Cholesterol loading of macrophages leads to marked enhancement of native lipoprotein(a) and apoprotein(a) internalization and degradation.
Lipoprotein(a) levels in the plasma are strongly correlated with atherosclerotic coronary artery disease. Although the mechanism of this effect is not known, the interaction of lipoprotein(a) with macrophages may be important. Previous work has shown that macrophages in culture internalize and degrade native lipoprotein(a) poorly. In the present study, the interaction of Lp(a) with mouse peritoneal and human monocyte-derived macrophages that were cholesterol-loaded, such as occur in atheromata, was investigated. 125I-Lp(a) degradation was increased 4-5-fold in macrophages that had been loaded with cholesterol by incubation with acetyl-LDL for 2-4 days. The enhanced degradation of Lp(a) by foam cells was chloroquine-sensitive and dependent upon the presence of calcium in the extracellular medium. Incubation of the macrophages with acetyl-LDL plus an inhibitor of acyl CoA:cholesterol acyltransferase, which increased the free cholesterol content and decreased the cholesteryl ester content of the cells, resulted in an even greater up-regulation of 125I-Lp(a) degradation (8-23-fold over control macrophages). The interaction of Lp(a) with cholesterol-loaded macrophages involved the apoprotein(a) moiety of Lp(a) since 125I-apoprotein(a), but not 125I-Lp(a-), was degraded to a much greater extent by foam cells compared to control macrophages. The uptake and degradation of Lp(a) in foam cells was not mediated by LDL, scavenger, LDL receptor-related protein (LRP), or plasminogen receptors. Thus, cholesterol loading of macrophages markedly enhances the internalization and lysosomal degradation of Lp(a) and apo(a) by a calcium-dependent receptor activity different from known lipoprotein receptors.
Bottalico
L A
LA
Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York 10032.
Keesler
G A
GA
Fless
G M
GM
Tabas
I
I
D000818:Animals; D001054:Apolipoproteins A / Q000378:metabolism*; D001665:Binding Sites; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism*; D005260:Female; D005487:Foam Cells / Q000378:metabolism; D006801:Humans; D017270:Lipoprotein(a) / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008813:Mice, Inbred ICR; D009000:Monocytes / Q000378:metabolism; D010537:Peritoneum / Q000166:cytology; D011817:Rabbits; D002785:Sterol O-Acyltransferase / Q000378:metabolism
D001054:Apolipoproteins A; D017270:Lipoprotein(a); D002784:Cholesterol; D002785:Sterol O-Acyltransferase