PCSK9 inhibitors in sepsis: a new potential indication?

Human PCSK9 (Proprotein convertase subtilisin kexin type 9) gene, located in chromosome 1p33–34.3 close to the third genetic locus associated with familial hypercholesterolemia (FH), encodes a serine protease enzyme belonging to the proteinase K subfamily of subtilases. It has been found that liver is not only the key source of PCSK9 biosynthesis but also the main target of PCSK9 activity. PCSK9 is a key regulator of serum cholesterol levels that acts through regulation of low-density lipoprotein cholesterol (LDL-C) by targeting liver low-density lipoprotein receptor (LDLR). Besides LDLR, PCSK9 can regulate very low-density lipoprotein receptors (VLDLRs) that also mediate LPS removal from the circulation. The best known function of PCSK9 is posttranslational regulation of LDLR on hepatocytes that is the major route for LDL-C clearance from the circulation. Mechanistically, secreted PCSK9 circulates in bloodstream binds to LDLR on the surface of hepatocytes and escorts it into the lysosome compartment through clathrin-mediated endocytosis. Moreover, PCSK9 can act intracellularly to enhance LDLR degradation as evidenced by the hypercholesterolemic effects of S127R mutation (which reduces PCSK9 secretion) [1]. PCSK9 binding inhibits recycling of LDLR to the cell surface and enhances lysosomal degradation of LDLR. Consequently, there are not many LDLRs remaining to clear LDL-C from the bloodstream when the plasma PCSK9 levels are elevated as a result of gain-of-function (GOF)mutations, leading to the accumulation of plasma cholesterol in the vascular endothelial cell wall and consequent atherosclerosis. Conversely, when there is low or no PCSK9 in plasma as a result of loss-of-function (LOF) mutations, there will be more intact LDLR which in turn trap more LDL-C from the bloodstream [2].