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The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol

Authors Poirier S, Mayer G

Received 26 July 2013

Accepted for publication 23 August 2013

Published 4 October 2013 Volume 2013:7 Pages 1135—1148

DOI https://doi.org/10.2147/DDDT.S36984

Checked for plagiarism Yes

Review by Single-blind

Peer reviewer comments 6


Steve Poirier,1,2 Gaétan Mayer1–3

1
Laboratory of Molecular Cell Biology, Montreal Heart Institute, Montréal, QC, Canada; 2Départements de Pharmacologie, 3Médecine, Faculté de Médecine, Université de Montréal, Montréal, QC, Canada

Abstract: Proprotein convertase subtilisin/kexin type 9 (PCSK9) directly binds to the epidermal growth factor-like repeat A domain of low-density lipoprotein receptor and induces its degradation, thereby controlling circulating low-density lipoprotein cholesterol (LDL-C) concentration. Heterozygous loss-of-function mutations in PCSK9 can decrease the incidence of coronary heart disease by up to 88%, owing to lifelong reduction of LDL-C. Moreover, two subjects with PCSK9 loss-of-function mutations on both alleles, resulting in a total absence of functional PCSK9, were found to have extremely low circulating LDL-C levels without other apparent abnormalities. Accordingly, PCSK9 could represent a safe and effective pharmacological target to increase clearance of LDL-C and to reduce the risk of coronary heart disease. Recent clinical trials using anti-PCSK9 monoclonal antibodies that block the PCSK9:low-density lipoprotein receptor interaction were shown to considerably reduce LDL-C levels by up to 65% when given alone and by up to 72% in patients already receiving statin therapy. In this review, we will discuss how major scientific breakthroughs in PCSK9 cell biology have led to the development of new and forthcoming LDL-C-lowering pharmacological agents.

Keywords: PCSK9, LDLR, LDL-cholesterol, lipoproteins, coronary heart disease, inhibitors, monoclonal antibody therapy

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