Apolipoprotein E Is the Determinant that Mediates the Receptor Uptake of B-Very Low Density Lipoproteins by Mouse Macrophages

Beta very low density lipoproteins (B-VLDL) from cholesterol-fed animals and from patients with Type III hyperlipoproteinemia are internalized by a receptor-mediated process in mouse macrophages. Once internalized, the cholesteryl esters of B-VLDL are hydrolyzed in lysosomes, and the released cholesterol is re-esterified, resulting in a massive accumulation of cholesteryl esters. In the present study, competitive binding experiments demonstrated that canine apo E HDLC (lipoproteins that contain almost exclusively apolipoprotein E) inhibited the receptor-mediated uptake of I-BVLDL. The incorporation of human apo E into B-VLDL was also shown to modulate binding. Reductively methylated B-VLDL (methyl B-VLDL) were not taken up by macrophages and did not stimulate cholesteryl ester synthesis. When unmodified human apo E-3 was incorporated into the lipoprotein in place of the canine methyl apo E, these hybrid B-VLDL (methyl B-VLDL [E-3]) were internalized and degraded and were as effective as native B-VLDL in stimulating cholesteryl ester synthesis in macrophages. In the reverse experiment, the incorporation of methyl apo E-3 into native canine B-VLDL (B-VLDL [methyl E-3]) reduced the binding activity of the B-VLDL and abolished their ability to stimulate cellular cholesteryl ester synthesis. Canine B-VLDL into which apo E-2(Arg158-»Cys) had been incorporated had less ability to stimulate cholesteryl ester synthesis (20%) than did native B-VLDL, but they were more active than B-VLDL [methyl E-2] or B-VLDL [methyl E-3], which had virtually no activity. These results demonstrate that apo E is the determinant mediating the receptor binding and uptake of B-VLDL by mouse macrophages. (Arteriosclerosis 6:114-122, January/February 1986)