Published online before print January 12, 2006, doi: 10.1161/01.ATV.0000203515.25574.19
© 2006 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Relative Contributions of ABCA1 and SR-BI to Cholesterol Efflux to Serum From Fibroblasts and Macrophages
From GI and Nutrition (M.D., H.L.C., G.H.R.), The Children’s Hospital of Philadelphia, Philadelphia, Pa; the School of Medicine (W.J.), University of Pennsylvania, Philadelphia, Pa; and the Department of Pharmacological and Biological Sciences and Applied Chemistries (I.Z., E.F.), University of Parma, Italy.
Correspondence to George H. Rothblat, Suite 1102 Abramson Building, The Children’s Hospital of Philadelphia, 3615 Civic Center Blvd, Philadelphia, PA 19104. E-mail rothblat{at}email.chop.edu
Objectives— Cholesterol efflux is achieved by several mechanisms. This study examines contributions of these pathways to efflux to human serum.
Methods and Results— Human fibroblasts were stably transfected with SR-BI while ABCA1 was upregulated. Quantitation of cholesterol efflux to human serum demonstrated that there was efflux from cells without either protein. Expression of ABCA1 produced a small increase in efflux, whereas SR-BI expression had a dramatic impact. To quantitate ABCA1 and SR-BI contribution, fibroblasts were pretreated with Probucol and BLT-1 to, respectively, inhibit these efflux proteins. Exposing SR-BI–expressing fibroblasts to BLT-1 inhibited efflux by 67%. Probucol pretreatment of ABCA1-expressing fibroblasts reduced efflux to serum by 26%. A large fraction of total efflux was uninhibited. For both J774 and mouse peritoneal macrophages, contributions of either ABCA1 or SR-BI to efflux to serum were low, with background/uninhibited efflux contributing from 70% to 90% of total efflux.
Conclusions— We have shown that ABCA1-mediated efflux to serum responds to the pool of lipid-free/poor apolipoproteins, whereas phospholipid-containing particles mediate SR-BI efflux. Although SR-BI and ABCA1 contribute to efflux from fibroblasts and cholesterol-enriched macrophages, a large proportion of the total efflux to human serum is mediated by a mechanism that is neither SR-BI nor ABCA1.
Key Words: ABCA1 • cholesterol efflux • fibroblasts • macrophage • SR-BI
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