TitleATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation.
Publication TypeJournal Article
Year of Publication2012
AuthorsGold, ES, Ramsey, SA, Sartain, MJ, Selinummi, J, Podolsky, I, Rodriguez, DJ, Moritz, RL, Aderem, A
JournalJ Exp Med
Date Published2012 Apr 09
KeywordsActivating Transcription Factor 3, Animals, Apolipoproteins E, Atherosclerosis, Cells, Cultured, Female, Hydroxycholesterols, Lipid Metabolism, Macrophages, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Promoter Regions, Genetic, Steroid Hydroxylases

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.

Alternate JournalJ Exp Med
PubMed ID22473958
PubMed Central IDPMC3328364
Grant ListPM50GMO76547 / / PHS HHS / United States
R03CA156667 / CA / NCI NIH HHS / United States
HHSN272200700038C / / PHS HHS / United States
P50 GM076547 / GM / NIGMS NIH HHS / United States
R03 CA156667 / CA / NCI NIH HHS / United States
R01AI025032 / AI / NIAID NIH HHS / United States
R01 AI025032 / AI / NIAID NIH HHS / United States
S10 RR027584 / RR / NCRR NIH HHS / United States
HHSN272200700038C / AI / NIAID NIH HHS / United States
K25HL098807 / HL / NHLBI NIH HHS / United States
K25 HL098807 / HL / NHLBI NIH HHS / United States