EFFECT OF BONE-MARROW TRANSPLANTATION ON LIPOPROTEIN METABOLISM AND ATHEROSCLEROSIS IN LDL RECEPTOR KNOCKOUT MICE

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 cel l types. In this study the relative importance of the LDLR on macropha ges for lipoprotein metabolism and atherogenesis was assessed. For thi s purpose, irradiated LDLR-knockout (-/-) mice were transplanted with bone marrow of normal C57BL/6J mice. DNA analysis showed that the tran splanted mice were chimeric. The transplantation resulted in a slight decrease of total serum cholesterol when compared with LDLR-/- mice th at were transplanted with LDLR-/- bone marrow. This modest decrease, h owever, did not reach statistical significance at all time points exam ined. This decrease can be almost completely attributed to a decrease in LDL cholesterol. The specific lowering of LDL cholesterol could cle arly be observed at 4 weeks after transplantation, but the decrease wa s less at 12 weeks after transplantation. Quantification of atheroscle rotic lesions of mice fed a 1% cholesterol diet for 6 months revealed that there were no differences in mean lesion area between mice transp lanted with wild-type bone marrow or LDLR-/- bone marrow. We anticipat e that in LDLR-/- mice transplanted with wild-type bone marrow, the LD LR is downregulated by the relatively high concentrations of circulati ng 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 tr ansplanted with LDLR-/- bone marrow, were able to degrade I-125-LDL, i ndicating that the capacity to express functional LDLR was achieved. I n conclusion, introduction of the LDLR into LDLR -/- mice via bone mar row transplantation resulted in only a relatively modest decrease of L DL cholesterol that became less pronounced at later time points, possi bly due to downregulation of the LDLR. To utilize the LDLR in macropha ges for effective cholesterol lowering, either the sterol-regulatory e lements have to be ''silenced'' or a high-expression LDLR construct ha s to be introduced into macrophages, eg, via transplantation of in vit ro transfected hematopoietic stem cells.