title: ATF3 protects against atherosclerosis by suppressing 25-hydroxycholesterol-induced lipid body formation.
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.
authors.affiliation: Seattle Biomedical Research Institute, Seattle, WA 98109, USA.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Gold
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Ramsey
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Sartain
authors.forename: Jyrki
authors.initials: J
authors.lastname: Selinummi
authors.forename: Irina
authors.initials: I
authors.lastname: Podolsky
authors.forename: David J
authors.initials: DJ
authors.lastname: Rodriguez
authors.forename: Robert L
authors.initials: RL
authors.lastname: Moritz
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
mesh_terms: D051700:Activating Transcription Factor 3 / Q000502:physiology*; D000818:Animals; D001057:Apolipoproteins E / Q000502:physiology; D050197:Atherosclerosis / Q000517:prevention & control*; D002478:Cells, Cultured; D005260:Female; D006888:Hydroxycholesterols / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D013250:Steroid Hydroxylases / Q000235:genetics
chemical_list: D051700:Activating Transcription Factor 3; D001057:Apolipoproteins E; C103002:Atf3 protein, mouse; D006888:Hydroxycholesterols; C007997:25-hydroxycholesterol; D013250:Steroid Hydroxylases; C507384:cholesterol 25-hydroxylase