Oxidation of low density lipoprotein (LDL) is a critical step for atherogenesis, and the role of the 12/15-lipoxygenase (12/15-LOX) as well as LDL receptor-related protein (LRP) expressed in macrophages in this process has been suggested. The oxygenation of cholesteryl linoleate in LDL by mouse macrophage-like J774A.1 cells overexpressing 12/15-LOX was inhibited by an anti-LRP antibody but not by an anti-LDL receptor antibody. When the cells were incubated with LDL double-labeled by [H-3]cholesteryl linoleate and [I-125]apoB, association with the cells of [H-3]cholesteryl linoleate expressed as LDL protein equivalent exceeded that of [I-125]apoB, indicating selective uptake of [H-3]cholesteryl linoleate from LDL to these cells. An anti-LRP antibody inhibited the selective uptake of [H-3]cholesteryl ester by 62% and 81%, with the 12/15-LOX-expressing cells and macrophages, respectively. Furthermore, addition of LDL to the culture medium of the [3H]cholesteryl linoleate-labeled 12/15-LOX-expressing cells increased the release of [H-3]cholesteryl linoleate to the medium in LDL concentration- and time-dependent manners. The transport of [H-3]cholesteryl linoleate from the cells to LDL was also inhibited by an anti-LRP antibody by 75%. These results strongly suggest that LRP contributes to the LDL oxidation by 12/15-LOX in macrophages by selective uptake and efflux of cholesteryl ester in the LDL particle. (c) 2005 Elsevier Inc. All rights reserved.