The PCSK9 decade

Abstract

PCSK9 proprotein convertase subtilisin/kexin type (PCSK9) is a crucial protein in LDL cholesterol (LDL-C) metabolism by virtue of its pivotal role in the degradation of the LDL receptor. In recent years, both in vitro and in vivo studies have greatly supplemented our understanding of the (patho)physiological role of PCSK9 in human biology. In the current review, we summarize studies published or in print before May 2012 concerning the physiological role of PCSK9 in cholesterol metabolism. Moreover, we briefly describe the clinical phenotypes encountered in carriers of mutations in the gene encoding PCSK9. As PCSK9 has emerged as a novel target for LDL-C lowering therapy, methods to inhibit PCSK9 will also be reviewed. Initial data from investigations of PCSK9 inhibition in humans are promising and indicate that PCSK9 inhibition may be a viable new therapeutic option for the treatment of dyslipidemia and associated cardiovascular diseases.

Fig. 1.

PCSK9-mediated degradation of LDLR. A complex of LDL-C, LDLR, and PCSK9 is internalized into hepatocytes into clathrin-coated pits and subsequently undergoes lysosomal degradation.

Fig. 2.

PCSK9 inhibition. Monoclonal antibodies bound to PCSK9 prevent the association between PCSK9 and the LDLR. The LDLR binds the LDL particle and is internalized, and then the LDL particle is degraded in the lysosome, whereas the LDLR is recycled back to the plasma membrane.