Arterial foam cells are central players of atherogenesis. Cholesterol acceptors, 
apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL), take up 
cholesterol and phospholipids effluxed from foam cells into the circulation. Due 
to the high abundance of cholesterol in foam cells, most previous studies 
focused on apoA-I/HDL-mediated free cholesterol (FC) transport. However, recent 
lipidomics of human atherosclerotic plaques also identified that oxidized 
sterols (oxysterols) and non-sterol lipid species accumulate as atherogenesis 
progresses. While it is known that these lipids regulate expression of 
pro-inflammatory genes linked to plaque instability, how cholesterol acceptors 
impact the foam cell lipidome, particularly oxysterols and non-sterol lipids, 
remains unexplored. Using lipidomics analyses, we found cholesterol acceptors 
remodel foam cell lipidomes. Lipid subclass analyses revealed various 
oxysterols, sphingomyelins, and ceramides, species uniquely enriched in human 
plaques were significantly reduced by cholesterol acceptors, especially by 
apoA-I. These results indicate that the function of lipid-poor apoA-I is not 
limited to the efflux of cholesterol and phospholipids but suggest that apoA-I 
serves as a major regulator of the foam cell lipidome and might play an 
important role in reducing multiple lipid species involved in the pathogenesis 
of atherosclerosis.