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Molecular Medicine

, Volume 17, Issue 9–10, pp 1056–1064 | Cite as

Adipocyte Enhancer-Binding Protein 1 (AEBP1) (a Novel Macrophage Proinflammatory Mediator) Overexpression Promotes and Ablation Attenuates Atherosclerosis in ApoE−/− and LDLR−/− Mice

  • Oleg Bogachev
  • Amin Majdalawieh
  • Xuefang Pan
  • Lei Zhang
  • Hyo-Sung Ro
Research Article

Abstract

Atherogenesis is a long-term process that involves inflammatory response coupled with metabolic dysfunction. Foam cell formation and macrophage inflammatory response are two key events in atherogenesis. Adipocyte enhancer-binding protein 1 (AEBP1) has been shown to impede macrophage cholesterol efflux, promoting foam cell formation, via peroxisome proliferator-activated receptor (PPAR)-γl and liver X receptor α (LXRα) downregulation. Moreover, AEBP1 has been shown to promote macrophage inflammatory responsiveness by inducing nuclear factor (NF)-κB activity via IκBα downregulation. Lipopolysaccharide (LPS)-induced suppression of pivotal macrophage cholesterol efflux mediators, leading to foam cell formation, has been shown to be mediated by AEBP1. Herein, we showed that AEBP1-transgenic mice (AEBP1TG) with macrophage-specific AEBP1 overexpression exhibit hyperlipidemia and develop atherosclerotic lesions in their proximal aortas. Consistently, ablation of AEBP1 results in significant attenuation of atherosclerosis (males: 3.2-fold, P = 0.001 (en face)), 2.7-fold, P = 0.0004 (aortic roots); females: 2.1-fold, P = 0.0026 (en face), 1.7-fold, P = 0.0126 (aortic roots)) in the AEBP1−/−/low-density lipoprotein receptor (LDLR)−/− double-knockout (KO) mice. Bone marrow (BM) transplantation experiments further revealed that LDLR−/− mice reconstituted with AEBP1−/−/LDLR−/− BM cells (LDLR−/−/KO-BM chimera) display significant reduction of atherosclerosis lesions (en face: 2.0-fold, P = 0.0268; aortic roots: 1.7-fold, P = 0.05) compared with control mice reconstituted with AEBP1+/+/LDLR−/− BM cells (LDLR−/−/WT-BM chimera). Furthermore, transplantation of AEBP1TG BM cells with the normal apolipoprotein E (ApoE) gene into ApoE−/− mice (ApoE−/−/TG-BM chimera) leads to significant development of atherosclerosis (males: 2.5-fold, P = 0.0001 (en face), 4.7-fold, P = 0.0001 [aortic roots]; females: 1.8-fold, P = 0.0001 (en face), 3.0-fold, P = 0.0001 [aortic roots]) despite the restoration of ApoE expression. Macrophages from ApoE−/−/TG-BM chimeric mice express reduced levels of PPARγ1, LXRα, ATP-binding cassette A1 (ABCA1) and ATP-binding cassette G1 (ABCG1) and increased levels of the inflammatory mediators interleukin (IL)-6 and tumor necrosis factor (TNF)-α compared with macrophages of control chimeric mice (ApoE−/−/NT-BM) that received AEBP1 nontransgenic (AEBP1NT) BM cells. Our in vivo experimental data strongly suggest that macrophage AEBP1 plays critical regulatory roles in atherogenesis, and it may serve as a potential therapeutic target for the prevention or treatment of atherosclerosis.

Notes

Acknowledgments

We thank Chris Webber, Janette Flemming, Debby Currie and Patricia Colp for their technical assistance. This work was supported by a grant from the Canadian Institutes of Health Research (to H-S Ro).

Supplementary material

10020_2011_1791056_MOESM1_ESM.pdf (274 kb)
Adipocyte Enhancer-Binding Protein 1 (AEBP1) (a Novel Macrophage Proinflammatory Mediator) Overexpression Promotes and Ablation Attenuates Atherosclerosis in ApoE−/− and LDLR−/− Mice

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Copyright information

© The Feinstein Institute for Medical Research 2011
www.feinsteininstitute.org

Authors and Affiliations

  • Oleg Bogachev
    • 1
  • Amin Majdalawieh
    • 1
  • Xuefang Pan
    • 1
  • Lei Zhang
    • 1
  • Hyo-Sung Ro
    • 1
  1. 1.Department of Biochemistry and Molecular Biology, Faculty of MedicineDalhousie UniversityHalifaxCanada

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