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

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.

• Authors: Hong-Yue Lai, Ling-Wei Hsu, Hsin-Hwa Tsai, Yu-Chih Lo, Shang-Hsun Yang, Ping-Yen Liu, Ju-Ming Wang
• Journal: Cardiovascular research (Cardiovasc Res) Vol. 113 Issue 11 Pg. 1376-1388 (Sep 01 2017) ISSN: 1755-3245 [Electronic] England
• PMID: 28859294 (Publication Type: Journal Article)
• Copyright: Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: [email protected].

Chemical References

• ATP Binding Cassette Transporter 1
• CEBPD protein, human
• Cebpd protein, mouse
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lipoproteins, LDL
• CCAAT-Enhancer-Binding Protein-delta
• Cholesterol

Topics

• ATP Binding Cassette Transporter 1 (genetics)
• Animals
• Atherosclerosis (drug therapy, metabolism)
• CCAAT-Enhancer-Binding Protein-delta (metabolism)
• Cholesterol (metabolism)
• Foam Cells (drug effects, metabolism)
• Homeostasis (drug effects)
• Humans
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology)
• Hypercholesterolemia (drug therapy, metabolism)
• Lipid Metabolism
• Lipoproteins, LDL (metabolism)
• Macrophages (drug effects, metabolism)
• Mice
• Mice, Inbred C57BL
• Up-Regulation