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Originally published In Press as doi:10.1194/jlr.M300224-JLR200 on September 1, 2003

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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{dagger}, Ginny Kellner-Weibel{dagger}, Lawrence L. Rudel§, George H. Rothblat{dagger} and David L. Williams1,*

* Department of Pharmacological Sciences, University Medical Center, State University of New York at Stony Brook, Stony Brook, NY 11794
{dagger} 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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