Ezetimibe belongs to a group of selective and very effective 2-azetidione cholesterol absorption inhibitors which act on the level of cholesterol entry into enterocytes. Recent data indicated that the drug prevents the formation of a heterocomplex consisting of annexin-2 and caveolin-1 and leads to specific inhibition of an NPC1L1-dependent cholesterol uptake pathway required for uptake of micellar cholesterol into enterocytes. Earlier studies have shown that caveolin-1 and annexin-2 are also expressed in human macrophages and we show in this study that human macrophages express NPC1L1. Moreover in human macrophages, Ezetimibe (SCH58235) and its analogue, SCH354909, are bound to specific cell surface receptors followed by endocytosis via the classical endocytic pathway. SCH58235 had no effect on uptake and/or processing of acetylated LDL (Ac-LDL). In contrast, the compound inhibited uptake of oxidized LDL (Ox-LDL) by similar to50% in a dose-dependent manner. SCH58235 blocked the lipid-induced induction of LXR/RXR target genes ABCA1, ABCG1, and apolipoprotein E distinctively more effectively in macrophages loaded with Ox-LDL than in those loaded with Ac-LDL. Based on these findings, we presume that the caveolin-1-, annexin-2-, and NPC1L1-dependent cholesterol uptake system that is operating in enterocytes may also contribute to class B scavenger receptor-dependent uptake of Ox-LDL in human monocyte-derived macrophages. (C) 2004 Elsevier Inc. All rights reserved.