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Introduction: Lipopolysaccharide (LPS) is a component of gram-negative bacteria, known for its ability to trigger inflammation. The main pathway of LPS clearance is the reverse lipopolysaccharide transport (RLT), with phospholipid transfer protein (PLTP) and lipoproteins playing central roles in this process in experimental animal models. To date, the relevance of this pathway has never been studied in humans. Cardiac surgery with cardiopulmonary bypass is known to favor LPS digestive translocation. Our objective was to determine whether pre-operative PLTP activity and triglyceride or cholesterol-rich lipoprotein concentrations were associated to LPS concentrations in patients undergoing cardiac surgery with cardiopulmonary bypass.Methods: A post-hoc analysis was conducted on plasma samples obtained from patients recruited in a randomized controlled trial.Total cholesterol, high density lipoprotein cholesterol (HDLc), low density lipoprotein cholesterol (LDLc), triglyceride and PLTP activity were measured before surgery. LPS concentration was measured by mass spectrometry before surgery, at the end of cardiopulmonary bypass and 24 h after admission to the intensive care unit.Results: High PLTP activity was associated with lower LPS concentration but not with inflammation nor post-operative complications. HDLc, LDLc and total cholesterol were not associated with LPS concentration but were lower in patients developing post-operative adverse events. HDLc was negatively associated with inflammation biomarkers (CRP, PCT). Triglyceride concentrations were positively correlated with LPS concentration, PCT and were higher in patients with post-operative complications.Conclusion: Our study supports the role of PLTP in LPS elimination and the relevance of RLT in human. PLTP activity, and not cholesterol rich lipoproteins pool size seemed to be the limiting factor for RLT. PLTP activity was not directly related to post-operative inflammation and adverse events, suggesting that LPS clearance is not the main driver of inflammation in our patients. However, HDLc was associated with lower inflammation and was associated with favorable outcomes, suggesting that HDL beneficial anti-inflammatory effects could be, at least in part independent of LPS clearance.

Diet-induced obesity (DIO) is associated with a defect of the orosensory detection of dietary lipids in rodents. This dysfunction is not anecdotic since it might worsen the negative effects of obesity by promoting the overconsumption of energy-dense foods. Previous studies have highlighted a progressive devaluation of reward value of lipid stimuli due to a desensitization of dopaminergic brain areas in DIO mice. Paradoxically, the putative deleterious impact of obesity on peripheral fat detection by the gustatory papillae remains poorly documented. Using a whole transcriptomic investigation of the circumvallate papillae (CVP), an analysis of CVP genes involved in fat taste transduction and signaling along the day, and two bottle choice tests, we have found that (i) CVP, known to house the most taste buds in the oral cavity, displays a genic circadian rhythm, (ii) DIO reduces the oscillation of key genes involved both in the circadian clock and lipid detection/signaling, and (iii) the gene invalidation of the clock gene Rev-Erbα does not significantly affect fat preference despite an oily solution intake slightly lower than littermate controls. Taken together these data bring the first demonstration that the gustatory function is under control of a peripheral clock in mammals, as already reported in fly and suggest that a disturbance of this rhythmicity might contribute to the lower fatty taste acuity found in obese mice.

Transmissible spongiform encephalopathies are fatal neurodegenerative diseases with an urgent need for therapeutic and prophylactic strategies. At the time when the blood-mediated transmission of prions was demonstrated, in vitro studies indicated a high binding affinity of the scrapie prion protein (PrPSc) with apoB-containing lipoproteins, i.e., the main carriers of cholesterol in human blood. The aim of the present study was to explore the relationship between circulating cholesterol-containing lipoproteins and the pathogenicity of prions in vivo. We showed that, in mice with a genetically engineered deficiency for the plasma lipid transporter, phospholipid transfer protein (PLTP), abnormally low circulating cholesterol concentrations were associated with a significant prolongation of survival time after intraperitoneal inoculation of the 22L prion strain. Moreover, when circulating cholesterol levels rose after feeding PLTP-deficient mice a lipid-enriched diet, a significant reduction in survival time of mice together with a marked increase in the accumulation rate of PrPSc deposits in their brain were observed. Our results suggest that the circulating cholesterol level is a determinant of prion propagation in vivo and that cholesterol-lowering strategies might be a successful therapeutic approach for patients suffering from prion diseases.

Abstract Although plasma phospholipid transfer protein (PLTP) has been mainly studied in the context of atherosclerosis, it shares homology with proteins involved in innate immunity. Here, we produced active recombinant human PLTP (rhPLTP) in the milk of new lines of transgenic rabbits. We successfully used rhPLTP as an exogenous therapeutic protein to treat endotoxemia and sepsis. In mouse models with injections of purified lipopolysaccharides or with polymicrobial infection, we demonstrated that rhPLTP prevented bacterial growth and detoxified LPS. In further support of the antimicrobial effect of PLTP, PLTP-knocked out mice were found to be less able than wild-type mice to fight against sepsis. To our knowledge, the production of rhPLTP to counter infection and to reduce endotoxemia and its harmful consequences is reported here for the first time. This paves the way for a novel strategy to satisfy long-felt, but unmet needs to prevent and treat sepsis.