Composition and lipid spatial distribution of HDL particles in subjects with low and high HDL-cholesterol

Abstract

A low level of high density lipoprotein cholesterol (HDL-C) is a powerful risk factor for cardiovascular disease. However, despite the reported key role of apolipo-proteins, specifically, apoA-I, in HDL metabolism, lipid molecular composition of HDL particles in subjects with high and low HDL-C levels is currently unknown. Here lipidomics was used to study HDL derived from well-characterized high and low HDL-C subjects. Low HDL-C subjects had elevated triacylglycerols and diminished lysophosphatidylcholines and sphingomyelins. Using information about the lipid composition of HDL particles in these two groups, we reconstituted HDL particles in silico by performing large-scale molecular dynamics simulations. In addition to confirming the measured change in particle size, we found that the changes in lipid composition also induced specific spatial distributions of lipids within the HDL particles, including a higher amount of triacylglycerols at the surface of HDL particles in low HDL-C subjects. Our findings have important implications for understanding HDL metabolism and function. For the first time we demonstrate the power of combining molecular profiling of lipoproteins with dynamic modeling of lipoprotein structure.

Fig. 1.

A: Partial least squares discriminant analysis (PLS/DA) of lipidomic profiles for low HDL-C and high HDL-C subjects. PLS/DA scores plot with two different HDL-C groups are marked. Two latent variables were used (Q² = 51%). B: Hierarchical clustering on most important variable importance in the projection (VIP) variables and samples in the heat map reflecting fold changes of lipids relative to mean intensity within the low HDL-C group. Bars show fold changes reflecting mean intensity of top VIP variables in the high HDL-C group relative to mean intensity within the low HDL-C group.

Fig. 2.

Box plots of the most abundant lipids within the TG, lysoPC, SM, ChoE, and ethanolamine plasmalogen (PEp) classes. Concentrations are shown in μmol/l [lipid] / mg/dl [apoA-I]. High, high HDL-C; Low, low HDL-C. ChoE, cholesteryl ester; lysoPC, lysophosphatidylcholine; SM, sphingomyelin; TG, triacylglycerol.

Fig. 3.

Coarse-grained simulations of HDL particles reconstituted based on lipidomics data. A: Snapshots from the end of high and low HDL-C simulations (8 μs). Apo-AIs are colored with red and green, cholesterol molecules are yellow, and all other lipids are gray. Water phase was removed from the snapshots for clarity. Middle snapshot demonstrates how the cholesterol molecules are localized next to and under apoA-Is in high HDL-C simulation. B: The number of contacts between apoA-Is and different lipid beads in each simulation (error bars indicate ± SD). The number of contacts was not normalized with the number of different lipid constituents. C: Radial distribution function for TG molecules g(r) with respect to the center of mass (COM) of HDL particle. When surface lipid concentration decreases, more TGs are able to penetrate the surface monolayer, which is seen as a formation of higher plateaus near 3.5 nm. The number of contacts between TG and water beads (per TG) in different simulations is shown in the inset. Apo, apolipoprotein; TG, triacylglycerol.