Inflammation modulates human HDL composition and function in vivo

ObjectivesInflammation may directly impair HDL functions, in particular reverse cholesterol transport (RCT), but limited data support this concept in humans.Methods and resultsWe employed low-dose human endotoxemia to assess the effects of inflammation on HDL and RCT-related parameters in vivo. Endotoxemia induced remodelling of HDL with depletion of pre-β1a HDL particles determined by 2-D gel electrophoresis (−32.2 ± 9.3% at 24 h, p < 0.05) as well as small (−23.0 ± 5.1%, p < 0.01, at 24 h) and medium (−57.6 ± 8.0% at 16 h, p < 0.001) HDL estimated by nuclear magnetic resonance (NMR). This was associated with induction of class II secretory phospholipase A2 (∼36 fold increase) and suppression of lecithin:cholesterol acyltransferase activity (−20.8 ± 3.4% at 24 h, p < 0.01) and cholesterol ester transfer protein mass (−22.2 ± 6.8% at 24 h, p < 0.001). The HDL fraction, isolated following endotoxemia, had reduced capacity to efflux cholesterol in vitro from SR-BI and ABCA1, but not ABCG1 transporter cell models.ConclusionsThese data support the concept that “atherogenic-HDL dysfunction” and impaired RCT occur in human inflammatory syndromes, largely independent of changes in plasma HDL-C and ApoA-I levels.

► Endotoxin challenge in humans results in marked alterations in HDL particle composition with reduced phospholipids and increased serum amyloid A but without significant change in cholesterol of apo-AI. ► Endotoxin induced selective remodeling of HDL particles with induction of specific HDL lipases and reductions in CETP mass and LCAT activity. ► HDL efflux function was reduced after endotoxin challenge with reduced capacity of particles to mediate efflux via ABCA1 and SR-BI cholesterol transporter pathways; reduced efflux correlated with alterations in HDL composition and reduction in specific HDL sub-populations.► Overall, these data support the concept that atherogenic HDL dysfunction and impaired RCT occur in human inflammatory syndromes, independent of significant change in plasma HDL-C levels.