Submitted on December 20, 2006
Revised on February 7, 2007
Accepted on February 13, 2007
Severely altered cholesterol homeostasis in macrophages lacking apoE and SR-BI1
Patricia G. Yancey, W. Gray Jerome, Hong Yu, Evelyn E. Griffin, Brian E. Cox, Vladimir R. Babaev, Sergio Fazio, and MacRae F. Linton
Medicine, Vanderbilt University Medical Center, Nashville, TN 37232-6300
Corresponding Author: patricia.g.yancey{at}vanderbilt.edu
Mice deficient in SR-BI and apoE (DKO) develop dyslipidemia, accelerated atherosclerosis, 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 (220-380µg/mg protein) compared to apoE-/- cells (40µg/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, 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 apoAI 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 likely contribute to the accelerated atherosclerosis in DKO mice.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?