Massive foam cell formation, atherosclerotic lesion development, and inflammation by combined deletion of ABCA1 and SR-BI in bone marrow-derived cells in LDL receptor knockout mice

Macrophages are incapable of limiting the uptake of lipids and therefore rely on cholesterol efflux mechanisms for maintaining cellular cholesterol homeostasis. Important mediators of macrophage cholesterol efflux are ABCA1, which mediates the efflux of cholesterol to lipid-poor apoAI, and SR-BI that promotes efflux to mature HDL. To get further insight into the putative synergistic roles of ABCA1 and SR-BI in foam cell formation and atherosclerosis, LDL receptor knockout mice were transplanted with bone marrow from ABCA1/SR-BI double knockout mice. Serum cholesterol levels were lower in ABCA1/SR-BI double knockout transplanted animals, as compared to the single knockout and wildtype transplanted animals on Western-type diet. Despite the lower serum cholesterol levels, massive foam cell formation was found in macrophages from spleen and the peritoneal cavity. Interestingly, ABCA1/SR-BI double knockout transplanted animals also showed a dramatic enhancement of systemic inflammation markers. Furthermore, after 10 weeks Western-type diet feeding atherosclerotic lesion development was more extensive in the LDL receptor knockout mice reconstituted with ABCA1/SR-BI double knockout bone marrow. These findings identify the essential function of both ABCA1 and SR-BI in macrophage foam cell formation and atherosclerotic lesion development and indicate that other cholesterol efflux mechanisms cannot compensate for the absence of these two cholesterol transporters.