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Low-density lipoprotein (LDL)-dependent uptake of Gram-positive lipoteichoic acid and Gram-negative lipopolysaccharide occurs through LDL receptor.
- Source :
-
Scientific reports [Sci Rep] 2018 Jul 12; Vol. 8 (1), pp. 10496. Date of Electronic Publication: 2018 Jul 12. - Publication Year :
- 2018
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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.
- Subjects :
- Enterococcus hirae metabolism
Enterococcus hirae pathogenicity
Escherichia coli metabolism
Escherichia coli pathogenicity
Flow Cytometry
Hep G2 Cells
Hepatocytes metabolism
Humans
Lipopolysaccharides toxicity
Lipoproteins, LDL metabolism
Low Density Lipoprotein Receptor-Related Protein-1 metabolism
Proprotein Convertase 9 blood
Sepsis blood
Sepsis microbiology
Teichoic Acids toxicity
Lipopolysaccharides metabolism
Proprotein Convertase 9 metabolism
Receptors, LDL metabolism
Sepsis pathology
Teichoic Acids metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2045-2322
- Volume :
- 8
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Scientific reports
- Publication Type :
- Academic Journal
- Accession number :
- 30002483
- Full Text :
- https://doi.org/10.1038/s41598-018-28777-0