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

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)-gamma 1 and liver X receptor alpha (LXR alpha) downregulation. Moreover, AEBP1 has been shown to promote macrophage inflammatory responsiveness by inducing nuclear factor (NF)-kappa B activity via I kappa B alpha 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 (AEBP1(TG)) 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-F 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 PPAR gamma l, LXR alpha, ATP-binding cassette A1 (ABCA1) and ATP-binding cassette GI (ABCG1) and increased levels of the inflammatory mediators interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha compared with macrophages of control chimeric mice (ApoE(-/-)/NT-BM) that received AEBP1 nontransgenic (AEBP1(NT)) 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. (C) 2011 The Feinstein Institute for Medical Research, www.feinsteininstitute.org Online address: http://www.molmed.org doi: 10.2119/molmed.2011.00141