Van Eck M, Herijgers N, Yates J, Pearce N J, Hoogerbrugge P M, Groot P H, Van Berkel T J
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, The Netherlands.
Arterioscler Thromb Vasc Biol. 1997 Nov;17(11):3117-26. doi: 10.1161/01.atv.17.11.3117.
Apolipoprotein E (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 to 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.
载脂蛋白E（apoE）是脂蛋白受体的高亲和力配体，由肝脏和包括单核细胞/巨噬细胞系细胞在内的肝外组织合成。小鼠apoE基因失活导致血清胆固醇和甘油三酯水平显著升高以及过早发生动脉粥样硬化。在本研究中，评估了单核细胞/巨噬细胞衍生的apoE在脂蛋白残粒代谢和动脉粥样硬化发生中的作用。通过将纯合apoE缺陷（apoE-/-）、杂合apoE缺陷（apoE+/-）和野生型（apoE+/+）骨髓移植到纯合apoE缺陷小鼠中，确定了apoE基因剂量对血清脂质浓度的影响。在接受apoE+/+、apoE+/-或apoE-/-骨髓移植的小鼠血清中检测到的apoE浓度呈基因剂量依赖性，分别为正常水平的3.52±0.30%、1.87±0.17%和0%。然而，这些低浓度的apoE由于极低密度脂蛋白（VLDL）的减少以及低密度脂蛋白（LDL）在较小程度上的减少，显著降低了血清胆固醇水平，而高密度脂蛋白（HDL）水平略有升高。在“西式”饮食4个月后，与对照移植小鼠相比，接受apoE+/+骨髓移植的小鼠动脉粥样硬化明显减轻。为了研究骨髓移植后脂蛋白变化的机制，研究了自体血清β-VLDL的体内周转率。与对照apoE缺陷小鼠相比，移植小鼠中β-VLDL的血清半衰期缩短，主要是由于肝脏识别和摄取增加。对肝实质细胞、内皮细胞和库普弗细胞（肝组织巨噬细胞）相对贡献的分析表明，实质细胞摄取增加，而对库普弗细胞的相对贡献减少。总之，巨噬细胞衍生的apoE可以剂量依赖性地降低apoE缺陷小鼠的高胆固醇血症，这是由于肝实质细胞对β-VLDL的识别和摄取增加，导致对动脉粥样硬化的易感性降低。
