TREATMENT OF SEVERE HYPERCHOLESTEROLEMIA IN APOLIPOPROTEIN E-DEFICIENT MICE BY BONE-MARROW TRANSPLANTATION
TREATMENT OF SEVERE HYPERCHOLESTEROLEMIA IN APOLIPOPROTEIN E-DEFICIENT MICE BY BONE-MARROW TRANSPLANTATION
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DOI：
10.1172/jci118098
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发表时间：
1995-08-01
影响因子：
15.9
通讯作者：
CURTISS, LK
中科院分区：
文献类型：
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作者：
BOISVERT, WA;SPANGENBERG, J;CURTISS, LK
载脂蛋白E是一种富含胆固醇的脂蛋白代谢的关键调节因子，由许多肝外组织合成，虽然其在巨噬细胞中的合成已被证实，但巨噬细胞衍生的载脂蛋白E对肝脏清除血清胆固醇的贡献尚不清楚，为了解决这个问题，我们对高胆固醇血症载脂蛋白E缺陷小鼠进行了骨髓移植，这些小鼠既有同基因apo E缺陷小鼠骨髓细胞(EO对照)，也有野生型apo E表达小鼠骨髓细胞(EO处理组)，EO对照和EO处理组小鼠分别喂以普通饲料或致动脉粥样硬化饲料(指定为EO对照HF和EO处理HF)。EO组小鼠血清胆固醇水平显著下降，这主要是由于极低密度脂蛋白胆固醇的降低，而EO对照组小鼠的血清胆固醇水平没有变化，4周后，EO处理组的HF小鼠的血清胆固醇水平比EO对照组的HF小鼠低约4倍，而且14-16周后EO处理的HF小鼠的动脉粥样硬化程度显著减轻，在EO处理的小鼠的肝、脾和脑中检测到野生型apo E基因，表明apo E基因的成功转移是通过骨髓移植实现的，更重要的是，Apo E的表达水平足以降低apo E缺陷小鼠的严重高胆固醇血症，无论是饮食还是致动脉粥样硬化的饮食。
Apo E, a key regulator of cholesterol-rich lipoprotein metabolism, is synthesized by numerous extrahepatic tissues, Although its synthesis in macrophages is documented, the contribution of macrophage-derived apo E to hepatic clearance of serum cholesterol is unknown, To address this issue bone marrow transplantation was performed on hypercholesterolemic apo E-deficient mice with either syngeneic apo E-deficient mouse bone marrow cells (EO-control) or wildtype mouse bone marrow cells expressing apo E (EO-treated), EO-control and EO-treated mice were fed either a regular chow diet or an atherogenic diet (designated EO-control-HF and EO-treated-HF). Serum cholesterol levels dropped dramatically in the EO-treated mice largely due to a reduction in their VLDL cholesterol, No changes were seen in the EO-control mice, After 4 wk serum cholesterol in EO-treated-HF mice was about four-fold lower compared to EO-control-HF animals, Moreover, the extent of atherosclerosis in the EO-treated-HF mice after 14-16 wk was greatly reduced, Wild-type apo E mRNA was detected in the liver, spleen, and brain of the EO-treated mice indicating that apo E gene transfer was successfully achieved through bone marrow transplantation, More importantly, the level of apo E expression was sufficient to reduce the severe hypercholesterolemia of the apo E-deficient mice fed either chow or atherogenic diets.