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RESEARCH PRODUCT

Inflammation et maladies métaboliques : analyse par imagerie du métabolisme des lipoprotéines et lipopolysaccharides au cours de l’inflammation

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description

LPS (lipopolysaccharides) are endotoxins originating from Gram-negative bacteria. They have been extensively described for their ability to interact with and disrupt the intestinal barrier. These toxins are able to cross the gut barrier and to pass into the blood (endotoxemia), leading tolow-grade metabolic inflammation or to a severe inflammatory syndrome (SIRS). Fortunately, some circulating proteins such as PLTP (Phospholipid Transfer Protein) are able to transfer LPS to plasma lipoproteins in order to inactivate and detoxify them.The main goals of this study were to investigate the metabolic fate of LPS from the gut and peritoneal cavity but also the influence of PLTP on these toxins in a context of inflammatory and infectious diseases such as obesity, type 2 diabetes (T2D) or peritonitis. Wild-type mice (presence of active endogenous PLTP) were compared with PLTP-deficient genetically engineered mice after oral or intraperitoneal administration of LPS.After oral administration of LPS, PLTP deficiency leads to incrased translocation of LPS from the gut lumen to the circulation, where its association with plasma lipoproteins is strongly decreased together with a defect of clearance of triglyceride-rich lipoproteins (TRL) due to decreased lipoprotein lipase (LPL) activity, a key enzyme involved in triglyceride hydrolysis. After intraperitoneal administration of LPS, the absence of PLTP leads to decrease the binding of LPS to high-density lipoproteins (HDL) in situ, preventing their early inactivation and their detoxification by the hepatobiliary pathway.The absence of PLTP is associated with a strong inability to efficiently detoxify LPS originating from the gut or from peritoneal cavity leading to an increased inflammatory response and potential more severe complications (obesity, insulin resistance, systemic acute inflammatory syndrome). Thus, PLTP plays a major role in the early neutralization of LPS in abdominal cavity and it could be an interesting therapeutic target in the treatment of metabolic and infectious diseases.