High-density lipoprotein (HDL) has been epidemiologically shown to be associated with the outcome of sepsis. One potential mechanism is that HDL possesses pleiotropic effects, such as anti-apoptosis, some of which can be ascribed to sphingosine 1-phosphate (S1P) carried on HDL via apolipoprotein M (apoM). Therefore, the aim of this study was to elucidate the roles of apoM/S1P in the consequent lethal conditions of sepsis, such as multiple organ failure caused by severe inflammation and/or disseminated intravascular coagulation.,In mice treated with lipopolysaccharide (LPS), both plasma apoM levels and the expression of apoM in the liver and kidney were suppressed. The overexpression of apoM improved the survival rate and ameliorated the elevated plasma alanine aminotransferase (ALT) and creatinine levels, while the knockout or knockdown of apoM deteriorated these parameters in mice treated with LPS. Treatment with VPC23019, an antagonist against S1P receptor 1 and 3, or LY294002, a PI3K inhibitor, partially reversed these protective properties arising from the overexpression of apoM. The overexpression of apoM inhibited the elevation of plasma plasminogen activator inhibitor-1, restored the phosphorylation of Akt, and induced anti-apoptotic changes in the liver, kidney and heart.,These results suggest that apoM possesses protective properties against LPS-induced organ injuries and could potentially be introduced as a novel therapy for the severe conditions that are consequent to sepsis.,Schattauer GmbH Stuttgart.