Bone marrow transplantation in apolipoprotein E deficient mice - Effect of ApoE gene dosage on serum lipid concentrations, (beta)VLDL catabolism, and atherosclerosis

ApolipoproteinE (apoE), a high-affinity ligand for lipoprotein receptors, is synthesized by the liver and extrahepatic tissues, including cells of the monocyte/macrophage lineage. Inactivation of the apoE gene in mice leads to a prominent increase in serum cholesterol and triglyceride levels and the development of premature atherosclerosis. In this study, the role of monocyte/macrophage-derived apoE in lipoprotein remnant metabolism and atherogenesis was assessed. The influence of apoE gene dosage on serum lipid concentrations was determined by transplantation of homozygous apoE-deficient (apoE(-/-)), heterozygous apoE-deficient (apoE(+/-)), and wild-type (apoE(+/+)) bone marrow in homozygous apoE-deficient mice. The concentration of apoE detected in serum was found to be gene dosage dependent, being 3.52+/-0.30%, 1.87+/-0.17%, and 0% of normal in transplanted mice receiving either apoE(+/+), apoE(+/-), or apoE(-/-) bone marrow, respectively. These low concentrations of apoE nevertheless dramatically reduced serum cholesterol levels owing to a reduction of VLDL and, to a lesser extent, LDL, while HDL levels were slightly raised. After 4 months on a ''Western-type'' diet, atherosclerosis was evidently reduced in mice transplanted with apoE(+/+) bone marrow, compared with control transplanted mice. To study the mechanism of the lipoprotein changes on bone marrow transplantation, the in vivo turnover of autologous serum (beta)VLDL was studied. The serum half-life of (beta)VLDL in transplanted mice, compared with control apoE-deficient mice, was shortened mainly as a consequence of an increased recognition and uptake by the liver. Analysis of the relative contribution of the liver parenchymal cells, endothelial cells, and Kupffer cells (liver tissue macrophages) indicated an increased uptake by parenchymal cells, while the relative contribution of Kupffer cells was decreased. In conclusion, macrophage-derived apoE can dose-dependently reduce hypercholesterolemia in apoE-deficient mice owing to increased recognition and uptake of (beta)VLDL by parenchymal liver cells, leading to a decreased susceptibility to atherosclerosis.