Characterization and properties of prebeta-HDL particles formed by ABCA1-mediated cellular lipid efflux to ApoA-I

Phu T. Duong, Ginny L. Weibel, Sissel Lund-Katz, George H. Rothblat, and Michael C. Phillips

GI/Nutrition, Children's Hospital of Philadelphia, Philadelphia, PA 19104-4318

Corresponding Author: phillipsmi{at}email.chop.edu

The contribution of ABCA1-mediated efflux of cellular phospholipid (PL) and cholesterol to human apoA-I to the formation of prebeta1-HDL or (lipid-poor apoA-I) is not well defined. To explore this issue, we characterized the nascent HDL particles formed when lipid-free apoA-I was incubated with fibroblasts in which expression of the ATP binding cassette transporter A-I (ABCA1) was upregulated. After a 2h incubation, the extracellular medium contained small apoA-I / PL particles (prebeta1-HDL, diameter = 7.5 ± 0.4nm) which were converted to 9 and 12 nm discoidal HDL particles upon longer incubation. The prebeta1-HDL (or lipid-poor apoA-I) particles contained a single apoA-I molecule and 3-4 PL molecules and 1-2 cholesterol molecules. An apoA-I variant lacking the C-terminal alpha-helix did not form such particles when incubated with the cell indicating that this helix is critical for formation of lipid-poor apoA-I particles. These prebeta1-HDL particles were as effective as lipid-free apoA-I molecules in mediating both efflux of cellular lipids via ABCA1 and formation of larger, discoidal, HDL particles. This phenomenon occurs because lipid-poor and lipid-free apoA-I molecules solubilize multilamellar vesicles of membrane lipids similarly, and such a solubilization process is the rate-limiting step in the mechanism of efflux of membrane lipids via ABCA1. In conclusion, prebeta1-HDL is both a product and a substrate in the ABCA1-mediated reaction to efflux cellular PL and cholesterol to apoA-I. A monomeric apoA-I molecule associated with 3-4 PL molecules (i.e. lipid-poor apoA-I) has similar properties to the lipid-free apoA-I molecule.

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