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Human cholesteryl ester transfer protein lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice.

ABSTRACT: Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS transfer assays to assess the ability of CETP to bind and transfer LPS. The effects of intravenous (iv) infusion of purified LPS or polymicrobial infection (cecal ligation and puncture [CLP]) were compared in transgenic mice expressing human CETP and wild-type mice naturally having no CETP activity. CETP displayed no LPS transfer activity in vitro, but it tended to reduce biliary excretion of LPS in vivo. The CETP expression in mice was associated with significantly lower basal plasma lipid levels and with higher mortality rates in both models of endotoxemia and sepsis. Furthermore, CETPTg plasma modified cytokine production of macrophages in vitro. In conclusion, despite having no direct LPS binding and transfer property, human CETP worsens sepsis outcomes in mice by altering the protective effects of plasma lipoproteins against endotoxemia, inflammation, and infection.

SUBMITTER: Dusuel A

PROVIDER: S-EPMC7859855 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Human cholesteryl ester transfer protein lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice.

Dusuel Aloïs A Deckert Valérie V Pais de Barros Jean-Paul JP van Dongen Kevin K Choubley Hélène H Charron Émilie É Le Guern Naig N Labbé Jérôme J Mandard Stéphane S Grober Jacques J Lagrost Laurent L Gautier Thomas T

Journal of lipid research 20201215

Bacterial lipopolysaccharides (LPSs or endotoxins) can bind most proteins of the lipid transfer/LPS-binding protein (LT/LBP) family in host organisms. The LPS-bound LT/LBP proteins then trigger either an LPS-induced proinflammatory cascade or LPS binding to lipoproteins that are involved in endotoxin inactivation and detoxification. Cholesteryl ester transfer protein (CETP) is an LT/LBP member, but its impact on LPS metabolism and sepsis outcome is unclear. Here, we performed fluorescent LPS tra ...[more]

PMID: 33500240

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Project description:BackgroundSepsis is a syndrome where the dysregulated host response to infection threatens the life of the patient. The isoform of the cholesteryl-ester transfer protein (CETPI) is synthesized in the small intestine, and it is present in human plasma. CETPI and peptides derived from its C-terminal sequence present the ability to bind and deactivate bacterial lipopolysaccharides (LPS). The present study establishes the relationship between the plasma levels of CETPI and disease severity of sepsis due to Gram-negative bacteria.MethodsPlasma samples from healthy subjects and patients with positive blood culture for Gram-negative bacteria were collected at the Intensive Care Unit (ICU) of INCMNSZ (Mexico City). 47 healthy subjects, 50 patients with infection, and 55 patients with sepsis and septic shock, were enrolled in this study. CETPI plasma levels were measured by an enzyme-linked immunosorbent assay and its expression confirmed by Western Blot analysis. Plasma cytokines (IL-1β, TNFα, IL-6, IL-8, IL-12p70, IFNγ, and IL-10) were measured in both, healthy subjects, and patients, and directly correlated with their CETPI plasma levels and severity of clinical parameters. Sequential Organ Failure Assessment (SOFA) scores were evaluated at ICU admission and within 24 h of admission. Plasma LPS and CETPI levels were also measured and studied in patients with liver dysfunction.ResultsThe level of CETPI in plasma was found to be higher in patients with positive blood culture for Gram-negative bacteria that in control subjects, showing a direct correlation with their SOFA values. Accordingly, septic shock patients showing a high CETPI plasma concentration, presented a negative correlation with cytokines IL-8, IL-1β, and IL-10. Also, in patients with liver dysfunction, since higher CETPI levels correlated with a high plasma LPS concentration, LPS neutralization carried out by CETPI might be considered a physiological response that will have to be studied in detail.ConclusionsElevated levels of plasma CETPI were associated with disease severity and organ failure in patients with Gram-negative bacteraemia, defining CETPI as a protein implicated in the systemic response to LPS.

Dataset Information

Human cholesteryl ester transfer protein lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice.

Publications

Human cholesteryl ester transfer protein lacks lipopolysaccharide transfer activity, but worsens inflammation and sepsis outcomes in mice.

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