Cholesterol esterification in macrophages. Stimulation by lipoproteins containing apo B isolated from human aortas.
A lipoprotein fraction possessing many of the characteristics of plasma low density lipoproteins (P-LDL) was isolated from homogenates of lesioned human aortas by affinity chromatography. In contrast to P-LDL, this fraction, termed A-LP, was found to be more electronegative than P-LDL and to stimulate cholesterol esterification in mouse peritoneal macrophages (MPM). This stimulation tended toward saturation at approximately 100 micrograms/ml lipoprotein cholesterol. Cholesterol esterification was partially inhibited by fucoidin, a competitive inhibitor of the scavenger receptor on MPM. These results suggest that A-LP is recognized by a high affinity binding site on MPM. Stimulation of cholesterol esterification in MPM by A-lP was inhibited by the lysosomotropic agent, chloroquine, indicating that degradation in lysosomes was a prerequisite for cholesterol esterification. Substantial degradation of apo B within the intact A-LP was demonstrated by SDS-PAGE and immunoblotting. This degradation could be responsible for the increased negative charge on A-LP, and the enhanced recognition of A-LP by a receptor on MPM. Stimulation of cholesterol esterification increased linearly over a 48-hour time period, suggesting that the receptor on MPM recognizing A-LP was not down-regulated. This unabated increase in cholesterol esterification resulted in massive accumulation of intracellular cholesteryl esters and a gradual increase in oil red O-positive droplets, giving the MPM the characteristic morphology of foam cells. If these mechanisms demonstrated in vitro also occur in the intact artery, they could explain how foam cells are formed within the fatty streak lesion.
D000818:Animals; D001011:Aorta / Q000032:analysis; D001053:Apolipoproteins / Q000302:isolation & purification / Q000378:metabolism; D001055:Apolipoproteins B; D001161:Arteriosclerosis / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism*; D002846:Chromatography, Affinity; D004951:Esterification; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood / Q000302:isolation & purification / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D011134:Polysaccharides / Q000494:pharmacology
D001053:Apolipoproteins; D001055:Apolipoproteins B; D008077:Lipoproteins, LDL; D011134:Polysaccharides; C007789:fucoidan; D002784:Cholesterol