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ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation
Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. We demonstrate that macrophage lipid body formation can be induced by modified lipoproteins or by inflammatory Toll-like receptor agonists. We used an unbiased approa...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
The Rockefeller University Press
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328364/ https://www.ncbi.nlm.nih.gov/pubmed/22473958 http://dx.doi.org/10.1084/jem.20111202 |
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author | Gold, Elizabeth S. Ramsey, Stephen A. Sartain, Mark J. Selinummi, Jyrki Podolsky, Irina Rodriguez, David J. Moritz, Robert L. Aderem, Alan |
author_facet | Gold, Elizabeth S. Ramsey, Stephen A. Sartain, Mark J. Selinummi, Jyrki Podolsky, Irina Rodriguez, David J. Moritz, Robert L. Aderem, Alan |
author_sort | Gold, Elizabeth S. |
collection | PubMed |
description | Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. We demonstrate that macrophage lipid body formation can be induced by modified lipoproteins or by inflammatory Toll-like receptor agonists. We used an unbiased approach to study the overlap in these pathways to identify regulators that control foam cell formation and atherogenesis. An analysis method integrating epigenomic and transcriptomic datasets with a transcription factor (TF) binding site prediction algorithm suggested that the TF ATF3 may regulate macrophage foam cell formation. Indeed, we found that deletion of this TF results in increased lipid body accumulation, and that ATF3 directly regulates transcription of the gene encoding cholesterol 25-hydroxylase. We further showed that production of 25-hydroxycholesterol (25-HC) promotes macrophage foam cell formation. Finally, deletion of ATF3 in Apoe(−/−) mice led to in vivo increases in foam cell formation, aortic 25-HC levels, and disease progression. These results define a previously unknown role for ATF3 in controlling macrophage lipid metabolism and demonstrate that ATF3 is a key intersection point for lipid metabolic and inflammatory pathways in these cells. |
format | Online Article Text |
id | pubmed-3328364 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | The Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-33283642012-10-09 ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation Gold, Elizabeth S. Ramsey, Stephen A. Sartain, Mark J. Selinummi, Jyrki Podolsky, Irina Rodriguez, David J. Moritz, Robert L. Aderem, Alan J Exp Med Article Atherosclerosis is a chronic inflammatory disease characterized by the accumulation of lipid-loaded macrophages in the arterial wall. We demonstrate that macrophage lipid body formation can be induced by modified lipoproteins or by inflammatory Toll-like receptor agonists. We used an unbiased approach to study the overlap in these pathways to identify regulators that control foam cell formation and atherogenesis. An analysis method integrating epigenomic and transcriptomic datasets with a transcription factor (TF) binding site prediction algorithm suggested that the TF ATF3 may regulate macrophage foam cell formation. Indeed, we found that deletion of this TF results in increased lipid body accumulation, and that ATF3 directly regulates transcription of the gene encoding cholesterol 25-hydroxylase. We further showed that production of 25-hydroxycholesterol (25-HC) promotes macrophage foam cell formation. Finally, deletion of ATF3 in Apoe(−/−) mice led to in vivo increases in foam cell formation, aortic 25-HC levels, and disease progression. These results define a previously unknown role for ATF3 in controlling macrophage lipid metabolism and demonstrate that ATF3 is a key intersection point for lipid metabolic and inflammatory pathways in these cells. The Rockefeller University Press 2012-04-09 /pmc/articles/PMC3328364/ /pubmed/22473958 http://dx.doi.org/10.1084/jem.20111202 Text en © 2012 Gold et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/). |
spellingShingle | Article Gold, Elizabeth S. Ramsey, Stephen A. Sartain, Mark J. Selinummi, Jyrki Podolsky, Irina Rodriguez, David J. Moritz, Robert L. Aderem, Alan ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation |
title | ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation |
title_full | ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation |
title_fullStr | ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation |
title_full_unstemmed | ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation |
title_short | ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation |
title_sort | atf3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3328364/ https://www.ncbi.nlm.nih.gov/pubmed/22473958 http://dx.doi.org/10.1084/jem.20111202 |
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