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

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.).

Keywords: LDL; LPS; PCSK9; human endotoxin model; inflammation; lipopolysaccharide; low-density lipoprotein; pathogen lipids; proprotein convertase subtilisin/kexin type 9.

Copyright © 2020 Heinzl et al.

Figures

FIG 1

Mean plasma concentrations of interleukin-6 (IL-6) and C-reactive protein (CRP). The difference between placebo and LPS administration was statistically significant for IL-6 (P = 0.018) as well as CRP (P < 0.001), as measured by RM-ANOVA. IL-6 values are given in picograms per milliliter on the lefthand side; the assay’s upper limit of normal is 15 pg/ml. CRP values are given in milligrams per deciliter on the righthand side; the assay’s upper limit of normal is 1.0 mg/dl.

FIG 2

RM-ANOVA for PCSK9. There was no statistically significant difference in PCSK9 plasma concentrations between placebo and LPS administration (P = 0.44 using the Greenhouse-Geisser correction). Time points are shown on the abscissa, and plasma concentrations of PCSK9 are shown on the ordinate (values given in nanograms per milliliter). Error bars depict 95% confidence intervals. The decrease of PCSK9 throughout the study day is due to fasting conditions and diurnal variation (26).

FIG 3

RM-ANOVA for LDL. The difference in LDL plasma concentrations between placebo and LPS administration was statistically significant (P < 0.001 using the Greenhouse-Geisser correction). Time points are shown on the abscissa, the ratio of LDL values to baseline is shown on the ordinate. Error bars depict 95% confidence intervals. Of note, there was a distinct peak in LDL levels 60 min after LPS administration. This relative elevation of LDL levels following LPS infusion was not statistically significant after correction for baseline difference (P = 0.065 using the Greenhouse-Geisser correction).

FIG 4

Scatter plot depicting the negative correlation between LDL levels at baseline and IL-6 levels 24 h after the administration of LPS. This negative correlation was statistically significant (Pearson coefficient of correlation = −0.699; P = 0.024).