Effect of bone marrow transplantation on lipoprotein metabolism and atherosclerosis in LDL receptor knockout mice
Effect of bone marrow transplantation on lipoprotein metabolism and atherosclerosis in LDL receptor knockout mice
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DOI：
10.1161/01.atv.17.10.1995
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发表时间：
1997-10-01
影响因子：
8.7
通讯作者：
VanBerkel, TJC
中科院分区：
文献类型：
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作者：
Herijgers, N;VanEck, M;VanBerkel, TJC
LDL受体（LDLR）在从血液循环中清除LDL及其前体（中密度脂蛋白和极低密度脂蛋白）中起重要作用。该受体在各种细胞类型上表达。本研究评估了巨噬细胞上LDLR对脂蛋白代谢和动脉粥样硬化形成的相对重要性。为此，将正常C57 BL/6 J小鼠的骨髓移植到经辐照的LDL R敲除（-/-）小鼠中。DNA分析表明，移植小鼠是嵌合体。与移植LDLR-/-骨髓的LDLR-/-小鼠相比，移植导致血清总胆固醇轻微降低。然而，这种适度的降低在所有检查的时间点都没有达到统计学显著性。这种降低几乎完全归因于LDL胆固醇的降低。移植后4周可明显观察到LDL胆固醇的特异性降低，但移植后12周降低幅度较小。对喂食1%胆固醇饲料6个月的小鼠的动脉粥样硬化病变进行定量，结果显示，移植野生型骨髓或LDLR-/-骨髓的小鼠之间的平均病变面积无差异。我们预计，在移植野生型骨髓的LDLR-/-小鼠中，LDLR被相对高浓度的循环胆固醇下调。在体外培养的腹腔巨噬细胞与I-125-LDL表明，这些细胞的LDLR可以下调25-羟基胆固醇。与移植有LDLR-/-骨髓的小鼠相比，从移植有野生型骨髓的LDLR-/-小鼠中分离的腹膜巨噬细胞能够降解I-125-LDL，这表明实现了表达功能性LDLR的能力。总之，通过骨髓移植将LDLR引入LDLR -/-小鼠仅导致LDL胆固醇相对适度的降低，在随后的时间点变得不那么明显，可能是由于LDLR的下调。为了利用巨噬细胞中的LDLR有效降低胆固醇，必须“沉默”固醇调节元件或必须将高表达LDLR构建体引入巨噬细胞，例如，通过移植体外转染的造血干细胞。
The LDL receptor (LDLR) plays an important role in the removal of LDL and its precursors, the intermediate and very low density lipoproteins, from the blood circulation. The receptor is expressed on various cell types. In this study the relative importance of the LDLR on macrophages for lipoprotein metabolism and atherogenesis was assessed. For this purpose, irradiated LDLR-knockout (-/-) mice were transplanted with bone marrow of normal C57BL/6J mice. DNA analysis showed that the transplanted mice were chimeric. The transplantation resulted in a slight decrease of total serum cholesterol when compared with LDLR-/- mice that were transplanted with LDLR-/- bone marrow. This modest decrease, however, did not reach statistical significance at all time points examined. This decrease can be almost completely attributed to a decrease in LDL cholesterol. The specific lowering of LDL cholesterol could clearly be observed at 4 weeks after transplantation, but the decrease was less at 12 weeks after transplantation. Quantification of atherosclerotic lesions of mice fed a 1% cholesterol diet for 6 months revealed that there were no differences in mean lesion area between mice transplanted with wild-type bone marrow or LDLR-/- bone marrow. We anticipate that in LDLR-/- mice transplanted with wild-type bone marrow, the LDLR is downregulated by the relatively high concentrations of circulating cholesterol. In vitro incubations of peritoneal macrophages with I-125-LDL indicated that the LDLR of these cells could be downregulated by 25-hydroxycholesterol. Peritoneal macrophages isolated from LDLR-/- mice transplanted with wild-type bone marrow, in contrast to those transplanted with LDLR-/- bone marrow, were able to degrade I-125-LDL, indicating that the capacity to express functional LDLR was achieved. In conclusion, introduction of the LDLR into LDLR -/- mice via bone marrow transplantation resulted in only a relatively modest decrease of LDL cholesterol that became less pronounced at later time points, possibly due to downregulation of the LDLR. To utilize the LDLR in macrophages for effective cholesterol lowering, either the sterol-regulatory elements have to be ''silenced'' or a high-expression LDLR construct has to be introduced into macrophages, eg, via transplantation of in vitro transfected hematopoietic stem cells.