Apolipoprotein E is the determinant that mediates the receptor uptake of beta-very low density lipoproteins by mouse macrophages.
Beta very low density lipoproteins (beta-VLDL) from cholesterol-fed animals from patients with Type III hyperlipoproteinemia are internalized by a receptor-mediated process in mouse macrophages. Once internalized, the cholesteryl esters of beta-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 125I-beta-VLDL. The incorporation of human apo E into beta-VLDL was also shown to modulate binding. Reductively methylated beta-VLDL (methyl beta-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 beta-VLDL (methyl beta-VLDL [E-3]) were internalized and degraded and were as effective as native beta-VLDL in stimulating cholesteryl ester synthesis in macrophages. In the reverse experiment, the incorporation of methyl apo E-3 into native canine beta-VLDL (beta-VLDL [methyl E-3]) reduced the binding activity of the beta-VLDL and abolished their ability to stimulate cellular cholesteryl ester synthesis. Canine beta-VLDL into which apo E-2(Arg158----Cys) had been incorporated had less ability to stimulate cholesteryl ester synthesis (20%) than did native beta-VLDL, but they were more active than beta-VLDL [methyl E-2] or beta-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 beta-VLDL by mouse macrophages.
D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism*; D002478:Cells, Cultured; D002788:Cholesterol Esters / Q000378:metabolism; D004285:Dogs; D005347:Fibroblasts / Q000378:metabolism; D008075:Lipoproteins, HDL / Q000378:metabolism; D008079:Lipoproteins, VLDL / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D010529:Peritoneal Cavity / Q000166:cytology; D011973:Receptors, LDL / Q000378:metabolism*; D013329:Structure-Activity Relationship
D001057:Apolipoproteins E; D002788:Cholesterol Esters; D008075:Lipoproteins, HDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; C036053:VLDL receptor