. 2021 Jan 19;131(2). doi: 10.1172/JCI128650.
Individuals harboring the loss-of-function (LOF) proprotein convertase subtilisin/kexin type 9 Gln152His variation (PCSK9Q152H) have low circulating low-density lipoprotein cholesterol levels and are therefore protected against cardiovascular disease (CVD). This uncleavable form of proPCSK9, however, is retained in the endoplasmic reticulum (ER) of liver hepatocytes, where it would be expected to contribute to ER storage disease (ERSD), a heritable condition known to cause systemic ER stress and liver injury. Here, we examined liver function in members of several French-Canadian families known to carry the PCSK9Q152H variation. We report that PCSK9Q152H carriers exhibited marked hypocholesterolemia and normal liver function despite their lifelong state of ER PCSK9 retention. Mechanistically, hepatic overexpression of PCSK9Q152H using adeno-associated viruses in male mice greatly increased the stability of key ER stress-response chaperones in liver hepatocytes and unexpectedly protected against ER stress and liver injury rather than inducing them. Our findings show that ER retention of PCSK9 not only reduced CVD risk in patients but may also protect against ERSD and other ER stress-driven conditions of the liver. In summary, we have uncovered a cochaperone function for PCSK9Q152H that explains its hepatoprotective effects and generated a translational mouse model for further mechanistic insights into this clinically relevant LOF PCSK9 variant.
个体携带蛋白酶原转化酶枯草溶菌素 9 型（PCSK9）Glu152His 无功能（LOF）变异（PCSK9Q152H），其循环中的低密度脂蛋白胆固醇水平较低，因此可预防心血管疾病（CVD）。然而，这种无活性的前蛋白转化酶原 9 形式会在肝细胞的内质网（ER）中滞留，这可能导致 ER 储存疾病（ERSD），这是一种已知可引起全身性 ER 应激和肝损伤的遗传性疾病。在此，我们检查了几个法裔加拿大家族成员的肝功能，这些家族已知携带 PCSK9Q152H 变异。我们报告称，尽管 PCSK9Q152H 携带者终生处于 ER PCSK9 滞留状态，但他们表现出明显的低胆固醇血症和正常肝功能。从机制上讲，通过腺相关病毒在雄性小鼠中肝过量表达 PCSK9Q152H，大大增加了关键 ER 应激反应伴侣在内质网肝细胞中的稳定性，出人意料地保护它们免受 ER 应激和肝损伤，而不是诱导它们。我们的发现表明，PCSK9 的 ER 滞留不仅降低了患者的 CVD 风险，而且还可能预防 ERSD 和肝脏的其他 ER 应激驱动疾病。总之，我们发现了 PCSK9Q152H 的共伴侣功能，解释了其对肝脏的保护作用，并为进一步研究这种临床上相关的 LOF PCSK9 变体提供了一种转化小鼠模型。
