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Journal of Lipid Research, Vol. 44, 2331-2338, December 2003
Copyright © 2003 by American Society for Biochemistry and Molecular Biology

Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression

Fayanne E. Thorngate^*, Patricia G. Yancey, Ginny Kellner-Weibel, Lawrence L. Rudel, George H. Rothblat and David L. Williams^1,*

^* Department of Pharmacological Sciences, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794
Division of Gastroenterology and Nutrition, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA 19104
Department of Pathology (Comparative Medicine), Wake Forest University School of Medicine, Winston-Salem, NC 27157

¹ To whom correspondence should be addressed. email: dave{at}pharm.sunysb.edu

Low levels of transgenic mouse apolipoprotein E (apoE) suppress atherosclerosis in apoE knockout (apoE^-/-) mice without normalizing plasma cholesterol. To test whether this is due to facilitation of cholesterol efflux from the vessel wall, we produced apoA-I^-/-/apoE^-/- mice with or without the transgene. Even without apoA-I and HDL, apoA-I^-/-/apoE^-/- mice had the same amount of aorta cholesteryl ester as apoE^-/- mice. Low apoE in the apoA-I^-/-/apoE^-/- transgenic mice reduced aortic lesions by 70% versus their apoA-I^-/-/apoE^-/- siblings. To define the free cholesterol (FC) efflux capacity of lipoproteins from the various genotypes, sera were assayed on macrophages expressing ATP-binding cassette transporter A1 (ABCA1). Surprisingly, ABCA1 FC efflux was twice as high to sera from the apoA-I^-/-/apoE^-/- or apoE^-/- mice compared with wild-type mice, and this activity correlated with serum apoA-IV. Immunodepletion of apoA-IV from apoA-I^-/-/apoE^-/- serum abolished ABCA1 FC efflux, indicating that apoAI-V serves as a potent acceptor for FC efflux via ABCA1. With increasing apoE expression, apoA-IV and FC acceptor capacity decreased, indicating a reciprocal relationship between plasma apoE and apoA-IV.

Low plasma apoE (1–3 x 10^-8 M) suppresses atherosclerosis by as yet undefined mechanisms, not dependent on the presence of apoA-I or HDL or an increased capacity of serum acceptors for FC efflux.

Abbreviations: ABCA1, ATP-binding cassette transporter A1; CE, cholesteryl ester; cpt-cAMP, 8-(4-chlorophenylthio)adenosine 3',5'-cyclic monophosphate; FC, free cholesterol; LRP, low density lipoprotein receptor-related protein; PDGF, platelet-derived growth factor

Supplementary key words apolipoprotein E • atherosclerosis • cholesterol efflux • ABCA1 • apolipoprotein A-IV • cholesteryl ester

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