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

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.


Differences at baseline between study days
baseline differences between the two study days None of the parameters shown in Table S1 differed significantly at baseline between the two study days. Nevertheless, for ANOVA-calculations, values of LDL, HDL, ApoA1 and ApoB were corrected for baseline values of the respective study day using a ratio to baseline. Baseline differences of PCSK9, IL-6, CRP and Lp(a) were considered insignificant. Of note, there was a distinct peak in HDL levels 60 minutes after LPS administration. This relative elevation of HDL levels following LPS infusion was not statistically significant after correction for baseline (p = 0.175 using the Greenhouse-Geisser correction).

Correlation between lipoproteins at baseline and markers of inflammation (IL-6 and CRP) after LPS infusion
In this online supplement, correlations between ApoA1 as well as HDL at baseline with inflammatory markers are depicted graphically. The correlation between LDL at baseline with IL-6 at 24 hours is shown in the manuscript. Figure  Scatter Plot depicting the negative correlation between LDL levels at baseline and IL-6 levels 24 hours after the administration of LPS. This negative correlation was statistically significant (Pearson coefficient of correlation = -,699; p = ,024)

"Change Ratio" calculation
To mathematically illustrate the course of LDL and HDL levels after LPS administration relative to placebo, a "change ratio" was calculated by dividing the ratio of a value at a given time point to baseline by the same ratio following placebo.
For example, to calculate the "change ratio" for LDL at 60 minutes after infusion, the following formula was used: Change ratio LDL (t 60) = This "change ratio" was then used to calculate correlations of relative changes at a given time point with markers of inflammation to evaluate, whether the extent of inflammatory response correlates with the LDL/HDL response to inflammation.

Table S3
Correlations between inflammatory markers and the course of LDL/HDL as calculated by the"change ratio" To illustrate the course of LDL and HDL levels after LPS administration relative to placebo, a "change ratio" was calculated by dividing the ratio of a value at a given time point after LPS administration to baseline by the same ratio following placebo.
The LDL "change ratio" at 60 minutes after LPS infusion as a calculated number depicting the relative, non-significant peak of LDL at this time point, correlated significantly with CRP and IL-6 levels. The HDL "change ratio" correlated significantly with IL-6 at 360 min after LPS. All correlations between inflammatory markers and "change ratios" at 60 minutes after LPS infusion were positive.

Figure S6
Scatter Plot depicting the negative correlation between the non-significant LDL peak, as calculated by the "change ratio" at 60 min after LPS infusion, and CRP levels at 24 hours after LPS.
This correlation was statistically significant (Pearson coefficient of correlation = 0.755; p = 0.12) Figure S7 Scatter Plot depicting the negative correlation between the non-significant LDL peak, as calculated by the "change ratio" at 60 min after LPS infusion, and CRP levels at 24 hours after LPS.
This correlation was statistically significant (Pearson coefficient of correlation = .686; p = .028)