Biology of proprotein convertase subtilisin kexin 9: beyond low-density lipoprotein cholesterol lowering

Abstract

Proprotein convertase subtilisin kexin 9 (PCSK9) is a key regulator of low-density lipoprotein receptor levels and LDL-cholesterol levels. Loss-of-function mutations in PCSK9 gene are associated with hypocholesterolaemia and protection against cardiovascular disease, identifying PCSK9 inhibition as a valid therapeutic approach to manage hypercholesterolaemia and related diseases. Although PCSK9 is expressed mainly in the liver, it is present also in other tissues and organs with specific functions, raising the question of whether a pharmacological inhibition of PCSK9 to treat hypercholesterolaemia and associated cardiovascular diseases might be helpful or deleterious in non-hepatic tissues. For example, PCSK9 is expressed in the vascular wall, in the kidneys, and in the brain, where it was proposed to play a role in development, neurocognitive process, and neuronal apoptosis. A link between PCSK9 and immunity was also proposed as both sepsis and viral infections are differentially affected in the presence or absence of PCSK9. Despite the increasing number of observations, the debate on the exact roles of PCSK9 in extrahepatic tissues is still ongoing, and as very effective drugs that inhibit PCSK9 have become available to the clinician, a better understanding of the biological roles of PCSK9 is warranted.

Keywords: APO B; LDL; LDLR; Monoclonal antibodies; PCSK9.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Figures

Figure 1

Plasma PCSK9. The intact form of PCSK9 (62 + 13 kDa) in plasma is found predominantly on LDL but not on VLDL. The furin-cleaved form of PCSK9 (55 + 13 kDa) in plasma is found predominantly as apoB-free.

Figure 2

PCSK9 and apoB-containing lipoproteins metabolism. PCSK9 regulates surface LDLR levels via targeting of both proteins to lysosomal degradation (1). The main consequence of the decreased PCSK9 interaction with the LDLR is the increase in the intracellular cholesterol pool which promotes: (2) a reduction of the activity of the SRE-dependent pathway and of intracellular cholesterol synthesis, (3) a reduction in the expression of non-SRE genes involved in lipogenesis, (4) a reduction of apoB lipidation, and (5) a reduction of apoB/apoE particle uptake and degradation.

Figure 3

Expression and function of PCSK9. PCSK9 is mainly expressed in the liver, where it is involved in the binding and degradation of LDLR. PCSK9 is expressed also in other tissues and organs, where it plays additional functions.

Figure 4

Pathways involved in PCSK9-mediated inflammation. Intracellular PCSK9, including the internalized one which escapes lysosomal degradation could eventually undergoes re-secretion but exerts cytoplasmic effects that might regulate the expression of genes controlling inflammation (1). PCSK9 could also target LRP-1 which is involved in the activation of JAK/STAT and ERK pathways (2).

Figure 5

PCSK9 and infection. (A) PCSK9 reduces LDL uptake thus reducing LPS clearance and increasing inflammatory response during sepsis. (B) PCSK9 reduces LDLR thus resulting in reduced LDL-associated HCV uptake and decreased viral infection.

Figure 6

PCSK9 and the brain. Role of PCSK9 in neuronal apoptosis and AD progression.