Severely altered cholesterol homeostasis in macrophages lacking apoE and SR-BI

Patricia G. Yancey, W. Gray Jerome, Hong Yu, Evelyn E. Griffin, Brian E. Cox, Vladimir R. Babaev, Sergio Fazio, MacRae F. Linton

    Research output: Contribution to journalArticle

    25 Scopus citations

    Abstract

    Mice deficient in scavenger receptor class B type I (SR-BI) and apolipoprotein E (apoE) [double knockout (DKO) mice] develop dyslipidemia, accelerated atherosclerosis, and myocardial infarction, and die prematurely. We examined effects of apoE and SR-BI deficiency on macrophage cholesterol homeostasis. DKO macrophages had increased total cholesterol (TC) stores (220-380 μg/mg protein) compared with apoE-/- cells (40 μg/mg), showed significant lysosomal lipid engorgement, and increased their TC by 34% after exposure to HDL. DKO macrophages from apoE-/- mice reconstituted with DKO bone marrow showed less cholesterol accumulation (89 μg/mg), suggesting that the dyslipidemia of DKO mice explains part of the cellular cholesterol defect. However, analyses of DKO and apoE-/- macrophages from transplanted apoE-/- mice revealed a role for macrophage SR-BI, inasmuch as the TC in DKO macrophages increased by 10% in the presence of HDL, whereas apoE-/- macrophage TC decreased by 33%. After incubation with HDL, the free cholesterol (FC) increased by 29% in DKO macrophages, and decreased by 8% in apoE2/2 cells, and only DKO cells had FC in large peri-nuclear pools. Similar trends were observed with apoA-I as an acceptor. Thus, the abnormal cholesterol homeostasis of DKO macrophages is due to the plasma lipid environment of DKO mice and to altered trafficking of macrophage cholesterol. Both factors are likely to contribute to the accelerated atherosclerosis in DKO mice.

    Original languageEnglish (US)
    Pages (from-to)1140-1149
    Number of pages10
    JournalJournal of lipid research
    Volume48
    Issue number5
    DOIs
    StatePublished - May 1 2007

    Keywords

    • Apolipoprotein E
    • Atherosclerosis
    • Cholesterol efflux
    • Cholesterol trafficking
    • HDL
    • Lysosomal lipid engorgement

    ASJC Scopus subject areas

    • Biochemistry
    • Endocrinology
    • Cell Biology

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  • Cite this

    Yancey, P. G., Jerome, W. G., Yu, H., Griffin, E. E., Cox, B. E., Babaev, V. R., Fazio, S., & Linton, M. F. (2007). Severely altered cholesterol homeostasis in macrophages lacking apoE and SR-BI. Journal of lipid research, 48(5), 1140-1149. https://doi.org/10.1194/jlr.M600539-JLR200