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The Proprotein Convertases in Hypercholesterolemia and Cardiovascular Diseases: Emphasis on Proprotein Convertase Subtilisin/Kexin 9

Seidah, Nabil G., Abifadel, Marianne, Prost, Stefan, Boileau, Catherine, Prat, Annik·2017·Pharmacological Reviews
DOI 10.1124/pr.116.012989
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Abstract

The secretory proprotein convertase (PC) family comprises nine members, as follows: PC1/3, PC2, furin, PC4, PC5/6, paired basic amino acid cleaving enzyme 4, PC7, subtilisin kexin isozyme 1/site 1 protease (SKI-1/S1P), and PC subtilisin/kexin type 9 (PCSK9). The first seven PCs cleave their substrates at single/paired basic residues and exhibit specific and often essential functions during development and/or in adulthood. The essential SKI-1/S1P cleaves membrane-bound transcription factors at nonbasic residues. In contrast, PCSK9 cleaves itself once, and the secreted inactive protease drags the low-density lipoprotein receptors (LDLR) and very LDLR (VLDLR) to endosomal/lysosomal degradation. Inhibitory PCSK9 monoclonal antibodies are now prescribed to treat hypercholesterolemia. This review focuses on the implication of PCs in cardiovascular functions and diseases, with a major emphasis on PCSK9. We present a phylogeny of the PCs and the analysis of PCSK9 haplotypes in modern and archaic human species. The absence of PCSK9 in mice led to the discovery of a sex- and tissue-specific subcellular distribution of the LDLR and VLDLR. PCSK9 inhibition may have other applications because it reduces inflammation and sepsis in a LDLR-dependent manner. Our present understanding of the cellular mechanism(s) that enables PCSK9 to induce the degradation of receptors is reviewed, as well as the consequences of its key natural mutations. The PCSK9 ongoing clinical trials are reviewed. Finall…

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  • ASGR1 levels could be regulated by those of the LDLR.

    “This suggests that ASGR1 levels could be regulated by those of the LDLR, as are circulating PCSK9 levels (6).”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [6]

  • Circulating PCSK9 is responsible for most of its activity to reduce the levels of cell-surface LDLR in hepatocytes.

    “Circulating PCSK9 is responsible for most of its activity to reduce the levels of cell-surface LDLR in hepatocytes (6).”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [6]

  • PCSK9 is highly expressed in the liver and, upon secretion into plasma, binds to and enhances the degradation of LDLR in a nonenzymatic fashion, thereby increasing circulating LDL cholesterol.

    “The proprotein convertase subtilisin/kexin type 9 (PCSK9) is highly expressed in the liver (2) and, upon its secretion into plasma, binds to and enhances the degradation of the LDLR in a nonenzymatic fashion (3, 4, 5, 6), thereby increasing circulating LDLc.”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [6]

  • Other surface proteins on hepatocytes that bind to and modulate their interaction with PCSK9 and/or LDLR as well as LDL cholesterol uptake have not been thoroughly characterized.

    “Despite these hallmark studies and their utility for lipid lowering to prevent CVD, other surface proteins on hepatocytes that bind to and modulate their interaction with PCSK9 and/or LDLR as well as LDLc uptake have not been thoroughly characterized (6).”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [6]

  • Circulating PCSK9 originating from hepatocytes binds to cell-surface LDLR and targets it to degradation in endosomes/lysosomes.

    “Circulating PCSK9 originating from hepatocytes (2) binds to cell-surface LDLR and targets it to degradation in endosomes/lysosomes (6).”

    From Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR cleaved by furin (2021) · cites this paper as [6]

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Metadata

Authors
Seidah, N. G., Abifadel, M., Prost, S., Boileau, C., & Prat, A.
Venue
Pharmacological Reviews
Publisher
Elsevier BV
Published
2017-01
Volume
69
Issue
1
Pages
33-52
ISSN
0031-6997
DOI
10.1124/pr.116.012989
Cited by
116
References
18
Language
en
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