Proprotein convertase subtilisin/kexin type 9 (PCSK9): Lessons learned from patients with hypercholesterolemia

Abstract

BACKGROUND: Identification of the proprotein convertase subtilisin/kexin type 9 (PCSK9) as the third gene causing familial hypercholesterolemia (FH) and understanding its complex biology has led to the discovery of a novel class of therapeutic agents. SUMMARY: PCSK9 has other biological roles observed in vitro and in animal studies, including viral entry into the cell, insulin resistance, and hepatic tissue repair. Given the potential number of humans exposed to this novel class of medications, careful evaluation of clinical trial results is warranted. © 2014 American Association for Clinical Chemistry Cellular processing of proteins is a complex process that includes posttranscriptional modifications, transport to and from subcellular compartments, and cleavage into mature protein. Proteins that enter the secretory pathway are initially synthetized as biologically inactive precursors requiring proteolytic cleavage by highly specialized and evolutionarily conserved proprotein convertases. In the past 2 and a half decades, 9 members of the proprotein convertase subtilisin/kexin (PCSK)3 have been identified in mammals, with broad substrate specificities. The last member of the PCSK family, PCSK9, was identified by Seidah et al. (1 ). The chromosomal region 1p32, harboring the proprotein convertase subtilisin/kexin type 9 (PCSK9)4 gene, was identified by Abifadel et al. as a novel locus for autosomal dominant hypercholesterolemia, with a phenotype clinically similar to familial hypercholesterolemia (FH) due to mutations in the low-density lipoprotein receptor (LDLR) gene (2 ). In an elegant collaboration, Abifadel et al. were able to show that mutations of the PCSK9 gene were causally related to FH3, the third identified genetic cause of autosomal dominant hypercholesterolemia in families of French origin. Strikingly, the FH phenotype is caused by gain-of-function mutations of PCSK9. CONTENT: PCSK9 undergoes autocatalytic cleavage in the endoplasmic reticulum and enters the secretory pathway. The PCSK9 gene is under the regulatory control of sterol receptor binding proteins 1 and 2. Statins increase PCSK9 and this may modulate the response to this class of medications. In plasma,PCSK9binds to the epidermal growth factor-like domain of the LDL receptor (LDL-R) on the cell and, once incorporated in the late endosomal pathway, directs the LDL-R toward lysosomal degradation rather than recycling to the plasma membrane. Thus, gain-of-function PCSK9 mutations lead to an FH phenotype, whereas loss-of-function mutations are associated with increased LDL-R-mediated endocytosis ofLDLparticles and lower LDL cholesterol in plasma. Inhibition of PCSK9 is thus an attractive therapeutic target. Presently, this is achieved by using monoclonal antibodies for allosteric inhibition of the PCSK9-LDL-R interaction. Phase 2 and 3 clinical trials in patients with moderate and severe hypercholesterolemia (including FH) show that this approach is safe and highly efficacious to lower LDL-C and lipoprotein(a).