Insight into the Evolving Role of PCSK9

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is the last discovered member of the family of proprotein convertases (PCs), mainly synthetized in hepatic cells. This serine protease plays a pivotal role in the reduction of the number of low-density lipoprotein receptors (LDLRs) on the surface of hepatocytes, which leads to an increase in the level of cholesterol in the blood. This mechanism and the fact that gain of function (GOF) mutations in PCSK9 are responsible for causing familial hypercholesterolemia whereas loss-of-function (LOF) mutations are associated with hypocholesterolemia, prompted the invention of drugs that block PCSK9 action. The high efficiency of PCSK9 inhibitors (e.g., alirocumab, evolocumab) in decreasing cardiovascular risk, pleiotropic effects of other lipid-lowering drugs (e.g., statins) and the multifunctional character of other proprotein convertases, were the cause for proceeding studies on functions of PCSK9 beyond cholesterol metabolism. In this article, we summarize the current knowledge on the roles that PCSK9 plays in different tissues and perspectives for its clinical use.

Keywords: PCSK9; alirocumab; anti-PCSK9; atherosclerosis; cardiovascular diseases; cholesterol; evolocumab; genetic; inclisiran.

Figure 1

Schematical structure of human PCs [1,2,3]. Abbreviations: CHRD, Cys-His-rich domain; CRD, Cys-rich domain; PCSK1 (PC1/3), proprotein convertase subtilisin/kexin type 1 (proprotein convertase 1/3); PCSK2 (PC2), proprotein convertase subtilisin/kexin type 2 (proprotein convertase 2); PCSK3, proprotein convertase subtilisin/kexin type 3; PCSK4 (PC4), proprotein convertase subtilisin/kexin type 4 (proprotein convertase 4); PCSK5 (PC5/6), proprotein convertase subtilisin/kexin type 5 (proprotein convertase 5/6); PCSK6 (PACE4), proprotein convertase subtilisin/kexin type 6 (paired basic amino acid cleaving enzyme 4); PCSK7 (PC7), proprotein convertase subtilisin/kexin type 7 (proprotein convertase 7); SKI-1 (S1P), subtilisin/kexin isozyme 1 (sphingosine 1-phosphate); PCSK9, proprotein convertase subtilisin/kexin type 9.

Figure 2

The cellular actions of PCSK9 and its inhibitors on cholesterol metabolism [22]. Abbreviations: ER, endoplasmatic reticulum; GA, Golgi apparatus; LDL, low-density lipoprotein; LDLR, low-density lipoprotein receptor; PCSK9, proprotein convertase subtilisin/kexin type 9; PCSK9 mAb, monoclonal antibody against PCSK9; siRNA, small interfering RNA (inclisiran). (A) LDLR gene is transcribed into mRNA, then translated within ER into mature protein and transferred on the cell surface. (B) LDL particles, after binding to the LDLRs on the cell surface, are internalized into an endosome. (C) As the endosome matures, LDL and LDLR decouple—LDLR (D) recycles, and LDL is catabolized in the lysosome (E). (F) PCSK9 gene is transcribed into mRNA and then translated within ER into the mature protein. It can bind to the LDLR intracellularly within Golgi apparatus (G) or be secreted to the extracellular space—both ways lead to lysosomal degradation of LDLR (H). (I) Inclisiran (siRNA) inhibits the translation of PCSK9 mRNA and prevents the formation of mature protein. (J) PCSK9 mAbs (e.g., alirocumab) bind to the soluble PCSK9 in the plasma and prevent from lysosomal degradation of LDLRs.