The d < 1.006
lipoproteins of patients in a kindred with atypical
dysbetalipoproteinemia induced marked
cholesteryl ester accumulation in mouse peritoneal macrophages. The affected family members had severe
hypercholesterolemia and
hypertriglyceridemia,
xanthomatosis, premature
vascular disease, the
apo-E3/3 phenotype, and a predominance of
cholesterol-rich
beta-very low density lipoproteins (
beta-VLDL) in the d < 1.006 fraction. When incubated with mouse peritoneal macrophages, the d < 1.006
lipoproteins or
beta-VLDL from the affected family members stimulated cholesteryl [(14)C]
oleate synthesis 15- to 30-fold above that caused by normal, control d < 1.006
lipoproteins (VLDL). The ability of the
beta-VLDL to stimulate macrophage
cholesteryl ester accumulation was greatly reduced as a consequence of treatment with
hypolipidemic agents, which specifically reduced the concentration of
beta-VLDL. Two important differences were noted in a comparison of the
beta-VLDL from these atypical dysbetalipoproteinemic subjects with that of classic E2/2 dysbetalipoproteinemics: (a) the
beta-VLDL from the atypical subjects were severalfold more active in stimulating
cholesteryl ester accumulation in macrophages, and (b) both the intestinal and hepatic
beta-VLDL from the atypical subjects were active. The triglyceriderich, alpha(2)-migrating VLDL from the affected family members constituted <10% of the d < 1.006 fraction and were similar to normal VLDL in that they did not stimulate
cholesteryl ester synthesis in the macrophages. Several lines of evidence indicate that the macrophage accumulation of
cholesteryl esters was induced by a receptor-mediated uptake process and that the
beta-VLDL were bound by a specific
beta-VLDL receptor. First, the uptake and degradation of the
lipoproteins and the induction of
cholesteryl ester formation displayed qualities of high affinity, saturable kinetics. Second, the uptake and degradation process was inhibited when the lysyl residues of the
beta-VLDL apoproteins were modified by reductive methylation. Third, the
beta-VLDL from the affected subjects competed with diet-induced canine (125)I-beta-VLDL for the same
cell surface receptors, but did not compete with chemically modified
low density lipoproteins. Finally, the receptor-mediated uptake of these
beta-VLDL resulted in lysosomal degradation of the
lipoproteins, which could be prevented by incubating the cells with
chloroquine. Normal,
triglyceride-rich VLDL were also degraded when incubated with the macrophages, but they were not degraded by the same receptor-mediated process responsible for the degradation of the
beta-VLDL of the patients. The degradation of the VLDL was not abolished by reductive methylation of the
lipoproteins or by treatment of the cells with choloroquine. These studies demonstrate that the
beta-VLDL from subjects with atypical
dysbetalipoproteinemia are taken up by macrophages via the same receptor-mediated process responsible for the uptake of diet induced
beta-VLDL. The accelerated
vascular disease seen in these patients may be the result of high concentrations of
beta-VLDL capable of binding to and delivering large quantities of
cholesterol to macrophages and converting them into cells resembling the foam cells of atherosclerotic lesions.