J. Lipid Res.
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A more recent version of this article appeared on December 1, 2003

Papers In Press, published online ahead of print September 1, 2003
J. Lipid Res., doi:10.1194/jlr.M300224-JLR200
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Submitted on May 27, 2003
Revised on August 25, 2003
Accepted on August 25, 2003

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

Pharmacological Sciences, University Medical Center, Stony Brook, NY 11777

Corresponding Author: Dave{at}pharm.sunysb.edu; Dave@pharm.sunysb.edu

Low levels of transgenic mouse apolipoprotein (apo) E, expressed in the adrenal gland, suppress atherosclerosis in apoE knockout (apoE-/-) mice without normalizing total plasma cholesterol. To test whether this effect of apoE is due to facilitation of cholesterol efflux from the vessel wall, we produced apoA-I{super-/-/apoE-/- mice with or without the transgene. In spite of the absence of apoA-I and HDL, apoA-I-/-/apoE-/- mice had the same amount of aorta cholesteryl ester accumulation as apoE-/- mice. The low level of apoE in the apoA-I-/-/apoE-/- transgenic mice protected the mice versus their apoA-I-/-/apoE-/- siblings, reducing aortic lesions by 70%. Clearly, the presence of apoA-I and HDL are not required for protection to occur. To define the free cholesterol (FC) efflux capacity of lipoproteins from the various genotypes, sera were assayed on macrophages expressing ABCA1. Surprisingly, ABCA1-meidated FC efflux was twice as high to sera from the apoA-I-/-/apoE-/- or apoE-/- mice compared to wild type mice, and this activity correlated with increased serum apoA-IV. Immunodepletion of apoA-IV from apoA-I-/-/apoE-/- serum abolished ABCA1 mediated FC efflux and the capacity of serum to mediate net cholesterol clearance from cholesterol-loaded macrophages. These data indicate that apoA-IV serves as a potent acceptor for FC efflux via the ABCA1 pathway. With increasing transgenic apoE expression, apoA-IV and FC acceptor capacity decreased, indicating a reciprocal relationship between plasma apoE and apoA-IV. Levels of plasma apoE at concentrations of 1-3 x 10-8 M suppress atherosclerosis by yet undefined mechanisms, but these data show that they do not depend on the presence of apoA-I or HDL or an increased capacity of serum acceptors for FC efflux.


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