Proprotein C onvertases S ubtilisin/ K exin T ype 9, an enzyme turned escort protein: Hepatic and extra hepatic functions (第9型前蛋白转换酶—枯草溶菌素/蛋白酶K，一种酶转变的护送蛋白：在肝脏与肝外的功能)

P roprotein C onvertases S ubtilisin/ K exin T ype 9 ( PCSK9 ) is a serine endoproteinase. 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‐density lipoprotein receptor ( LDLR ) at the surface of hepatocytes and, after co‐endocytosis, directs it into lysosomes where it is degraded. By downregulating LDLR , PCSK9 reduces hepatic clearance of LDL ‐cholesterol. Inborn or induced increase of this function causes hypercholesterolemia; its decrease causes hypocholesterolemia. This has been experimentally demonstrated ex vivo and in vivo , and corroborated by epidemiological studies associating PCSK9 genetic variations with plasma cholesterol levels. PCSK9 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‐effects. Some experimental data suggest that PCSK9 could contribute positively to the physiology of non‐hepatic cells such as pancreatic islets β cells, adipocytes and macrophages, protecting them from excessive lipid uptake, in an endocrine, autocrine, or paracrine manner. Genetic variations that attenuate PCSK9 anti‐ LDLR 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.