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Biosynthesized as a zymogen, it cleaves itself once, and then turns into an escort protein for transmembrane proteins, leading them into lysosomes for degradation. It is primarily produced and secreted by the liver. It attaches to the low\u2010density lipoprotein receptor (<jats:styled-content style=\"fixed-case\">LDLR<\/jats:styled-content>) at the surface of hepatocytes and, after co\u2010endocytosis, directs it into lysosomes where it is degraded. By downregulating <jats:styled-content style=\"fixed-case\">LDLR<\/jats:styled-content>, <jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content> reduces hepatic clearance of <jats:styled-content style=\"fixed-case\">LDL<\/jats:styled-content>\u2010cholesterol. Inborn or induced increase of this function causes hypercholesterolemia; its decrease causes hypocholesterolemia. This has been experimentally demonstrated <jats:italic>ex vivo<\/jats:italic> and <jats:italic>in vivo<\/jats:italic>, and corroborated by epidemiological studies associating <jats:italic><jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content><\/jats:italic> genetic variations with plasma cholesterol levels. <jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content> is now a proven target for inactivation in the treatment of hypercholesterolemia and associated atherosclerosis. However, it is still uncertain whether its severe or complete inactivation, combined with other predispositions, will be without undesirable side\u2010effects. Some experimental data suggest that <jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content> could contribute positively to the physiology of non\u2010hepatic cells such as pancreatic islets \u03b2 cells, adipocytes and macrophages, protecting them from excessive lipid uptake, in an endocrine, autocrine, or paracrine manner. Genetic variations that attenuate <jats:styled-content style=\"fixed-case\">PCSK9<\/jats:styled-content> anti\u2010<jats:styled-content style=\"fixed-case\">LDLR<\/jats:styled-content> activity are common in human populations. Their evolutionary significance still needs to be evaluated on the background of environmental pressures, such as infectious diseases, cold weather and famine, which have threatened survival and reproduction in the course of human prehistory and history.<\/jats:p>","DOI":"10.1111\/1753-0407.12064","type":"journal-article","created":{"date-parts":[[2013,5,29]],"date-time":"2013-05-29T07:44:44Z","timestamp":1369813484000},"page":"391-405","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Proprotein <scp>C<\/scp>onvertases <scp>S<\/scp>ubtilisin\/<scp>K<\/scp>exin <scp>T<\/scp>ype 9, an enzyme turned escort protein: Hepatic and extra hepatic functions 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