ABSTRACIResident mouse peritoneal macro hages were shown to take up and degrade acetylated 1251 abeled low density lipoprotein (15I-acetyl-LDL) in vitro at rates that were 20fold greater than those for the uptake and degradation of 125I-LDL. The uptake of 1251-acetyl-LDL and its subsequent degradation in lysosomes were attributable to a high-affinity, trypsin-sensitive, surface binding site that recognized acetyl-LDL but not native LDL. When 25I-acetyl-LDL was bound to this site at 4VC and the macrophages were subsequently warmed to 370C, 75% of the cell-bound radioactivity was Studies in cultured human fibroblasts and blood lymphocytes have defined a receptor-mediated pathway by which cells take up and degrade low density lipoprotein (LDL), the major cholesterol-transport protein in human plasma (1, 2). This LDL uptake pathway is believed to function primarily in extrahepatic parenchymal cells where it serves a dual function: it provides the major physiologic route of LDL degradation in the human body and, at the same time, it supplies cholesterol to cells for the synthesis of membranes and steroid hormones.Patients with familial hypercholesterolemia (FH) have a mutation in the gene specifying the LDL receptor (1, 2). In these patients, LDL degradation through the physiologic pathway is blocked, and each LDL particle survives in the circulation 2-3 times longer than it does in normal subjects (3-5). As a result, the lipoprotein accumulates to abnormally high levels in plasma. Eventually the LDL is degraded through an alternate pathway. Inasmuch as the excess LDL-cholesterol becomes deposited in nonparenchymal cells throughout the body, including hepatic Kupffer cells and macrophages of the spleen, kidney, bone marrow, skin, tendons, and other organs (2, 6, 7), we have postulated that the alternate pathway for LDL degradation is expressed primarily in such scavenger cells (2, 5). Because this scavenger mechanism acts on plasma LDL that has circulated for an abnormally long time in vio, it may recognize some form of LDL that has become denatured or chemically modified. The clearance of denatured proteins in vivo by macrophages is well known (8, 9).As a first step in a search for the postulated macrophage system mediating the uptake and degradation of modified or denatured LDL, we have used as a probe 125I-labeled LDL (125I-LDL) that has been extensively acetylated in vitro (125I-acetyl-LDL). The rationale for this choice was based on previous studies showing that acetylation of LDL altered the lipoprotein to the extent that it was no longer recognized by the LDL receptor in fibroblasts (10). As a model cell system for studying the metabolism of '25I-acetyl-LDL, we have used resident mouse peritoneal macrophages isolated by the techniques developed by Cohn and coworkers (11, 12). We demonstrate that these cells possess a high-affinity binding site that recognizes acetyl-LDL but not native LDL. This binding site, which so far appears to occur only on macrophages, mediates the rapid uptake and degradation of acety...
