Leukocyte low density lipoprotein receptor (LDL-R) does not contribute to LDL clearance in vivo: Bone marrow transplantation studies in the mouse

Sergio Fazio, Alyssa H. Hasty, Kathy J. Carter, Alisa B. Murray, James O. Price, MacRae R.F. Linton

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    Abstract

    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 liver is the central organ for receptor mediated clearance of LDL, the in vivo role of other organs and tissues in LDL catabolism has not been directly studied. Since bone marrow-derived cells such as blood leukocytes and tissue macrophages express LDL receptors and contribute a large cell mass to the body, we designed bone marrow transplantation (BMT) experiments to reconstitute LDL receptor null mice [LDL-R(-/-)] with marrow obtained from LDL-R wild-type mice [(+/+)] and evaluate the effects of parameters of plasma lipid metabolism. Although reconstitution of the transplanted mice with donor bone marrow cells was complete, no differences in plasma lipid levels and lipoprotein distribution were found between groups, irrespective of the diet used, and turnover studies using 125I-labeled LDL showed that LDL receptor expression by leukocytes and macrophages does not significantly contribute plasma LDL clearance. The complementary experiment of transplanting LDL-R(-/-) marrow into C57BL/6 recipients [LDL-R(-/- )→LDL(+/+)], performed to evaluate the role of leukocyte LDL-R in normocholesterolemic conditions, also produced no effects on plasma lipid parameters. LDL binding studies using macrophages isolated from transplanted mice showed a lack of LDL-R expression. Thus, despite their large number and wide distribution, bone marrow-derived cells do not significantly influence receptor-mediated clearance of plasma LDL.

    Original languageEnglish (US)
    Pages (from-to)391-400
    Number of pages10
    JournalJournal of lipid research
    Volume38
    Issue number2
    StatePublished - Feb 1 1997

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    Keywords

    • bone marrow transplantation
    • dyslipidemias
    • familial hypercholesterolemia
    • gene delivery
    • macrophages
    • mouse models

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology
    • Cell Biology

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