Abstract
Circulating lipoproteins are thought to play an important role in the detoxification of lipopolysaccharide (LPS) by binding the bioactive lipid A portion of LPS to the lipoprotein surface. It has been assumed that hypocholesterolemia contributes to inflammation during critical illness by impairing LPS neutralization. We tested whether critical illness impaired LPS binding to lipoproteins and found, to the contrary, that LPS binding was enhanced and that LPS binding to the lipoprotein classes correlated with their phospholipid content. Whereas low serum cholesterol was almost entirely due to the loss of esterified cholesterol (a lipoprotein core component), phospholipids (the major lipoprotein surface lipid) were maintained at near normal levels and were increased in a hypertriglyceridemic subset of septic patients. The levels of phospholipids found in the LDL and VLDL fractions varied inversely with those in the HDL fraction, and LPS bound predominantly to lipoproteins in the LDL and VLDL fractions when HDL levels were low. Lipoproteins isolated from the serum of septic patients neutralized the bioactivity of the LPS that had bound to them. Our results show that the host response to acute inflammation and infection tends to maintain lipoprotein phospholipid levels and that, despite hypocholesterolemia and reduced HDL levels, circulating lipoproteins maintain their ability to bind and neutralize an important bacterial agonist, LPS.
Highlights
Circulating lipoproteins are thought to play an important role in the detoxification of lipopolysaccharide (LPS) by binding the bioactive lipid A portion of LPS to the lipoprotein surface
Phospholipids are the most abundant lipid components of the surface domain of lipoprotein particles (15), and several lines of evidence suggest that lipoprotein phospholipids are the most important determinants of LPSlipoprotein binding: Parker and coworkers (16) showed that the ability of the various lipoprotein classes to neutralize the bioactivity of LPS depends upon their phospholipid content and not upon their content of cholesterol or triglycerides; LPS binding protein (LBP) can transfer LPS into phospholipid vesicles (17); and artificial phospholipid-rich particles (4, 18) and emulsions (19) are effective LPS scavengers
Our results show that the lipoproteins in human serum can rapidly sequester LPS, even when total cholesterol levels are low during critical illness
Summary
Circulating lipoproteins are thought to play an important role in the detoxification of lipopolysaccharide (LPS) by binding the bioactive lipid A portion of LPS to the lipoprotein surface. Our results show that the host response to acute inflammation and infection tends to maintain lipoprotein phospholipid levels and that, despite hypocholesterolemia and reduced HDL levels, circulating lipoproteins maintain their ability to bind and neutralize an important bacterial agonist, LPS.—Kitchens, R. LPS binding to VLDL was only modestly increased (Ͻ2-fold) in the blood of subjects with type IV hyperlipidemia; in these specimens, HDL remained the dominant LPS acceptor despite severe hypertriglyceridemia and high VLDL levels (27). These results suggest that VLDL may play a minor role in LPS neutralization, infusion of exogenous VLDL or CM can protect rodents from LPSinduced lethality and can prevent septic death in a model of infectious peritonitis (6). The role that these triglyceriderich particles play in LPS neutralization is uncertain
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