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LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling
The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene p...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
eLife Sciences Publications, Ltd
2015
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517437/ https://www.ncbi.nlm.nih.gov/pubmed/26173179 http://dx.doi.org/10.7554/eLife.08009 |
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author | Ito, Ayaka Hong, Cynthia Rong, Xin Zhu, Xuewei Tarling, Elizabeth J Hedde, Per Niklas Gratton, Enrico Parks, John Tontonoz, Peter |
author_facet | Ito, Ayaka Hong, Cynthia Rong, Xin Zhu, Xuewei Tarling, Elizabeth J Hedde, Per Niklas Gratton, Enrico Parks, John Tontonoz, Peter |
author_sort | Ito, Ayaka |
collection | PubMed |
description | The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation. DOI: http://dx.doi.org/10.7554/eLife.08009.001 |
format | Online Article Text |
id | pubmed-4517437 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2015 |
publisher | eLife Sciences Publications, Ltd |
record_format | MEDLINE/PubMed |
spelling | pubmed-45174372015-07-29 LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling Ito, Ayaka Hong, Cynthia Rong, Xin Zhu, Xuewei Tarling, Elizabeth J Hedde, Per Niklas Gratton, Enrico Parks, John Tontonoz, Peter eLife Cell Biology The liver X receptors (LXRs) are transcriptional regulators of lipid homeostasis that also have potent anti-inflammatory effects. The molecular basis for their anti-inflammatory effects is incompletely understood, but has been proposed to involve the indirect tethering of LXRs to inflammatory gene promoters. Here we demonstrate that the ability of LXRs to repress inflammatory gene expression in cells and mice derives primarily from their ability to regulate lipid metabolism through transcriptional activation and can occur in the absence of SUMOylation. Moreover, we identify the putative lipid transporter Abca1 as a critical mediator of LXR's anti-inflammatory effects. Activation of LXR inhibits signaling from TLRs 2, 4 and 9 to their downstream NF-κB and MAPK effectors through Abca1-dependent changes in membrane lipid organization that disrupt the recruitment of MyD88 and TRAF6. These data suggest that a common mechanism-direct transcriptional activation-underlies the dual biological functions of LXRs in metabolism and inflammation. DOI: http://dx.doi.org/10.7554/eLife.08009.001 eLife Sciences Publications, Ltd 2015-07-14 /pmc/articles/PMC4517437/ /pubmed/26173179 http://dx.doi.org/10.7554/eLife.08009 Text en © 2015, Ito et al http://creativecommons.org/licenses/by/4.0/ This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use and redistribution provided that the original author and source are credited. |
spellingShingle | Cell Biology Ito, Ayaka Hong, Cynthia Rong, Xin Zhu, Xuewei Tarling, Elizabeth J Hedde, Per Niklas Gratton, Enrico Parks, John Tontonoz, Peter LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling |
title | LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling |
title_full | LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling |
title_fullStr | LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling |
title_full_unstemmed | LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling |
title_short | LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling |
title_sort | lxrs link metabolism to inflammation through abca1-dependent regulation of membrane composition and tlr signaling |
topic | Cell Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4517437/ https://www.ncbi.nlm.nih.gov/pubmed/26173179 http://dx.doi.org/10.7554/eLife.08009 |
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