Abstract
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 LXRbeta/RXR complex binds directly to ABCA1 on the plasma membrane of macrophages and modulates cholesterol secretion. When cholesterol does not accumulate, ABCA1-LXRbeta/RXR localizes on the plasma membrane, but is inert. When cholesterol accumulates, oxysterols bind to LXRbeta, and the LXRbeta/RXR complex dissociates from ABCA1, restoring ABCA1 activity and allowing apoA-I-dependent cholesterol secretion. LXRbeta 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 LXRbeta is involved in both the transcriptional and post-transcriptional regulation of the ABCA1 transporter.
Highlights
Cholesterol and phospholipids to an extracellular acceptor in the plasma, apoA-I, to form high density lipoprotein (HDL)3 (2, 3)
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)
The co-precipitation of LXR and retinoid X receptor (RXR) with ABCA1 was impaired when an LXR agonist, TO901317 or 25-hydroxycholesterol, was added to the lysate; in contrast, the addition of an RXR agonist, retinoic acid, did not affect the co-precipitation. These results suggest that LXR/RXR interacts with ABCA1 in THP-1 cells under conditions in which cholesterol does not accumulate in the cells and that the heterodimer dissociates from ABCA1 when LXR agonists accumulate
Summary
Cholesterol and phospholipids to an extracellular acceptor in the plasma, apoA-I, to form high density lipoprotein (HDL)3 (2, 3). In WI-38 and THP-1 cells, endogenous LXR interacts with ABCA1 under conditions in which cholesterol does not accumulate, i.e. when cholesterol is not in excess. ABCA1 and LXR␣ or LXR were transiently expressed in HEK293 cells, and a membrane fraction was prepared as described under “Experimental Procedures.” Under these conditions, LXR␣ or LXR was detected in the lysate of the membrane fraction (Fig. 1, lanes 1 and 5).
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