Binding Site on Macrophages That Mediates Uptake and Degradation of Acetylated Low Density Lipoprotein, Producing Massive Cholesterol Deposition

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 1979 Jan 1

PMID 218198

Citations 520

Authors

J L Goldstein

Y K Ho

S K Basu

M S Brown

Affiliations

Soon will be listed here.

Abstract

Resident mouse peritoneal macrophages were shown to take up and degrade acetylated (125)I-labeled low density lipoprotein ((125)I-acetyl-LDL) in vitro at rates that were 20-fold greater than those for the uptake and degradation of (125)I-LDL. The uptake of (125)I-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 (125)I-acetyl-LDL was bound to this site at 4 degrees C and the macrophages were subsequently warmed to 37 degrees C, 75% of the cell-bound radioactivity was degraded to mono[(125)I]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 monocytes 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.

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References

Mego J, McQUEEN J . THE UPTAKE AND DEGRADATION OF INJECTED LABELED PROTEINS BY MOUSE-LIVER PARTICLES. Biochim Biophys Acta. 1965; 100:136-43. DOI: 10.1016/0304-4165(65)90436-8. View

COHN Z, Benson B . THE DIFFERENTIATION OF MONONUCLEAR PHAGOCYTES. MORPHOLOGY, CYTOCHEMISTRY, AND BIOCHEMISTRY. J Exp Med. 1965; 121:153-70. PMC: 2137972. DOI: 10.1084/jem.121.1.153. View

Garvey J . Separation and in vitro culture of cells from liver tissue. Nature. 1961; 191:972-4. DOI: 10.1038/191972a0. View

LOWRY O, ROSEBROUGH N, FARR A, RANDALL R . Protein measurement with the Folin phenol reagent. J Biol Chem. 1951; 193(1):265-75. View

Goldstein J, Brown M . Atherosclerosis: the low-density lipoprotein receptor hypothesis. Metabolism. 1977; 26(11):1257-75. DOI: 10.1016/0026-0495(77)90119-6. View

Goldstein J, Brown M . The low-density lipoprotein pathway and its relation to atherosclerosis. Annu Rev Biochem. 1977; 46:897-930. DOI: 10.1146/annurev.bi.46.070177.004341. View

Goldstein J, Brown M . Familial hypercholesterolemia: pathogenesis of a receptor disease. Johns Hopkins Med J. 1978; 143(1):8-16. View

Basu S, Goldstein J, Anderson G, Brown M . Degradation of cationized low density lipoprotein and regulation of cholesterol metabolism in homozygous familial hypercholesterolemia fibroblasts. Proc Natl Acad Sci U S A. 1976; 73(9):3178-82. PMC: 430973. DOI: 10.1073/pnas.73.9.3178. View

Pratten M, Williams K, Lloyd J . A quantitative study of pinocytosis and intracellular proteolysis in rat peritoneal macrophages. Biochem J. 1977; 168(3):365-72. PMC: 1183781. DOI: 10.1042/bj1680365. View

10.

Nilsson M, Berg T . Uptake and degradation of formaldehyde-treated 125I-labelled human serum albumin in rat liver cells in vivo and in vitro. Biochim Biophys Acta. 1977; 497(1):171-82. DOI: 10.1016/0304-4165(77)90150-7. View

11.

Moore A, Williams K, Lloyd J . The effect of chemical treatments of albumin and orosomucoid on rate of clearance from the rat bloodstream and rate of pinocytic capture of rat yolk sac cultured in vitro. Biochem J. 1977; 164(3):607-16. PMC: 1164838. DOI: 10.1042/bj1640607. View

12.

Johnson Jr W, Mei B, COHN Z . The separation, long-term cultivation, and maturation of the human monocyte. J Exp Med. 1977; 146(6):1613-26. PMC: 2181917. DOI: 10.1084/jem.146.6.1613. View

13.

Boyum A . Isolation of mononuclear cells and granulocytes from human blood. Isolation of monuclear cells by one centrifugation, and of granulocytes by combining centrifugation and sedimentation at 1 g. Scand J Clin Lab Invest Suppl. 1968; 97:77-89. View

14.

Goldstein J, Brown M . Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia. J Biol Chem. 1974; 249(16):5153-62. View

15.

Goldstein J, Dana S, Brown M . Esterification of low density lipoprotein cholesterol in human fibroblasts and its absence in homozygous familial hypercholesterolemia. Proc Natl Acad Sci U S A. 1974; 71(11):4288-92. PMC: 433867. DOI: 10.1073/pnas.71.11.4288. View

16.

Werb Z, COHN Z . Cholesterol metabolism in the macrophage. 3. Ingestion and intracellular fate of cholesterol and cholesterol esters. J Exp Med. 1972; 135(1):21-44. PMC: 2139123. DOI: 10.1084/jem.135.1.21. View

17.

Goldstein J, Basu S, Brunschede G, Brown M . Release of low density lipoprotein from its cell surface receptor by sulfated glycosaminoglycans. Cell. 1976; 7(1):85-95. DOI: 10.1016/0092-8674(76)90258-0. View

18.

Simons L, REICHL D, MYANT N, Mancini M . The metabolism of the apoprotein of plasma low density lipoprotein in familial hyperbetalipoproteinaemia in the homozygous form. Atherosclerosis. 1975; 21(2):283-98. DOI: 10.1016/0021-9150(75)90087-8. View

19.

Brown M, Faust J, Goldstein J . Role of the low density lipoprotein receptor in regulating the content of free and esterified cholesterol in human fibroblasts. J Clin Invest. 1975; 55(4):783-93. PMC: 301815. DOI: 10.1172/JCI107989. View

20.

Bilheimer D, Goldstein J, Grundy S, Brown M . Reduction in cholesterol and low density lipoprotein synthesis after portacaval shunt surgery in a patient with homozygous familial hypercholesterolemia. J Clin Invest. 1975; 56(6):1420-30. PMC: 333120. DOI: 10.1172/JCI108223. View