LEUKOCYTE LOW-DENSITY-LIPOPROTEIN RECEPTOR (LDL-R) DOES NOT CONTRIBUTE TO LDL CLEARANCE IN-VIVO - BONE-MARROW TRANSPLANTATION STUDIES IN THE MOUSE

The targeted disruption of the low density lipoprotein (LDL) receptor gene in mice results in accumulation of plasma LDL cholesterol and in predisposition to diet-induced aortic atherosclerosis. Although the li ver is the central organ for receptor mediated clearance of LDL, the i n vivo role of other organs and tissues in LDL catabolism has not been directly studied. Since bone marrow-derived cells such as blood leuko cytes and tissue macrophages express LDL receptors and contribute a la rge cell mass to the body, we designed bone marrow transplantation (BM T) experiments to reconstitute LDL receptor null mice [LDL-R(-/-)] wit h marrow obtained from LDL-R wild-type mice [LDL-R(+/+)] and evaluate the effects on parameters of plasma lipid metabolism. Although reconst itution of the transplanted mice with donor bone marrow cells was comp lete, no differences in plasma lipid levels and lipoprotein distributi on were found between groups, irrespective of the diet used, and turno ver studies using I-125-labeled LDL showed that LDL receptor expressio n by leukocytes and macrophages does not significantly contribute to p lasma LDL clearance. The complementary experiment of transplanting LDL -R(-/-) marrow into C57BL/6 recipients [LDL-R(-/-)-->LDL(+/+)], perfor med to evaluate the role of leukocyte LDL-R in normocholesterolemic co nditions, also produced no effects on plasma lipid parameters. LDL bin ding studies using macrophages isolated from transplanted mice showed a lack of LDLR expression. Thus, despite their large number and wide d istribution, bone marrow-derived cells do not significantly influence receptor-mediated clearance of plasma LDL.