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Journal of Lipid Research, Vol. 46, 2091-2101, October 2005
Copyright © 2005 by American Society for Biochemistry and Molecular Biology

Peptides derived from serum amyloid A prevent, and reverse, aortic lipid lesions in apoE^–/– mice

Shui Pang Tam^*, John B. Ancsin^*, Ruth Tan^* and Robert Kisilevsky^1,*,

^* Departments of Pathology and Molecular Medicine, Queen's University, and The Syl and Molly Apps Research Centre, Kingston General Hospital, Kingston, Ontario, Canada
Biochemistry, Queen's University, and The Syl and Molly Apps Research Centre, Kingston General Hospital, Kingston, Ontario, Canada

Published, JLR Papers in Press, August 1, 2005. DOI 10.1194/jlr.M500191-JLR200

¹ To whom correspondence should be addressed. e-mail: kisilevsky{at}cliff.path.queensu.ca

Macrophages (M) at sites of acute tissue injury accumulate and export cholesterol quickly. This metabolic activity is likely dependent on the physiological function of a major acute-phase protein, serum amyloid A 2.1 (SAA2.1), that is synthesized by hepatocytes as part of a systemic response to acute injury. Our previous studies using cholesterol-laden J774 mouse M showed that an N-terminal domain of SAA2.1 inhibits acyl-CoA:cholesterol acyltransferase activity, and a C-terminal domain enhances cholesteryl ester hydrolase activity. The net effect of this enzymatic regulation is to drive intracellular cholesterol to its unesterified state, the form readily exportable to an extracellular acceptor such as HDL. Here, we demonstrate that these domains from mouse SAA2.1, when delivered in liposomal formulation, are effective at preventing and reversing aortic lipid lesions in apolipoprotein E-deficient mice maintained on high-fat diets. Furthermore, mouse SAA peptides, in liposomal formulation, are effective at regulating cholesterol efflux in THP-1 human M, and homologous domains from human SAA are effective in mouse J774 cells. These peptides operate at the level of the foam cell in the reverse cholesterol pathway and therefore may be used in conjunction with other agents that act more distally in this process.

Such human peptides, or small molecule mimics of their structure, may prove to be potent antiatherogenic agents in humans.

Abbreviations: AP-HDL, acute-phase high density lipoprotein; apoE^–/–, apolipoprotein E-deficient; CEH, cholesteryl ester hydrolase; M, macrophages; RBC, red blood cell; SAA, serum amyloid A

Supplementary key words atherosclerosis • cholesterol • acute-phase proteins • apolipoprotein E-deficient mice • high density lipoprotein

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