ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol–induced lipid body formation

Author:

Gold Elizabeth S.1,Ramsey Stephen A.1,Sartain Mark J.2,Selinummi Jyrki34,Podolsky Irina1,Rodriguez David J.2,Moritz Robert L.2,Aderem Alan1

Affiliation:

1. Seattle Biomedical Research Institute, Seattle, WA 98109

2. Institute for Systems Biology, Seattle, WA 98109

3. Department of Signal Processing, Tampere University of Technology, 33720 Tampere, Finland

4. Quva Oy, 33720 Tampere, Finland

Abstract

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.

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

Reference58 articles.

1. 25-Hydroxycholesterol secreted by macrophages in response to Toll-like receptor activation suppresses immunoglobulin A production;Bauman;Proc. Natl. Acad. Sci. USA.,2009

2. Controlling the false discovery rate: a practical and powerful approach to multiple testing;Benjamini;J.R. Stat. Soc. Ser. B.,1995

3. Leukocyte lipid bodies regulation and function: contribution to allergy and host defense;Bozza;Pharmacol. Ther.,2007

4. Cholesterol ester formation in cultured human fibroblasts. Stimulation by oxygenated sterols;Brown;J. Biol. Chem.,1975

5. Effects of sex and age on atherosclerosis and autoimmunity in apoE-deficient mice;Caligiuri;Atherosclerosis.,1999

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3