Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) Is Not Induced in Artificial Human Inflammation and Is Not Correlated with Inflammatory Response.

Matthias Wolfgang Heinzl,Benjamin Dieplinger,Carmen Klammer,Martin Clodi,Margot Egger,Michael Resl,Manuela Raffatellu

doi:10.1128/iai.00842-19

Abstract

Lipoproteins, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9), have been shown to play a key role in the innate immune response. However, knowledge about the role and kinetics of PCSK9 in human inflammation is currently insufficient. This study aimed to investigate the interaction between inflammation and lipid metabolism, including the possible role of PCSK9. A single-blinded, placebo-controlled cross-over study using the human endotoxin model was performed. Ten healthy men received lipopolysaccharide (LPS) or placebo on two different study days after overnight fasting. Lipoproteins as well as PCSK9 were measured repetitively over 48 h. PCSK9 plasma concentrations were not induced by LPS infusion, and no correlation between PCSK9 plasma concentrations and the degree of inflammation could be identified. The observed low-density lipoprotein (LDL) response to inflammation was more complex than anticipated, especially in the very early phase after the inflammatory stimulus. Baseline concentrations of LDL, as well as high-density lipoprotein (HDL), correlated negatively with inflammatory response. Our data suggest that the lipoprotein response to inflammation is independent of PCSK9. The proposed elevations of PCSK9 and suspected correlations between PCSK9 levels and inflammatory response are not supported by our data. (This study has been registered at ClinicalTrials.gov under registration no. NCT03392701.).

Highlights

Lipoproteins, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9), have been shown to play a key role in the innate immune response
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is produced in the liver and secreted into the plasma
The aim of this study was to evaluate the effect of human inflammation on lipid metabolism and PCSK9 using the human endotoxin model in healthy volunteers

Summary

Introduction

Lipoproteins, as well as proprotein convertase subtilisin/kexin type 9 (PCSK9), have been shown to play a key role in the innate immune response. Clearance of pathogen lipids such as lipopolysaccharide (LPS) from the circulation usually occurs through hepatic Kupffer cells and other macrophages During this process, these cells are activated and secrete proinflammatory cytokines such as tumor necrosis factor alpha (TNF-␣) [7]. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that is produced in the liver and secreted into the plasma It plays a major role in regulating LDL cholesterol by binding to hepatic LDL receptors and promoting their degeneration. PCSK9 knockout mice show considerably lower levels of proinflammatory cytokines, such as TNF-␣, interleukin-6 (IL-6), IL-8, and IL-10, following LPS administration and were shown to eliminate LPS much more rapidly than controls This reduced clearance of LPS under the influence of PCSK9 seems to be due to a lower uptake of LPS by human hepatocytes [10]. The pharmacological inhibition of PCSK9 using monoclonal anti-PCSK9 antibodies in a murine sepsis model leads to lower plasma concentrations of inflammatory cytokines and, importantly, significantly increased survival rates [10]

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