Lipidomics of Plasma High-Density Lipoprotein: Insights into Anti-Atherogenic Function

Low concentrations of high-density lipoprotein-cholesterol (HDL-C) represent a strong, independent risk factor for cardiovascular (CV) disease and atherosclerosis. The association between HDL-C and CV risk is thought to reflect multiple atheroprotective properties of HDL particles. Indeed, HDL can efflux cholesterol from lipid-loaded macrophages, reduce proinflammatory responses, decrease oxidative stress, attenuate cellular apoptosis, diminish platelet activation, improve beta-cell function and enhance vasodilation. The multiple biological functions of HDL particles are directly related to the presence of key bioactive lipid and protein components. The HDL lipidome is dominated by phospholipids (PLs) that contribute to 20-25% of total HDL mass, followed by cholesteryl esters (CEs; 14-18 wt %), sphingolipids (SLs; 3-4 wt %), triglycerides (TGs; 3-6 wt %) and free cholesterol (FC; 3-5 wt %) [8]. Phosphatidylcholine (PC) represents the major subclass of HDL PLs (15-18 wt %) followed by lysophosphatidylcholine (LPC; up to 3 wt %) and plasmalogens (1-2.5 wt %). In addition, HDL contains several low-abundance PLs (<1 wt %), including phosphatidylethanolamine (PE), phosphatidylinositol (PI), phosphatidylserine (PS), phosphatidylglycerol (PG), phosphatidic acid (PA) and cardiolipin. Among SLs, sphingomyelin (SM) clearly prevails, providing >90% of the total mass of this subclass.

HDL particles feature a high level of structural, compositional and functional heterogeneity, differing in physical (shape, size, density, electrophoretic mobility) and biological properties. Interestingly, small, dense HDL3, which feature distinct structure and are enriched in several bioactive lipids and proteins display enhanced capacity to efflux cellular cholesterol via the ATP-binding cassette transporter A1 (ABCA1), to reduce apoptosis in endothelial cells and to protect low-density lipoprotein (LDL) from oxidative stress. The content of major lipid classes per HDL particle typically diminishes with progressive increase in HDL density, reflecting depletion of total lipid relative to protein components. By contrast, the proportions of most lipid classes relative to total lipid content remain relatively constant across plasma HDL subspecies. Two remarkable exceptions from this rule are represented by SM and sphingosine-1-phosphate (S1P). Thus, HDL % content of SM is reduced in small, dense HDL, whereas that of S1P, a minor bioactive lipid, is elevated. These data suggest that heterogeneity in HDL composition can impact biological function of HDL.