Cholesterol is an essential component of eukaryotic cells; at the same time, however, hyperaccumulation of cholesterol is harmful. Therefore, the ABCA1 gene, the product of which mediates secretion of cholesterol, is highly regulated at both the transcriptional and post-transcriptional levels. The transcription of ABCA1 is regulated by intracellular oxysterol concentration via the nuclear liver X receptor (LXR)/retinoid X receptor (RXR); once synthesized, ABCA1 protein turns over rapidly with a half-life of 1-2 h. Here, we show that the LXR/RXR complex binds directly to ABCA1 on the plasma membrane of macrophages and modulates cholesterol secretion. When cholesterol does not accumulate, ABCA1-LXR/RXR localizes on the plasma membrane, but is inert. When cholesterol accumulates, oxysterols bind to LXR, and the LXR/RXR complex dissociates from ABCA1, restoring ABCA1 activity and allowing apoA-I-dependent cholesterol secretion. LXR can exert an immediate post-translational response, as well as a rather slow transcriptional response, to changes in cellular cholesterol accumulation. Thus, we provide the first demonstration that protein-protein interaction suppresses ABCA1 function. Furthermore, we show that LXR is involved in both the transcriptional and post-transcriptional regulation of the ABCA1 transporter.Maintenance of cellular cholesterol homeostasis is important for normal human physiology. Disruption of cellular cholesterol homeostasis leads to a variety of pathological conditions, including cardiovascular disease (1). ABCA1 (ATPbinding cassette protein A1), one of the key proteins in cholesterol homeostasis, mediates secretion of cellular free cholesterol and phospholipids to an extracellular acceptor in the plasma, apoA-I, to form high density lipoprotein (HDL) 3 (2, 3). HDL formation is the only known pathway that can eliminate excess cholesterol from peripheral cells. Defects in ABCA1 cause Tangier disease (4 -6), in which patients have a near absence of circulating HDL, prominent cholesterol ester accumulation in tissue macrophages, and premature atherosclerotic vascular disease (1, 7).ABCA1-mediated cholesterol efflux is highly regulated at both the transcriptional and post-transcriptional levels. When cholesterol accumulates in cells, intracellular concentrations of oxysterols increase; subsequently, the liver X receptor (LXR), activated via binding of oxysterols, stimulates the transcription of ABCA1 (8 -10). ABCA1 protein eliminates excess cellular cholesterol and turns over rapidly with a half-life of 1-2 h (11-15). Several proteins, including apoA-I, ␣1-syntrophin, and 1-syntrophin, have been reported to interact with ABCA1 and reduce the rate of ABCA1 protein degradation (13-16). Syntrophins play critical roles in regulating the apoA-I-dependent cholesterol efflux (and thus in lipid homeostasis) by suppressing protein degradation in brain (14) and liver (15). Because cholesterol is an essential component of cells, however, excessive elimination of cholesterol could result in cell death. Con...
ABCA1 plays a major role in cholesterol homeostasis and high density lipoprotein (HDL) metabolism. ABCA1 contains disulfide bond(s) between its N-and C-terminal halves, but it remains unclear whether disulfide bond formation is important for the functions of ABCA1 and which cysteines are involved in disulfide bond formation. To answer these questions, we constructed >30 ABCA1 mutants in which 16 extracellular domain (ECD) cysteines were replaced with serines and examined disulfide bond formation, apoA-I binding, and HDL formation in these mutants. From the single cysteine replacements, two cysteines (Cys 75 and Cys 309 ) in ECD1 were found to be essential for apoA
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