Biochem. J. (2007) 402
(117–124) (Printed in Great Britain)
The lipidation status of acute-phase protein serum amyloid A determines cholesterol mobilization via scavenger receptor class B, type I
Gunther MARSCHE*, S
sa FRANK*, John G. RAYNES†, Karen F. KOZARSKY‡, Wolfgang SATTLER* and Ernst MALLE*
1*Institute of Molecular Biology and Biochemistry, Center of Molecular Medicine, Medical University of Graz, A-8010 Graz, Austria, †Immunology Unit, Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, U.K., and ‡GlaxoSmithKline, 709 Swedeland Rd, King of Prussia, PA 19406, U.S.A.
During the acute-phase reaction, SAA (serum amyloid A) replaces apoA-I (apolipoprotein A-I) as the major HDL (high-density lipoprotein)-associated apolipoprotein. A remarkable portion of SAA exists in a lipid-free/lipid-poor form and promotes ABCA1 (ATP-binding cassette transporter A1)-dependent cellular cholesterol efflux. In contrast with lipid-free apoA-I and apoE, lipid-free SAA was recently reported to mobilize SR-BI (scavenger receptor class B, type I)-dependent cellular cholesterol efflux [Van der Westhuyzen, Cai, de Beer and de Beer (2005) J. Biol. Chem. 280, 35890–35895]. This unique property could strongly affect cellular cholesterol mobilization during inflammation. However, in the present study, we show that overexpression of SR-BI in HEK-293 cells (human embryonic kidney cells) (devoid of ABCA1) failed to mobilize cholesterol to lipid-free or lipid-poor SAA. Only reconstituted vesicles containing phospholipids and SAA promoted SR-BI-mediated cholesterol efflux. Cholesterol efflux from HEK-293 and HEK-293[SR-BI] cells to lipid-free and lipid-poor SAA was minimal, while efficient efflux was observed from fibroblasts and CHO cells (Chinese-hamster ovary cells) both expressing functional ABCA1. Overexpression of SR-BI in CHO cells strongly attenuated cholesterol efflux to lipid-free SAA even in the presence of an SR-BI-blocking IgG. This implies that SR-BI attenuates ABCA1-mediated cholesterol efflux in a way that is not dependent on SR-BI-mediated re-uptake of cholesterol. The present in vitro experiments demonstrate that the lipidation status of SAA is a critical factor governing cholesterol acceptor properties of this amphipathic apolipoprotein. In addition, we demonstrate that SAA mediates cellular cholesterol efflux via the ABCA1 and/or SR-BI pathway in a similar way to apoA-I.
Key words: apolipoprotein, ATP-binding cassette transporter A1 (ABCA1), cholesterol, phospholipid, scavenger receptor, serum amyloid A.
Abbreviations used: ABCA1, ATP-binding cassette transporter A1; apoA-I, apolipoprotein A-I; apoE, apolipoprotein E; CE, cholesteryl ester; CHO cell, Chinese-hamster ovary cell; DMEM, Dulbecco's modified Eagle's medium; FBS, fetal bovine serum; b-gal, b-galactosidase; HDL, high-density lipoprotein; HDL3, HDL particles subclass 3; HEK-293 cell, human embryonic kidney cell; IEF, isoelectric focusing; MOI, multiplicity of infection; PC, phosphatidylcholine; SAA, serum amyloid A; SR-BI, scavenger receptor class B, type I; hSR-BI, human SR-BI; mSR-BI, murine SR-BI; TBS, Tris-buffered saline.
1To whom correspondence should be addressed (email ernst.malle@meduni-graz.at).
Received 13 September 2006/2 October 2006; accepted 11 October 2006
Published as BJ Immediate Publication 11 October 2006, doi:10.1042/BJ20061406
The Biochemical Society, London ©2007
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