Proprotein Convertases Subtilisin/Kexin Type 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)

Abstract

Proprotein Convertases Subtilisin/Kexin Type 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.

Circulating PCSK9 Over SREBP-2 Expression Affects Serum LDL and Cholesterol Levels

“…9 In the present study, the participants' lipid profiles, PCSK9 protein levels and SREBP-2 expression levels were evaluated. Some studies have suggested that the effect of PCSK9 on cellular membrane LDLR levels might be different in extra-hepatic tissues producing steroids 10,11 In the present study, the circulating PCSK9 level was significantly correlated with LDL-C and total cholesterol levels, confirming other studies 12,13 The results also revealed that the PCSK9 level is strictly correlated with the total cholesterol/HDL-C ratio, which might be a better indicator for assessing PCSK9. The data also showed a linear correlation, but not a significant one, between the plasma PCSK9 protein and SREBP-2 expression levels.…”

Induction of Sustained Hypercholesterolemia by Single Adeno-Associated Virus–Mediated Gene Transfer of Mutant hPCSK9

“…Hepatocytes control blood LDL levels through the expression of PCSK9, the major regulator of the LDLR. 23,24 Dysregulation of this pathway by gain-of-function mutations in PCSK9, such as D374Y 25,26 (PCSK9 DY ), is linked to hypercholesterolemia and atherosclerosis. [27][28][29] To test the effect of stable liver transexpression of this mutant on plasma lipoprotein homeostasis and atherosclerosis development in adult animals, we generated an AAV vector encoding human PCSK9 DY ( Figure 1A).…”

Mutation spectrum and polygenic score in German patients with familial hypercholesterolemia

“…2 Furthermore, mutations in three genes are known to cause FH: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). [3][4][5] Mutations in the LDL receptor adapter protein 1 gene (LDLRAP1) cause a very rare autosomal-recessive (AR) form of the disease, that is, AR hypercholesterolemia with a FH-like clinical phenotype. 6 The majority of FH causing variants have been found in the LDLR gene with currently over 1900 reported sequence alterations (https://databases.lovd.nl/ shared/genes/LDLR).…”