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

dLow 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 wildtype mice, and this activity correlated with serum apoA-IV. Inummodepletion 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.-Thorngate, F. E., P. G. Yancey, G. Kellner-Weibel, L. L. Rudel, G. H. Rothblat, and D. L. Williams. Testing the role of apoA-I, HDL, and cholesterol efflux in the atheroprotective action of low-level apoE expression.