Molecular defects in the ABCA1 pathway affect HDL metabolism and function of macrophages

Abstract The ATP-binding cassette transporter 1 (ABCA1) facilitates the cellular release of cholesterol and choline-phospholipids and the formation of apoA-I-rich preβ-HDL. ABCA1 itself is probably not an active transporter, but may act as a regulator protein for the secretion of cholesterol and phospholipid containing vesicles, similar to the role of the sulfonylurea receptor in the vesicular release mechanism that mediates insulin secretion. ABCA1 contains a PDZ binding domain at its C-terminus and associates with β2-syntrophin and utrophin. This protein complex associates within endosomal vesicles but does not co-localize with ABCA1 in Lubrol insoluble membrane rafts, indicating that β2-syntrophin retains ABCA1 in cytoplasmic vesicles and releases ABCA1 to plasma membrane microdomains. Syntaxins play a major role in the fusion of vesicles and have also been demonstrated to interact with members of the ABC-transporter family such as the cystic fibrosis transmembrane conductance regulator. Syntaxin 13 was found to co-localize with ABCA1 in Lubrol rafts and to co-purify with ABCA1 in the phagosome compartment, suggesting a role for syntaxin 13 in ABCA1 processing through the early secretory pathway, the raft compartment and maturing phagosomes.