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Originally published In Press as doi:10.1194/jlr.M800095-JLR200 on July 12, 2008

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Journal of Lipid Research, Vol. 49, 2312-2322, November 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

Enhancing apolipoprotein A-I-dependent cholesterol efflux elevates cholesterol export from macrophages in vivo

Nigora Mukhamedova*, Genevieve Escher*, Wilissa D'Souza*, Urbain Tchoua*, Angela Grant{dagger}, Zigmund Krozowski*, Michael Bukrinsky{dagger} and Dmitri Sviridov1,*

* BakerIDI Heart & Diabetes Institute, Melbourne, Victoria, Australia
{dagger} Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC

Published, JLR Papers in Press, July 12, 2008.

This work was supported by a grant from the National Heart Foundation of Australia to D.S. and Z.K. (G 04M 1536), a grant from the Swiss National Foundation to G.E., and by a grant from the Perpetual Charitable Trust to D.S. D.S. is a Fellow of the National Health and Medical Research Council of Australia.

1 To whom correspondence should be addressed. e-mail: Dmitri.Sviridov{at}Bakeridi.edu.au

Eight proteins potentially involved in cholesterol efflux [ABCA1, ABCG1, CYP27A1, phospholipid transfer protein (PLTP), scavenger receptor type BI (SR-BI), caveolin-1, cholesteryl ester transfer protein, and apolipoprotein A-I (apoA-I)] were overexpressed alone or in combination in RAW 264.7 macrophages. When apoA-I was used as an acceptor, overexpression of the combination of ABCA1, CYP27A1, PLTP, and SR-BI (Combination I) enhanced the efflux by 4.3-fold. It was established that the stimulation of efflux was due to increased abundance of ABCA1 and increased apoA-I binding to non-ABCA1 sites on macrophages. This combination caused only a small increase of the efflux to isolated HDL. When HDL was used as an acceptor, overexpression of caveolin-1 or a combination of caveolin-1 and SR-BI (Combination II) was the most active, doubling the efflux to HDL, without affecting the efflux to apoA-I. When tested in the in vivo mouse model of cholesterol efflux, overexpression of ABCA1 and Combination I elevated cholesterol export from macrophages to plasma, liver, and feces, whereas overexpression of caveolin-1 or Combination II did not have an effect. We conclude that pathways of cholesterol efflux using apoA-I as an acceptor make a predominant contribution to cholesterol export from macrophages in vivo.

Supplementary key words reverse cholesterol transport • atherosclerosis • lipoproteins • lipids • ABC transporters

Abbreviations: apo, apolipoprotein; CETP, cholesteryl ester transfer protein; PLTP, phospholipid transfer protein; RCT, reverse cholesterol transport; SR-BI, scavenger receptor type BI


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