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J. Biol. Chem., Vol. 280, Issue 43, 35890-35895, October 28, 2005

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Serum Amyloid A Promotes Cholesterol Efflux Mediated by Scavenger Receptor B-I^*

Deneys R. van der Westhuyzen12, Lei Cai1, Maria C. de Beer, and Frederick C. de Beer¶

From the Departments of Internal Medicine and Physiology, Graduate Center for Nutrition Sciences, the University of Kentucky Medical Center, Lexington, Kentucky 40536 and the ^¶Department of Veterans Affairs Medical Center, Lexington, Kentucky 40511

Serum amyloid A (SAA) is an acute phase protein whose expression is markedly up-regulated during inflammation and infection. The physiological function of SAA is unclear. In this study, we reported that SAA promotes cellular cholesterol efflux mediated by scavenger receptor B-I (SR-BI). In Chinese hamster ovary cells, SAA promoted cellular cholesterol efflux in an SR-BI-dependent manner, whereas apoA-I did not. Similarly, SAA, but not apoA-I, promoted cholesterol efflux from HepG2 cells in an SR-BI-dependent manner as shown by using the SR-BI inhibitor BLT-1. When SAA was overexpressed in HepG2 cells using adenovirus-mediated gene transfer, the endogenously expressed SAA promoted SR-BI-dependent efflux. To assess the effect of SAA on SR-BI-mediated efflux to high density lipoprotein (HDL), we compared normal HDL, acute phase HDL (AP-HDL, prepared from mice injected with lipopolysaccharide), and AdSAA-HDL (HDL prepared from mice overexpressing SAA). Both AP-HDL and AdSAA-HDL promoted 2-fold greater cholesterol efflux than normal HDL. Lipid-free SAA was shown to also stimulate ABCA1-dependent cholesterol efflux in fibroblasts, in line with an earlier report (Stonik, J. A., Remaley, A. T., Demosky, S. J., Neufeld, E. B., Bocharov, A., and Brewer, H. B. (2004) Biochem. Biophys. Res. Commun. 321, 936–941). When added to cells together, SAA and HDL exerted a synergistic effect in promoting ABCA1-dependent efflux, suggesting that SAA may remodel HDL in a manner that releases apoA-I or other efficient ABCA1 ligands from HDL. SAA also facilitated efflux by a process that was independent of SR-BI and ABCA1. We conclude that the acute phase protein SAA plays an important role in HDL cholesterol metabolism by promoting cellular cholesterol efflux through a number of different efflux pathways.

Received for publication, May 24, 2005 , and in revised form, August 18, 2005.

^* This work was supported by National Institutes of Health Grants HL-63763, HL-65730 (to D. R. v. d. W.), and AG-17237 (to F. C. d. B.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Both authors contributed equally to this work.

² To whom correspondence should be addressed: University of Kentucky, Graduate Center for Nutritional Sciences, Wethington Health Science Bldg. 541, 900 S. Limestone St., Lexington, KY 40536-0200. Tel.: 859-323-4933 (ext. 81397); Fax: 859-257-3646; E-mail: dvwest1{at}uky.edu.

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