期刊
CARDIOVASCULAR RESEARCH
卷 113, 期 11, 页码 1376-1388出版社
OXFORD UNIV PRESS
DOI: 10.1093/cvr/cvx134
关键词
CEBPD; Inflammation; Macrophages; PTX3; Statins
资金
- Ministry of Science and Technology [MOST 106-2320-B-006-063-MY3]
- National Health Research Institutes [NHRI-EX106-10422BI]
Aims Lipid homeostasis is reprogrammed in the presence of inflammation, which results in excessive lipid accumulation in macrophages, and leads to the formation of lipid-laden foam cells. We aimed to link an inflammation-responsive transcription factor CCAAT/enhancer-binding protein delta (CEBPD) with polarized macrophages and dissect its contribution to lipid accumulation. Methods and results We found that CEBPD protein colocalized with macrophages in human and mouse (C57BL/6, Apoe(-/-)) atherosclerotic plaques and that Cebpd deficiency in bone marrow cells suppressed atherosclerotic lesions in hyperlipidemic Apoe(-/-) mice. CEBPD was responsive to modified low-density lipoprotein (LDL) via the p38(MAPK)/CREB pathway, and it promoted lipid accumulation in M1 macrophages but not in M2 macrophages. CEBPD up-regulated pentraxin 3 (PTX3), which promoted the macropinocytosis of LDL, and down-regulated ATP-binding cassette subfamily A member 1 (ABCA1), which impaired the intracellular cholesterol efflux in M1 macrophages. We further found that simvastatin (a HMG-CoA reductase inhibitor) could target CEBPD to block lipid accumulation in a manner not directly related to its cholesterol-lowering effect in M1 macrophages. Conclusion This study underscores how CEBPD functions at the junction of inflammation and lipid accumulation in M1 macrophages. Therefore, CEBPD-mediated lipid accumulation in M1 macrophages could represent a new therapeutic target for the treatment of cardiovascular diseases.
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