{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T04:09:03Z","timestamp":1790050143789,"version":"4.0.1"},"reference-count":70,"publisher":"Oxford University Press (OUP)","issue":"11","license":[{"start":{"date-parts":[[2014,11,1]],"date-time":"2014-11-01T00:00:00Z","timestamp":1414800000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2014,11,1]]},"abstract":"<jats:sec>\n                  <jats:title>BACKGROUND<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>CONTENT<\/jats:title>\n                  <jats:p>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\u2013like 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\u2013mediated 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\u2013LDL-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).<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>SUMMARY<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1373\/clinchem.2014.225946","type":"journal-article","created":{"date-parts":[[2014,9,24]],"date-time":"2014-09-24T02:51:58Z","timestamp":1411527118000},"page":"1380-1389","source":"Crossref","is-referenced-by-count":39,"title":["Proprotein Convertase Subtilisin\/Kexin Type 9 (PCSK9): Lessons Learned from Patients with Hypercholesterolemia"],"prefix":"10.1093","volume":"60","author":[{"given":"Zuhier","family":"Awan","sequence":"first","affiliation":[{"name":"King Abdulaziz University, Jeddah, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Baass","sequence":"first","affiliation":[{"name":"The McGill University Health Centre, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacques","family":"Genest","sequence":"first","affiliation":[{"name":"The McGill University Health Centre, Montreal, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2014,11,1]]},"reference":[{"key":"2020022705522262100_B1","doi-asserted-by":"crossref","first-page":"928","DOI":"10.1073\/pnas.0335507100","article-title":"The secretory proprotein convertase neural apoptosis-regulated convertase 1 (NARC-1): liver regeneration and neuronal differentiation","volume":"100","author":"Seidah","year":"2003","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2020022705522262100_B2","doi-asserted-by":"crossref","first-page":"154","DOI":"10.1038\/ng1161","article-title":"Mutations in PCSK9 cause autosomal dominant hypercholesterolemia","volume":"34","author":"Abifadel","year":"2003","journal-title":"Nat 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