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- Title
Adipocyte Enhancer-Binding Protein 1 (AEBP1) (a Novel Macrophage Proinflammatory Mediator) Overexpression Promotes and Ablation Attenuates Atherosclerosis in ApoE<sup>-/-</sup> and LDLR<sup>-/-</sup> Mice.
- Authors
Bogachev, Oleg; Majdalawieh, Amin; Xuefang Pan; Lei Zhang; Hyo-Sung Ro
- 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)-γ1 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 )-/- doubleknockout (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.
- Subjects
FAT cells; CARRIER proteins; LABORATORY mice; MACROPHAGES; APOLIPOPROTEIN E; PEROXISOMES
- Publication
Molecular Medicine, 2011, Vol 17, Issue 9/10, p1056
- ISSN
1076-1551
- Publication type
Article
- DOI
10.2119/molmed.2011.00141