Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 44, Pages 30057-30063Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M804599200
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Funding
- Ministry of Education, Culture, Sports, Science, and Technology of Japan
- Program for Promotion of Fundamental Studies in Health Sciences
- National Institute of Biomedical Innovation
- World Premier International Research Center Initiative
- Grants-in-Aid for Scientific Research [20228001] Funding Source: KAKEN
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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 beta/RXR complex binds directly to ABCA1 on the plasma membrane of macrophages and modulates cholesterol secretion. When cholesterol does not accumulate, ABCA1-LXR beta/RXR localizes on the plasma membrane, but is inert. When cholesterol accumulates, oxysterols bind to LXR beta, and the LXR beta/RXR complex dissociates from ABCA1, restoring ABCA1 activity and allowing apoA-I-dependent cholesterol secretion. LXR beta 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 beta is involved in both the transcriptional and post-transcriptional regulation of the ABCA1 transporter.
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