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New developments in proprotein convertase subtilisin–kexin 9's biology and clinical implications

Seidah, Nabil G.·2016·Current Opinion in Lipidology
DOI 10.1097/mol.0000000000000295
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Abstract

Purpose of review High levels of LDL-cholesterol (LDL-C) are directly associated with devastating cardiovascular complications. Statins downregulate cholesterol synthesis and upregulate hepatic mRNA levels of LDL receptor (LDLR) and proprotein convertase subtilisin-kexin 9 (PCSK9), a validated enhancer of LDLR protein degradation. Herein, we summarize recent discoveries of the biological properties of PCSK9 in both health and disease states. Recent findings PCSK9 downregulation of the LDLR protein likely explains the observed protective effect of the loss of PCSK9 in reducing lipoprotein(a) and incidence of septic shock. Injectable inhibitory PCSK9 monoclonal antibodies are now prescribed to hypercholesterolemic patients that do not reach target levels of LDL-C with available drugs. PCSK9 also reduces the levels of other receptors, for example, VLDL receptor (VLDLR), ApoER2, CD36, and CD81. The efficacy of the upregulation of LDLR and VLDLR cell surface levels in the absence of PCSK9 is both tissue and sex dependent. As LDLR, CD81, and VLDLR are hepatitis C receptors, PCSK9 may protect against certain viral infections. Summary New functions of PCSK9 and other receptor targets are beginning to emerge to explain the observed changes in LDL-C and triglycerides. The effect of PCSK9 loss-of-function on glucose metabolism, factors that regulate the expression of PCSK9, and the roles of PCSK9 in other tissues, for example, intestine, kidney, and brain require further investigations.

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Metadata

Authors
Seidah, N. G.
Venue
Current Opinion in Lipidology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2016-06
Volume
27
Issue
3
Pages
274-281
ISSN
0957-9672
DOI
10.1097/mol.0000000000000295
Cited by
43
References
5
Language
en

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