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...
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eLife Sciences Publications Ltd
2015-07-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/08009 |
| _version_ | 1811181472785104896 |
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| author | Ayaka Ito Cynthia Hong Xin Rong Xuewei Zhu Elizabeth J Tarling Per Niklas Hedde Enrico Gratton John Parks Peter Tontonoz |
| author_facet | Ayaka Ito Cynthia Hong Xin Rong Xuewei Zhu Elizabeth J Tarling Per Niklas Hedde Enrico Gratton John Parks Peter Tontonoz |
| author_sort | Ayaka Ito |
| collection | DOAJ |
| 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. |
| first_indexed | 2024-04-11T09:18:21Z |
| format | Article |
| id | doaj.art-a65257c0bcd14049a95bc1d2c032f38d |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-11T09:18:21Z |
| publishDate | 2015-07-01 |
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| spelling | doaj.art-a65257c0bcd14049a95bc1d2c032f38d2022-12-22T04:32:17ZengeLife Sciences Publications LtdeLife2050-084X2015-07-01410.7554/eLife.08009LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signalingAyaka Ito0Cynthia Hong1Xin Rong2Xuewei Zhu3Elizabeth J Tarling4Per Niklas Hedde5Enrico Gratton6John Parks7Peter Tontonoz8https://orcid.org/0000-0003-1259-0477Department of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United StatesDepartment of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United StatesDepartment of Pathology and Laboratory Medicine, Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United StatesDepartment of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, United States; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, United StatesDepartment of Medicine, University of California, Los Angeles, Los Angeles, United StatesLaboratory of Fluorescence Dynamics, Biomedical Engineering Department, Center for Complex Biological Systems, University of California, Irvine, Irvine, United StatesLaboratory of Fluorescence Dynamics, Biomedical Engineering Department, Center for Complex Biological Systems, University of California, Irvine, Irvine, United StatesDepartment of Internal Medicine-Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, United States; Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, United StatesHoward Hughes Medical Institute, University of California, Los Angeles, Los Angeles, United StatesThe 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.https://elifesciences.org/articles/08009nuclear receptorLXRlipid metabolismToll-like receptor |
| spellingShingle | Ayaka Ito Cynthia Hong Xin Rong Xuewei Zhu Elizabeth J Tarling Per Niklas Hedde Enrico Gratton John Parks Peter Tontonoz LXRs link metabolism to inflammation through Abca1-dependent regulation of membrane composition and TLR signaling eLife nuclear receptor LXR lipid metabolism Toll-like receptor |
| 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 | nuclear receptor LXR lipid metabolism Toll-like receptor |
| url | https://elifesciences.org/articles/08009 |
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