| Summary: | 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 × 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.
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