Low-density lipoprotein (LDL)-dependent uptake of Gram-positive lipoteichoic acid and Gram-negative lipopolysaccharide occurs through LDL receptor

Abstract

Lipoteichoic acid (LTA) and lipopolysaccharide (LPS) are bacterial lipids that stimulate pro-inflammatory cytokine production, thereby exacerbating sepsis pathophysiology. Proprotein convertase subtilisin/kexin type 9 (PCSK9) negatively regulates uptake of cholesterol by downregulating hepatic lipoprotein receptors, including low-density lipoprotein (LDL) receptor (LDLR) and possibly LDLR-related protein-1 (LRP1). PCSK9 also negatively regulates Gram-negative LPS uptake by hepatocytes, however this mechanism is not completely characterized and mechanisms of Gram-positive LTA uptake are unknown. Therefore, our objective was to elucidate the mechanisms through which PCSK9 regulates uptake of LTA and LPS by investigating the roles of lipoproteins and lipoprotein receptors. Here we show that plasma PCSK9 concentrations increase transiently over time in septic and non-septic critically ill patients, with highly similar profiles over 14 days. Using flow cytometry, we demonstrate that PCSK9 negatively regulates LDLR-mediated uptake of LTA and LPS by HepG2 hepatocytes through an LDL-dependent mechanism, whereas LRP1 and high-density lipoprotein do not contribute to this uptake pathway. Bacterial lipid uptake by hepatocytes was not associated with cytokine production or hepatocellular injury. In conclusion, our study characterizes an LDL-dependent and LDLR-mediated bacterial lipid uptake pathway regulated by PCSK9, and provides evidence in support of PCSK9 inhibition as a potential therapeutic strategy for sepsis.

Reduced plasma PCSK9 response in patients with bacteraemia is associated with mortality

“…We could not detect any differences in the levels of plasma PCSK9 between patients with Gram‐negative or Gram‐positive infections. This is in accordance with findings that the major lipoproteins of both Gram‐negative (LPS) and Gram‐positive (LTA) bacteria are removed from the circulation in an LDLR/PCSK9‐dependent manner .…”

“…Proprotein convertase subtilisin/kexin enzyme 9 levels are elevated by an inflammatory response and in critically ill ICU patients , but how PCSK9 levels vary in different types of bacterial infections has not previously been explored. Our bacteraemia cases had a median day 0 PCSK9 level of 376 ng mL −1 , which is approximately double the value reported in a meta‐analysis of 15 cholesterol studies (final pooled 95% confidence interval 170–220 ng mL −1 ).…”

“…The authors found that PCSK9 was markedly increased in patients compared to reference values from healthy individuals and that there was a positive correlation between high PCSK9 levels and cardiovascular and respiratory failure. Two other studies have explored the circulating PCSK9 levels in critically ill patients who were admitted to the intensive care unit (ICU) . The results showed that plasma concentrations were similarly elevated in patients with and without sepsis and were higher than normal in ICU patients with severe trauma injury, which suggests that plasma PCSK9 is also upregulated by noninfectious stress to the body.…”

Hepatitis B core antigen can regulate NLRP3 inflammasome pathway in HepG2 cells

“…In vitro study, the concentration of LPS is varied. Some studies used 2.5 or 1 µg/mL LPS to stimulate HepG2 cells to produce proinflammatory factors . Another study found that when the LPS concentration was 40 µg/mL, LO2 cell expression of proinflammatory factors peaked .…”

In vitro and in vivo defensive effect of probiotic LAB against Pseudomonas aeruginosa using Caenorhabditis elegans model

“…The pathogenic factors of P. aeruginosa mainly based on lipopolysaccharide (LPS), flagella endotoxin and extracellular toxin [16]. Most of the Gram-positive pathogens depends on, lipoteichoic acid, which induce pro-inflammatory cytokines mediates by Toll-like receptor 4 is a protein (TLR-2) [17,18]. But Non-pathogenic Gram-positive bacteria, such Pediococcus, Enterococcus, Lactobacilli , persuade a dissimilar pattern of cytokines in peripheral blood cells[19–21].…”