title: The biology of PCSK9 from the endoplasmic reticulum to lysosomes: new and emerging therapeutics to control low-density lipoprotein cholesterol.
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.
authors.affiliation: Laboratory of Molecular Cell Biology, Montreal Heart institute, Montréal, QC, Canada ; Départements de Pharmacologie, Montréal, Université de Montréal, Montréal, QC, Canada.
authors.forename: Steve
authors.initials: S
authors.lastname: Poirier
authors.forename: Gaétan
authors.initials: G
authors.lastname: Mayer
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D008078:Cholesterol, LDL / Q000097:blood*; D003327:Coronary Disease / Q000503:physiopathology / Q000517:prevention & control; D015195:Drug Design; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D058990:Molecular Targeted Therapy; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D000924:Anticholesteremic Agents; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases
keywords: LDL-cholesterol; LDLR; PCSK9; coronary heart disease; inhibitors; lipoproteins; monoclonal antibody therapy