PCSK9降解低密度脂蛋白受体分子机制研究进展
收稿日期: 2020-04-06
修回日期: 2020-05-20
网络出版日期: 2020-05-21
基金资助
国家自然科学基金项目资助编号(91754101)
Progress on the molecular mechanisms of PCSK9-mediated degradation of low density lipoprotein receptor
Received date: 2020-04-06
Revised date: 2020-05-20
Online published: 2020-05-21
Supported by
Supported by the National Natural Science Foundation of China No(91754101)
血清低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)水平的升高是导致心血管疾病发生的主要危险因素。低密度脂蛋白受体(LDL receptor, LDLR)介导的低密度脂蛋白(low density lipoprotein, LDL)清除是决定循环中LDL-C水平的主要因素。LDL与细胞表面的LDLR结合后通过经典的网格蛋白小窝(clathrin-coated vesicles)内化进入细胞。在酸性核内体中,LDLR与LDL解离并循环回到细胞表面,释放的LDL将被运送到溶酶体中降解。前蛋白转化酶枯草溶菌素9 (proprotein convertase subtilisin kexin type 9, PCSK9)编码一种肝脏分泌型蛋白,其突变与LDL-C水平密切相关。前期研究已经证明,PCSK9直接与细胞表面的LDLR相互作用,二者一起通过网格蛋白小窝内化进入细胞。然而,在酸性核内体中,PCSK9和LDLR形成紧密的复合物,并进入溶酶体中进行降解,从而减少肝细胞表面LDLR的水平,降低肝脏对LDL-C的清除,该过程对于维持血浆中LDL在相对恒定的水平具有重要作用。因此,阻断PCSK9功能已成为治疗高胆固醇血症的新策略。本文综述了PCSK9的功能和机制研究的最新进展,并着重介绍了PCSK9抑制剂的研究进展,旨在为PCSK9-LDLR通路的研究和胆固醇代谢的调控提供参考。
吴玉娴, 王琰 . PCSK9降解低密度脂蛋白受体分子机制研究进展[J]. 遗传, 2020 , 42(10) : 965 -978 . DOI: 10.16288/j.yczz.20-065
Elevated serum level of low density lipoprotein cholesterol (LDL-C) is the leading risk factor for cardiovascular disease. LDL receptor (LDLR)-mediated LDL clearance is the major factor determining the LDL-C level in the circulation. LDL binds to the LDLR on the cell surface and enters the cells through classical clathrin-coated vesicles. In the acidic endosome, LDLR is uncoupled from LDL and recycles back to the cell surface. The released LDL is transported to the lysosome for degradation. The proprotein convertase subtilisin kexin type 9 (PCSK9) gene encodes a hepatic secretory protein, and its mutations are strongly associated with levels of LDL-C. We and others have shown that PCSK9 directly interacts with LDLR on the cell surface and both are internalized through the clathrin-coated vesicles. However, in the acidic endosome, PCSK9 and LDLR form a tight complex and are targeted to lysosome for degradation, thereby reducing the level of LDLR on the surface of hepatocytes and decreasing hepatic clearance of LDL-C, which plays an important role in maintaining a relatively constant level of LDL in the plasma. Thus, blocking PCSK9 function has become a new strategy to treat hypercholesterolemia.In this review, we will summarize the latest progress in the functional and mechanistic studies of PCSK9 and also highlight the research progress of PCSK9 inhibitors. It aims to provide a reference for the study of PCSK9-LDLR pathway and the regulation of cholesterol metabolism.
Key words： LDL-C; LDL receptor; PCSK9; endocytosis; PCSK9 inhibitor
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