Lagace Thomas A
Department of Pathology and Laboratory Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada.
Curr Opin Lipidol. 2014 Oct;25(5):387-93. doi: 10.1097/MOL.0000000000000114.
Proprotein convertase subtilisin/kexin type-9 (PCSK9) binds to LDL receptor (LDLR) and targets it for lysosomal degradation in cells. Decreased hepatic clearance of plasma LDL-cholesterol is the primary gauge of PCSK9 activity in humans; however, PCSK9's evolutionary role may extend to other lipoprotein classes and processes. This review highlights studies that are providing novel insights into physiological regulation of PCSK9 transcription and plasma PCSK9 activity.
Recent studies indicate that circulating PCSK9 binds to apolipoprotein B100 on LDL particles, which in turn inhibits PCSK9's ability to bind to cell surface LDLRs. Negative feedback of secreted PCSK9 activity by LDL could serve to increase plasma excursion of triglyceride-rich lipoproteins and monitor lipoprotein remodeling. Recent findings have identified hepatocyte nuclear factor-1α as a key transcriptional regulator that cooperates with sterol regulatory element-binding protein-2 to control PCSK9 expression in hepatocytes in response to nutritional and hormonal inputs, as well as acute inflammation.
PCSK9 is an established target for cholesterol-lowering therapies. Further study of PCSK9 regulatory mechanisms may identify additional control points for pharmacological inhibition of PCSK9-mediated LDLR degradation. PCSK9 function could reflect ancient roles in the fasting-feeding cycle and in linking lipoprotein metabolism with innate immunity.
前蛋白转化酶枯草溶菌素/kexin 9型（PCSK9）与低密度脂蛋白受体（LDLR）结合，并将其靶向细胞内溶酶体进行降解。肝脏对血浆低密度脂蛋白胆固醇清除率的降低是人类PCSK9活性的主要指标；然而，PCSK9在进化中的作用可能扩展到其他脂蛋白类别和过程。本综述重点介绍了一些研究，这些研究为PCSK9转录的生理调节和血浆PCSK9活性提供了新的见解。
最近的研究表明，循环中的PCSK9与低密度脂蛋白颗粒上的载脂蛋白B100结合，进而抑制PCSK9与细胞表面LDLR结合的能力。低密度脂蛋白对分泌的PCSK9活性的负反馈可能有助于增加富含甘油三酯脂蛋白的血浆清除率，并监测脂蛋白重塑。最近的研究发现，肝细胞核因子-1α是一种关键的转录调节因子，它与固醇调节元件结合蛋白-2协同作用，以响应营养和激素输入以及急性炎症来控制肝细胞中PCSK9的表达。
PCSK9是降胆固醇疗法的既定靶点。对PCSK9调节机制的进一步研究可能会确定PCSK9介导的LDLR降解的药理学抑制的其他控制点。PCSK9的功能可能反映了其在禁食-进食周期以及将脂蛋白代谢与先天免疫联系起来的古老作用。
