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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...

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Autores principales: Gold, Elizabeth S., Ramsey, Stephen A., Sartain, Mark J., Selinummi, Jyrki, Podolsky, Irina, Rodriguez, David J., Moritz, Robert L., Aderem, Alan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2012
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.
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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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