Abstract
ABCA1 plays a major role in HDL metabolism. Cholesterol secretion by ABCA1 is dependent on the presence of extracellular acceptors, such as lipid-free apolipoprotein A-I (apoA-I). However, the importance of the direct interaction between apoA-I and ABCA1 in HDL formation remains unclear. In contrast, ABCB4 mediates the secretion of phospholipids and cholesterol in the presence of sodium taurocholate (NaTC) but not in the presence of apoA-I. In this study, we analyzed apoA-I binding and NaTC-dependent lipid efflux by ABCA1. ABCA1 mediated the efflux of cholesterol and phospholipids in the presence of NaTC as well as in the presence of apoA-I in an ATP-dependent manner. The Tangier disease mutation W590S, which resides in the extracellular domain and impairs apoA-I-dependent lipid efflux, greatly decreased NaTC-dependent cholesterol and phospholipid efflux. However, the W590S mutation did not impair apoA-I binding and, conversely, retarded the dissociation of apoA-I from ABCA1. These results suggest that the W590S mutation impairs ATP-dependent lipid translocation and that lipid translocation or possibly lipid loading, facilitates apoA-I dissociation from ABCA1. NaTC is a good tool for analyzing ABCA1-mediated lipid efflux and allows dissection of the steps of HDL formation by ABCA1.
Highlights
ABCA1 plays a major role in HDL metabolism
The efflux of cholesterol from human embryonic kidney (HEK)/ ABCA1-green fluorescent protein (GFP) cells was increased by the addition of 1 mM sodium taurocholate (NaTC) (Fig. 1A, closed bar), compared with efflux measured in the presence of 0.02% BSA
Phospholipid was secreted slightly less efficiently by 1 mM NaTC than by 5 mg/ml apolipoprotein A-I (apoA-I). These results suggest that 1 mM NaTC is as efficient an acceptor as the physiological lipid acceptor apoA-I and that cholesterol is transferred to NaTC by ABCA1 more efficiently than phospholipids
Summary
Cholesterol secretion by ABCA1 is dependent on the presence of extracellular acceptors, such as lipid-free apolipoprotein A-I (apoA-I). The importance of the direct interaction between apoA-I and ABCA1 in HDL formation remains unclear. We analyzed apoA-I binding and NaTC-dependent lipid efflux by ABCA1. ABCA1 mediated the efflux of cholesterol and phospholipids in the presence of NaTC as well as in the presence of apoA-I in an ATP-dependent manner. ABCA1, a key protein in cholesterol homeostasis, mediates the secretion of cellular-free cholesterol and phospholipids to an extracellular acceptor, apolipoprotein A-I (apoA-I), to form HDL [2, 3]. Cholesterol secretion by ABCA1 is strongly dependent on the presence of extracellular acceptors, such as lipidfree apoA-I.
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