Arteriosclerosis and Thrombosis, Vol 11, 1356-1367, Copyright © 1991 by American Heart Association

ARTICLES

Enhanced uptake and impaired intracellular metabolism of low density lipoprotein complexed with anti-low density lipoprotein antibodies

MF Lopes-Virella, RL Griffith, KA Shunk and GT Virella
Department of Medicine, Medical University of South Carolina, Charleston.

We have previously shown that incubation of human macrophages with antigen-antibody complexes prepared with native human low density lipoprotein (LDL) and rabbit anti-LDL antibodies (LDL-ICs) results in an increased intracellular accumulation of cholesteryl esters (CEs) and induces a marked increase in the number of LDL receptors. To determine whether the increased CE accumulation in these cells occurred during incubation of the cells with LDL-ICs or whether it was secondary to the uptake of LDL by overexpressed LDL receptors, we incubated human macrophages with LDL-ICs for 22 hours, followed by incubation with native LDL for another 20 hours. We found that about 90% of the accumulated CEs could be accounted for by the first incubation with LDL- ICs. We then proceeded to show that the CEs accumulated during incubation of cells with LDL-ICs was secondary to enhanced uptake and impaired degradation of the LDL complexed with immunoglobulin G (IgG) (LDL-IC), which led to a marked intracellular accumulation of undergraded LDL (levels 199-fold higher than those obtained when the cells were incubated with the same concentration of native LDL not complexed with IgG). We have also shown that not all CEs accumulated in these cells were derived from accumulation of undegraded LDL and that some of them were derived from the reesterification of free cholesterol released during hydrolysis of LDL. LDL-ICs promoted increased CE accumulation and foam cell formation at concentrations as low as 25 micrograms/ml. To determine which receptors were involved in the uptake of LDL-ICs, we performed experiments in which the uptake of LDL-ICs was competitively inhibited with heat-aggregated gamma globulin, native LDL, beta-very low density lipoprotein, or acetylated LDL. Our results demonstrated that LDL-IC uptake was most effectively inhibited by heat- aggregated gamma globulin, partially inhibited by native LDL or by a monoclonal antibody to the LDL receptor, and not inhibited by acetylated LDL or beta-very low density lipoprotein. Thus, we conclude that the majority of LDL-ICs are taken up through Fc gamma receptors. Finally, we investigated whether the increase in LDL receptor expression was dependent on the receptor pathway used by the LDL-ICs, and we were able to demonstrate that when macrophages were incubated with LDL-ICs prepared with F(ab')2 fragments of the anti-LDL antibody, LDL receptor expression was not enhanced. Therefore, we postulate that the uptake of LDL-ICs through Fc gamma receptors results in an uncoupling of the normal regulation of the LDL receptor expression.

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