INVITED REVIEW Molecular and cellular function of the proprotein convertase subtilisin/kexin type 9 (PCSK9)

Abstract The proprotein convertase subtilisin/kexin type 9 (PCSK9) has emerged as a promising treatment target to lower serum cholesterol, a major risk factor of cardiovas-cular diseases. Gain-of-function mutations of PCSK9 are associated with hypercholesterolemia and increased risk of cardiovascular events. Conversely, loss-of-function muta-tions cause low-plasma LDL-C levels and a reduction of cardiovascular risk without known unwanted effects on individual health. Experimental studies have revealed that PCSK9 reduces the hepatic uptake of LDL-C by increasing the endosomal and lysosomal degradation of LDL recep-tors (LDLR). A number of clinical studies have demon-strated that inhibition of PCSK9 alone and in addition to statins potently reduces serum LDL-C concentrations. This review summarizes the current data on the regulation of PCSK9, its molecular function in lipid homeostasis and the emerging evidence on the extra-hepatic effects of PCSK9