Alterations in lipoprotein homeostasis during experimental and clinical sepsis in primates

Abstract number: P0458

Levels^* J. H. M., Pajkrt^* D., Schultz^* M., Van Den Ende^* A. E., Hoek^* F. J., Van Tol† A., Taylor† F. B., Hack§ C. E., Meijers^* J. C., Van Deventer^* S. J.

^*AMC, Netherlands; †Erasmus Medical Center, Netherlands; †Oklahoma Medical Center, USA; §Sanquin, Netherlands

Cell wall constituents of Gram-negative or Gram-positive bacteria such as lipopolysaccharides (LPS) and lipoteichoic acids (LTA), respectively, are potent endotoxins that initiate inflammatory responses in sepsis. During the acute phase response, dramatic changes in lipid metabolism occur which are predicted to affect the ability of lipoproteins to scavenge bacterial toxins. The pathophysiological processes responsible for these changes have not been completely elucidated. Sequential changes in lipid binding proteins and in lipoprotein composition in two experimental models (lethal bacteremia in baboons and low-dose endotoxemia in humans) as well as in patients with severe sepsis were studied. In addition, the effect of reconstituted HDL (rHDL) administration on lipid homeostasis in a human endotoxemia model was investigated. Decreases in lipoprotein concentrations and changes in composition accompanied by an increase in acute phase marker proteins were similar in all clinical and experimental settings. rHDL infusion did not alter the acute phase specific lipid changes during low-dose endotoxemia. However, infusion of rHDL caused long-lasting increases of circulating HDL cholesterol and apolipoprotein A-I. High initial turnover of phosphatidylcholine (PC), lyso-PC and phosphatidyl-ethanolamine was observed, indicative of extensive remodeling of the rHDL particle. Two-dimensional SDS–PAGE of normal and acute phase HDL in baboons showed marked differences in protein composition. Strong negative correlations between the levels of the lipid transfer proteins (LCAT and CETP) and CRP were observed. In contrast, plasma phospholipid transfer protein (PLTP) activity showed remarkably positive correlations with levels of CRP and LPS binding protein (LBP). The triglyceride alterations during acute phase proved to be species dependent. PLTP seems to act as a positive acute phase protein which may play a role in the alterations in lipid homeostasis. During rHDL infusion the changes in HDL and LDL phospholipid composition may contribute to the attenuation of the inflammatory response.