期刊
ATHEROSCLEROSIS
卷 248, 期 -, 页码 62-75出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.atherosclerosis.2016.02.018
关键词
PCSK9; LDL-C; LDL-receptor; VLDL; PCSK9-Centric lipid lowering; Pleiotropic; Monoclonal antibody; CRISPR-CAS9; Anti-sense oligonucleotide; Peptide-mimetic; Adnectin; Vaccine; Lipoprotein-apheresis
Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) regulates the expression of low-density lipoprotein (LDL)-receptors, through reducing their recycling by binding to the receptor along with LDL and targeting it for lysosomal destruction. PCSK9 also enhances the degradation of very-low-density-lipoprotein receptor (VLDLR) and lipoprotein receptor-related protein 1 (LRP-1) in a LDL-receptor independent manner. This role in lipid homeostasis presents PCSK9 as an attractive target for the therapeutic management of familial hypercholesterolemia as well as other refractory dyslipidaemias. However, PCSK9 mediates multifarious functions independent of its role in lipid homeostasis, which can be grouped under pleiotropic functions of the protein. This includes PCSK9's role in: trafficking of epithelial sodium channel; hepatic regeneration; pancreatic integrity and glucose homeostasis; antiviral activity; antimalarial activity; regulation of different cell signalling pathways; cortical neural differentiation; neuronal apoptosis and Alzheimer's disease. The question that needs to be investigated in depth is How will the pleotropic functions of PCSK9, be affected by the therapeutic intervention of the protease's LDL-receptor lowering activity? In this review, we appraise the different lipid lowering strategies targeting PCSK9 in light of the protein's different pleiotropic functions. Additionally, we delineate the key areas that require further examination, to ensure the long-term safety of the above lipid-lowering strategies. (C) 2016 Elsevier Ireland Ltd. All rights reserved.
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