Enhanced macrophage uptake of low density lipoprotein after self-aggregation.
Incubation of mouse peritoneal macrophages with native human low density lipoprotein (LDL) did not cause any significant storage of intracellular cholesteryl esters. However, when the LDL was subjected to brief (30-second) vortexing, it formed self-aggregates that were rapidly ingested and degraded by macrophages, converting them to cholesteryl ester-rich foam cells. Such aggregates were as potent as acetyl-LDL in stimulating cholesterol esterification in the macrophages. The degradation of LDL aggregates was strongly inhibited by cytochalasin B (85%), whereas degradation of native LDL was only weekly inhibited (23%), suggesting that uptake occurred by phagocytosis rather than pinocytosis. Several lines of evidence suggest that the phagocytic uptake depends, in part, upon the LDL receptor and not the acetyl-LDL receptor: 1) soluble, native LDL and beta-VLDL (but not acetyl-LDL) competed for uptake and degradation of LDL aggregates; 2) reductive methylation of LDL before vortexing reduced the effect of the aggregates on degradation and cholesterol esterification; 3) heparin, which inhibits binding of native LDL to its receptor, reduced the degradation of LDL aggregates. These studies show that self-aggregation of LDL markedly enhances its uptake by macrophages, probably by phagocytosis and at least, in part, via the LDL receptor. Aggregates of LDL in the artery wall--either self-aggregates or mixed aggregates including matrix components--may induce foam cell formation and favor the formation of the fatty streak.
Khoo
J C
JC
Department of Medicine, University of California, San Diego, La Jolla 92093.
Miller
E
E
McLoughlin
P
P
Steinberg
D
D
D000818:Animals; D001055:Apolipoproteins B / Q000502:physiology; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D003571:Cytochalasin B / Q000494:pharmacology; D004951:Esterification; D005487:Foam Cells / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010587:Phagocytosis; D011973:Receptors, LDL / Q000502:physiology
D001055:Apolipoproteins B; D002788:Cholesterol Esters; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D003571:Cytochalasin B