title: Proprotein convertase subtilisin/kexin type 9 (PCSK9): lessons learned from patients with hypercholesterolemia.
abstract: BACKGROUND
  Identification of the proprotein convertase subtilisin/kexin type 9 (PCSK9) as the third gene causing familial hypercholesterolemia (FH) and understanding its complex biology has led to the discovery of a novel class of therapeutic agents.
  
  
  BACKGROUND
  PCSK9 undergoes autocatalytic cleavage in the endoplasmic reticulum and enters the secretory pathway. The PCSK9 gene is under the regulatory control of sterol receptor binding proteins 1 and 2. Statins increase PCSK9 and this may modulate the response to this class of medications. In plasma, PCSK9 binds to the epidermal growth factor-like domain of the LDL receptor (LDL-R) on the cell and, once incorporated in the late endosomal pathway, directs the LDL-R toward lysosomal degradation rather than recycling to the plasma membrane. Thus, gain-of-function PCSK9 mutations lead to an FH phenotype, whereas loss-of-function mutations are associated with increased LDL-R-mediated endocytosis of LDL particles and lower LDL cholesterol in plasma. Inhibition of PCSK9 is thus an attractive therapeutic target. Presently, this is achieved by using monoclonal antibodies for allosteric inhibition of the PCSK9-LDL-R interaction. Phase 2 and 3 clinical trials in patients with moderate and severe hypercholesterolemia (including FH) show that this approach is safe and highly efficacious to lower LDL-C and lipoprotein(a).
  
  
  CONCLUSIONS
  PCSK9 has other biological roles observed in vitro and in animal studies, including viral entry into the cell, insulin resistance, and hepatic tissue repair. Given the potential number of humans exposed to this novel class of medications, careful evaluation of clinical trial results is warranted.
authors.affiliation: King Abdulaziz University, Jeddah, Saudi Arabia;
authors.forename: Zuhier
authors.initials: Z
authors.lastname: Awan
authors.affiliation: The McGill University Health Centre, Montreal, Canada.
authors.forename: Alexis
authors.initials: A
authors.lastname: Baass
authors.affiliation: The McGill University Health Centre, Montreal, Canada. jacques.genest@mcgill.ca.
authors.forename: Jacques
authors.initials: J
authors.lastname: Genest
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D008078:Cholesterol, LDL / Q000378:metabolism; D017326:Clinical Trials, Phase III as Topic; D004195:Disease Models, Animal; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics; D009154:Mutation; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000235:genetics / Q000378:metabolism*; D016032:Randomized Controlled Trials as Topic; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D012697:Serine Endopeptidases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; D008078:Cholesterol, LDL; D011973:Receptors, LDL; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases