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首页> 外文期刊>Current opinion in lipidology >PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells
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PCSK9 and LDLR degradation: regulatory mechanisms in circulation and in cells

机译：PCSK9和LDLR降解：循环和细胞中的调节机制

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Purpose of review: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 findings: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-1alpha 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.Summary: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.
机译：综述目的：前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）与LDL受体（LDLR）结合，并将其靶向细胞中的溶酶体降解。血浆LDL-胆固醇的肝清除率降低是人类PCSK9活性的主要指标;但是，PCSK9的进化作用可能会扩展到其他脂蛋白类别和过程。最近的研究表明，循环中的PCSK9与LDL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。 LDL分泌的PCSK9活性的负反馈可能有助于增加富含甘油三酸酯的脂蛋白的血浆偏移并监测脂蛋白重塑。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，可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。降低胆固醇治疗的既定目标。 PCSK9调控机制的进一步研究可能会确定药理抑制PCSK9介导的LDLR降解的其他控制点。 PCSK9的功能可能反映了古代的禁食-喂养周期以及将脂蛋白代谢与先天免疫联系起来的作用。

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