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Cardiovasc Res. 2017 Sep 1;113(11):1376-1388. doi: 10.1093/cvr/cvx134.

CCAAT/enhancer-binding protein delta promotes intracellular lipid accumulation in M1 macrophages of vascular lesions.

Lai HY1, Hsu LW1, Tsai HH2, Lo YC2, Yang SH3, Liu PY4,5, Wang JM1,2,6,7,8.

Author information

1
Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
2
Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, No. 1 University Rd., Tainan 70101, Taiwan.
3
Department of Physiology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
4
Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
5
Division of Cardiology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
6
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
7
Center of Molecular Inflammation Research, National Cheng Kung University, Tainan, Taiwan.
8
Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei, Taiwan.

Abstract

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 p38MAPK/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.

KEYWORDS:

CEBPD; Inflammation; Macrophages; PTX3; Statins

PMID:
28859294
DOI:
10.1093/cvr/cvx134
[Indexed for MEDLINE]

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