Contribution of ABCA1 to macrophage cholesterol efflux, HDL levels, and centripetal cholesterol flux. ABCA1 probably has a major role in the efflux of phospholipids and cholesterol from different cells (macrophages, hepatocytes) to apoA-I. This is followed by further growth of the HDL particle, involving the addition of lipids and apoproteins, cholesterol esterification by lecithin-cholesterol acyltransfer (LCAT), and influx of phospholipids under the control of phospholipid transfer protein (PLTP), and eventuates in the formation of mature HDL. Macrophage ABCA1 makes only a minor contribution to the maintenance of circulating HDL, while hepatic expression of ABCA1 probably has a major role in this regard (thick arrow). Studies in ABCA1 KO mice indicate that although ABCA1 has a key role in maintaining HDL levels, overall centripetal flow of cholesterol from periphery to liver appears not to be affected by the absence of ABCA1. Nonetheless, the phenotype of Tangier disease indicates that ABCA1 has an essential role in removing cholesterol deposited in macrophages, but probably not other cells. The amount of cholesterol lost from macrophages is too small to be measured in the overall centripetal flow of cholesterol. Moreover, macrophage-derived cholesterol could be redistributed to VLDL/LDL and taken up in other peripheral tissues, without substantially changing VLDL/LDL cholesterol levels or centripetal cholesterol flux.