Abstract 1097: Very-low Dose Endotoxemia Induces High Density Lipoprotein Remodeling and Reduces Cholesterol Efflux in the Absence of a Clinical Inflammatory Response
Introduction: Chronic low-grade inflammation is thought to induce atherogenic changes in HDL function. Indeed, we have demonstrated HDL particle remodeling during experimental human endotoxemia (3ng/kg). However, this model is associated with marked clinical symptoms, and may not reflect the chronic low-grade inflammation characteristic of insulin resistant atherogenic states.
Hypothesis: We hypothesized that very low-dose human endotoxemia (LPS; 0.6ng/kg) induces sub-clinical inflammation causing changes in HDL composition and function, without generating measurable clinical responses.
Methods: Ten healthy, human volunteers (50% male, 90% Caucasian, mean age 22.7 ± 3.8) were randomized to separate 36-hour inpatient visits (placebo versus intravenous LPS 0.6ng/kg) in a double-masked, placebo-controlled, crossover study. Serial plasma and serum samples were collected for measurement of cytokines, acute phase reactants, lipids and lipoproteins. Ex-vivo 3H-cholesterol efflux from FU5AH cells (SR-BI model) to the HDL fraction from serum, serially isolated during placebo/endotoxemia, was examined (N=5). Repeated measures ANOVA was applied to the data.
Results: There was no significant difference between placebo and LPS in the clinical measures of inflammatory response, including body temperature and heart rate. Relative to placebo, LPS produced a peak 20-fold increase in TNFα (p = 0.01) and a 15-fold increase in CRP (p <0.001). LPS had no effect on levels of HDL cholesterol, apoA-I, apoA-II or apoB lipoproteins. However, endotoxemia was associated with a significant decrease in plasma phospholipids (p = 0.03) and a 7-fold increase in HDL-associated SAA (p <0.001). Further, LPS induced a 40% reduction in cholesterol efflux to HDL by 12 hours post-LPS administration (p = 0.026) which recovered only slightly by 24 hours post-LPS.
Conclusions: A very low-dose of endotoxin produces relatively low-grade innate immune responses, without clinical symptoms, but with significant changes in HDL composition and function. This study provides evidence that a modest inflammatory response, consistent with chronic inflammation in atherogenic states in vivo, induces atherogenic changes in HDL.