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Originally published In Press as doi:10.1194/jlr.M600539-JLR200 on February 13, 2007

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Journal of Lipid Research, Vol. 48, 1140-1149, May 2007
Copyright © 2007 by American Society for Biochemistry and Molecular Biology

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

Patricia G. Yancey1,*, W. Gray Jerome{dagger},§, Hong Yu*, Evelyn E. Griffin{dagger}, Brian E. Cox{dagger}, Vladimir R. Babaev*, Sergio Fazio1,*,{dagger} and MacRae F. Linton1,*,**

* Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN
{dagger} Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Pathology, Vanderbilt University Medical Center, Nashville, TN
§ Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, TN
** Atherosclerosis Research Unit, Division of Cardiovascular Medicine, Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN

Published, JLR Papers in Press, February 13, 2007.

1 To whom correspondence should be addressed. e-mail: patricia.g.yancey{at}vanderbilt.edu; sergio.fazio{at}vanderbilt.edu; macrae.linton{at}vanderbilt.edu

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 apoE–/– 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.

Supplementary key words apolipoprotein E • cholesterol efflux • lysosomal lipid engorgement • HDL • cholesterol trafficking • atherosclerosis

Abbreviations: apoE, apolipoprotein E; BM, bone marrow; CE, cholesteryl ester; DKO, double knockout; EM, electron microscopy; FC, free cholesterol; SR-BI, scavenger receptor class B type I; TC, total cholesterol


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