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 (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 (-/-) 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 AEBP1(TG) 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 (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.
Highlights
Atherosclerosis is a killer disease responsible for >50% of deaths in the developed world [1,2]
We demonstrated that Adipocyte enhancer-binding protein 1 (AEBP1) represses the expression of PPARγ1 and liver X receptor α (LXRα) in a dose-dependent, DNA binding–dependent fashion, which is accompanied by concurrent repression of major cholesterol efflux mediators (for example, ATP-binding cassette A1 (ABCA1), ATP-binding cassette G1 (ABCG1) and apolipoprotein [Apo]-E), leading to foam cell formation [9]
AEBP1TG mice were raised on the FVB/N background, whereas ApoE –/– and low-density lipoprotein receptor (LDLR)–/– mice were raised on the C57BL/6 background
Summary
Atherosclerosis is a killer disease responsible for >50% of deaths in the developed world [1,2]. Lipid accumulation in macrophages leads to the activation of signaling pathways that involve activation of peroxisome proliferator–activated receptor (PPAR)-γ1 and liver X receptor α (LXRα), nuclear receptors that function as transcription factors controlling macrophage cholesterol homeostasis [3,4,5,6,7]. Genetic defects or pharmacological inhibition of any component of the macrophage cholesterol efflux pathway leads to an imbalance in cholesterol homeostasis. This result eventually leads to massive accumulation of lipids in the cytoplasmic compartment of macrophages, which acquire a foamy appearance and transform into lipid-engorged foam cells, a hallmark of fatty streak and atherosclerotic lesion formation. Because atherosclerosis is a multigenic disease, understanding the roles and expression patterns of genes with known and unknown functions is critical in understanding the molecular mechanisms underlying atherogenesis
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