Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
Mol Med. 2011 Sep-Oct;17(9-10):1056-64. doi: 10.2119/molmed.2011.00141. Epub 2011 Jun 14.
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.
动脉粥样硬化是一个长期的过程，涉及炎症反应和代谢功能障碍。泡沫细胞的形成和巨噬细胞炎症反应是动脉粥样硬化形成的两个关键事件。脂肪细胞增强结合蛋白 1（AEBP1）已被证明通过过氧化物酶体增殖物激活受体（PPAR）-γ1 和肝 X 受体α（LXRα）下调来阻碍巨噬细胞胆固醇流出，从而促进泡沫细胞的形成。此外，AEBP1 通过下调 IκBα 诱导核因子（NF）-κB 活性，促进巨噬细胞炎症反应。脂多糖（LPS）诱导的关键巨噬细胞胆固醇流出介质的抑制，导致泡沫细胞的形成，已被证明是由 AEBP1 介导的。在此，我们表明，具有巨噬细胞特异性 AEBP1 过表达的 AEBP1 转基因（AEBP1（TG））小鼠表现出高脂血症，并在其主动脉近端形成动脉粥样硬化病变。一致地，AEBP1 的缺失导致动脉粥样硬化显著减弱（雄性：3.2 倍，P = 0.001[正面]，2.7 倍，P = 0.0004[主动脉根部]；雌性：2.1 倍，P = 0.0026[正面]，1.7 倍，P = 0.0126[主动脉根部]）在 AEBP1（-/-）/低密度脂蛋白受体（LDLR）（-/-）双敲除（KO）小鼠中。骨髓（BM）移植实验进一步表明，用 AEBP1（-/-）/LDLR（-/-）BM 细胞（LDLR（-/-）/KO-BM 嵌合体）重建的 LDLR（-/-）小鼠显示出明显减少的动脉粥样硬化病变（正面：2.0 倍，P = 0.0268；主动脉根部：1.7 倍，P = 0.05）与用 AEBP1（+/+）/LDLR（-/-）BM 细胞（LDLR（-/-）/WT-BM 嵌合体）重建的对照小鼠相比。此外，将具有正常载脂蛋白 E（ApoE）基因的 AEBP1（TG）BM 细胞移植到 ApoE（-/-）小鼠中（ApoE（-/-）/TG-BM 嵌合体）导致明显的动脉粥样硬化发展（雄性：2.5 倍，P = 0.0001[正面]，4.7 倍，P = 0.0001[主动脉根部]；雌性：1.8 倍，P = 0.0001[正面]，3.0 倍，P = 0.0001[主动脉根部]），尽管 ApoE 表达得到恢复。与接受非转基因 AEBP1（AEBP1（NT））BM 细胞的对照嵌合小鼠（ApoE（-/-）/NT-BM）相比，ApoE（-/-）/TG-BM 嵌合小鼠的巨噬细胞表达的 PPARγ1、LXRα、ATP 结合盒 A1（ABCA1）和 ATP 结合盒 G1（ABCG1）水平降低，炎症介质白细胞介素（IL）-6 和肿瘤坏死因子（TNF）-α水平升高。我们的体内实验数据强烈表明，巨噬细胞 AEBP1 在动脉粥样硬化形成中发挥关键的调节作用，它可能成为预防或治疗动脉粥样硬化的潜在治疗靶点。
