Binding site on macrophages that mediates uptake and degradation of acetylated low density lipoprotein, producing massive cholesterol deposition

J. L. Goldstein, Y. K. Ho, S. K. Basu, M. S. Brown

Research output: Contribution to journalArticle

1839 Scopus citations

Abstract

Resident mouse peritoneal macrophages were shown to take up and degrade acetylated 125I-labeled low density lipoprotein (125I-acetyl-LDL) in vitro at rates that were 20-fold greater than those for the uptake and degradation of 125I-LDL. The uptake of 125I-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 125I-acetyl-LDL was bound to this site at 4°C and the macrophages were subsequently warmed to 37°C, 75% of the cell-bound radioactivity was degraded to mono[125I]iodotyrosine within 1 hr. The macrophage binding site also recognized maleylated LDL, maleylated albumin, and two sulfated polysaccharides (fucoidin and dextran sulfate) indicating that negative charges were important in the binding reaction. A similar binding site was present on rat peritoneal macrophages, guinea pig Kupffer cells, and cultured human mococytes but not on human lymphocytes or fibroblasts, mouse L cells or Y-1 adrenal cells, or Chinese hamster ovary cells. Uptake and degradation of acetyl-LDL via this binding site stimulated cholesterol esterification 100-fold and produced a 38-fold increase in the cellular content of cholesterol in mouse peritoneal macrophages. although the physiologic significance, if any, of this macrophage uptake mechanism is not yet known, we hypothesize that it may mediate the degradation of denatured LDL in the body and thus serve as a 'backup' mechanism for the previously described receptor-mediated degradation of native LDL that occurs in parenchymal cells. Such a scavenger pathway might account for the widespread deposition of LDL-derived cholesteryl esters in macrophages of patients with familial hypercholesterolemia in whom the parenchymal cell pathway for LDL degradation is blocked, owing to a genetic deficiency of receptors for native LDL.

Original languageEnglish (US)
Pages (from-to)333-337
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume76
Issue number1
DOIs
StatePublished - Jan 1 1979

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