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.
Highlights
IntroductionLPS, or endotoxins, are amphipathic molecules with proinflammatory properties
Supplementary key words cholesterol infection inflammation lipoproteins plasma lipid transfer proteins endotoxins lipopolysaccharide (LPS) sterol metabolism sepsis bacteremia
Cholesteryl ester transfer protein (CETP) belongs to the lipid transfer/LPS-binding protein (LT/LBP) family, which includes members with well-described LPS transfer activities, the role of CETP in LPS transfer remains unclear
Summary
LPS, or endotoxins, are amphipathic molecules with proinflammatory properties They activate TLR-4/CD14 complex in leukocytes, leading to cytokine release and SIRS [3]. Whereas lipoproteins are recognized as the main carriers of LPS in plasma, RLT involves key proteins that belong to the lipid transfer/LPS binding protein (LT/ LBP) gene family and play differential roles in LPS metabolism. It includes LBP, BPI, PLTP, and CETP. BPI inhibits bacterial growth by binding LPS and forming complexes directly to the outer membrane of bacteria, preventing leukocyte activation [7, 8].
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have