The locus of the human proprotein convertase subtilisin–kexin type‐7 (PC7) gene (PCSK7) is on chromosome 11q23.3 close to the gene cluster APOA5/APOA4/APOC3/APOA1, a region implicated in the regulation of lipoprotein metabolism. A GWAS reported the association of PCSK7 SNPs with plasma triglyceride (TG), and exome sequencing of African Americans revealed the association of a low‐frequency coding variant of PC7 (R504H; SNP rs142953140) with a ~ 30% TG reduction. Another PCSK7 SNP rs508487 is in linkage disequilibrium with a promoter variant of the liver‐derived apolipoprotein A‐V (apoA‐V), an indirect activator of the lipoprotein lipase (LpL), and is associated with elevated TG levels. We thus hypothesized that PC7 regulates the levels/activity of apoA‐V. Studies in the human hepatic cell line HuH7 revealed that wild‐type (WT) PC7 and its endoplasmic reticulum (ER)‐retained forms bind to and enhance the degradation of human apoA‐V in acidic lysosomes in a nonenzymatic fashion. PC7‐induced degradation of apoA‐V is inhibited by bafilomycin A1 and the alkalinizing agents: chloroquine and NH₄Cl. Thus, the PC7‐induced apoA‐V degradation implicates an ER‐lysosomal communication inhibited by bafilomycin A1. In vitro, the natural R504H mutant enhances PC7 Ser⁵⁰⁵ phosphorylation at the structurally exposed Ser‐X‐Glu⁵⁰⁷ motif recognized by the secretory kinase Fam20C. Co‐expression of the phosphomimetic PC7‐S505E with apoA‐V resulted in lower degradation compared to WT, suggesting that Ser⁵⁰⁵ phosphorylation of PC7 lowers TG levels via reduced apoA‐V degradation. In agreement, in Pcsk7^−/− mice fed high‐fat diet, plasma apoA‐V levels and adipocyte LpL activity are increased, providing an in vivo mechanistic link for a role of liver PC7 in enhanced TG storage in adipocytes.

中文翻译：

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前蛋白转化酶7（PCSK7）降低apoA-V水平。

人类前蛋白转化酶7型枯草杆菌蛋白酶-kexin基因（PCSK7）的基因座位于11q23.3染色体上，靠近基因簇APOA5 / APOA4 / APOC3 / APOA1，该区域与脂蛋白代谢的调控有关。GWAS报告了PCSK7 SNP与血浆甘油三酸酯（TG）的关联，非洲裔美国人的外显子组测序显示PC7的低频编码变异体（R504H; SNP rs142953140）与TG降低约30％有关。另一个PCSK7 SNP rs508487与肝脏衍生的载脂蛋白A-V（apoA-V）的启动子变异（脂蛋白脂肪酶（LpL）的间接激活剂）存在连锁不平衡，并且与TG水平升高有关。因此，我们假设PC7调节apoA-V的水平/活性。对人类肝细胞系HuH7的研究表明，野生型（WT）PC7及其内质网（ER）保留的形式以非酶促方式结合并增强了酸性溶酶体中人apoA-V的降解。bafilomycin A1和碱化剂：氯喹和NH ₄ Cl抑制PC7诱导的apoA-V降解。因此，PC7诱导的apoA-V降解牵涉被bafilomycin A1抑制的ER-溶酶体通讯。在体外，天然R504H突变体增强PC7 Ser ⁵⁰⁵分泌激酶Fam20C识别的结构暴露的Ser-X-Glu ⁵⁰⁷基序的磷酸化。与WT相比，拟磷酸酯类PC7-S505E与apoA-V的共表达导致降解更低，这表明PC7的Ser ⁵⁰⁵磷酸化通过减少的apoA-V降解降低了TG水平。一致的是，在高脂饮食的Pcsk7 ^-/-小鼠中，血浆apoA-V水平和脂肪细胞LpL活性增加，为肝脏PC7在增强脂肪细胞中TG储存中的作用提供了体内机制联系。