Abstract 15: Proteomic Analysis of HDL from Inbred Strains of Mice Implicates APOE in Reduced Cholesterol Efflux Capacity via the ABCA1 Pathway

Background: Human HDL’s efflux capacity-the ability to promote cholesterol efflux from macrophages-associates strongly and negatively with risk of future cardiac events. However, the molecular factors that regulate efflux capacity remain poorly understood. Methods and Results: We investigated the relationships between HDL’s size, protein cargo, and sterol efflux capacity, using HDLs from five inbred mouse strains with different HDL-cholesterol levels and susceptibilities to atherosclerosis. Like human HDL, mouse HDL carried >70 proteins linked to lipid metabolism, the acute-phase response, proteinase inhibition, and the immune system. Hierarchical cluster analysis recapitulated the genealogy of the mouse strains, indicating that the HDL proteome is under genetic control. HDL particle size from the different strains correlated strongly and positively with APOA2 content. Analysis of HDL isolated from Apoa2-/- or Apoa2transgenic mice confirmed that APOA2 is a major determinant of HDL particle size. Unexpecte...