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 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 125I-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 125I-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.
Herijgers
N
N
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Sylvius Laboratories, Leiden University, Netherlands. Herijgers@LACDR.LeidenUniv.nl
Van Eck
M
M
Groot
P H
PH
Hoogerbrugge
P M
PM
Van Berkel
T J
TJ
D000818:Animals; D001161:Arteriosclerosis / Q000209:etiology*; D016026:Bone Marrow Transplantation; D002784:Cholesterol / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D005260:Female; D008074:Lipoproteins / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*
D008078:Cholesterol, LDL; D008074:Lipoproteins; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D002784:Cholesterol