Majdalawieh Amin, Zhang Lei, Fuki Ilia V, Rader Daniel J, Ro Hyo-Sung
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Sir Charles Tupper Medical Building, Halifax, NS, Canada B3H 1X5.
Proc Natl Acad Sci U S A. 2006 Feb 14;103(7):2346-51. doi: 10.1073/pnas.0508139103. Epub 2006 Feb 6.
Peroxisome proliferator-activated receptor gamma1 (PPARgamma1) and liver X receptor alpha (LXRalpha) play pivotal roles in macrophage cholesterol homeostasis and inflammation, key biological processes in atherogenesis. Herein we identify adipocyte enhancer-binding protein 1 (AEBP1) as a transcriptional repressor that impedes macrophage cholesterol efflux, promoting foam cell formation, via PPARgamma1 and LXRalpha down-regulation. Contrary to AEBP1 deficiency, AEBP1 overexpression in macrophages is accompanied by decreased expression of PPARgamma1, LXRalpha, and their target genes ATP-binding cassette A1, ATP-binding cassette G1, apolipoprotein E, and CD36, with concomitant elevation in IL-6, TNF-alpha, monocyte chemoattractant protein 1, and inducible NO synthase levels. AEBP1, but not the C-terminally truncated DNA-binding domain mutant (AEBP1DeltaSty), represses PPARgamma1 and LXRalpha in vitro. Expectedly, AEBP1-overexpressing transgenic (AEBP1TG) macrophages accumulate considerable amounts of lipids compared with AEBP1 nontransgenic macrophages, making them precursors for foam cells. Indeed, AEBP1-overexpressing transgenic macrophages exhibit diminished cholesterol efflux compared with AEBP1 nontransgenic macrophages, whereas AEBP1-knockout (AEBP1-/-) macrophages exhibit enhanced cholesterol efflux compared with wild-type (AEBP1+/+) macrophages. Our in vitro and ex vivo experimental data strongly suggest that AEBP1 plays critical regulatory roles in macrophage cholesterol homeostasis, foam cell formation, and proinflammation. Thereby, we speculate that AEBP1 may be critically implicated in the development of atherosclerosis, and it may serve as a molecular target toward developing antiinflammatory, antiatherogenic therapeutic approaches.
过氧化物酶体增殖物激活受体γ1（PPARγ1）和肝X受体α（LXRα）在巨噬细胞胆固醇稳态和炎症中起关键作用，而这是动脉粥样硬化形成过程中的关键生物学过程。在此，我们确定脂肪细胞增强子结合蛋白1（AEBP1）为一种转录抑制因子，它通过下调PPARγ1和LXRα来阻碍巨噬细胞胆固醇外流，促进泡沫细胞形成。与AEBP1缺乏相反，巨噬细胞中AEBP1的过表达伴随着PPARγ1、LXRα及其靶基因ATP结合盒A1、ATP结合盒G1、载脂蛋白E和CD36表达的降低，同时白细胞介素-6、肿瘤坏死因子-α、单核细胞趋化蛋白1和诱导型一氧化氮合酶水平升高。AEBP1而非C末端截短的DNA结合结构域突变体（AEBP1ΔSty）在体外抑制PPARγ1和LXRα。不出所料，与AEBP1非转基因巨噬细胞相比，过表达AEBP1的转基因（AEBP1TG）巨噬细胞积累了大量脂质，使其成为泡沫细胞的前体。事实上，与AEBP1非转基因巨噬细胞相比，过表达AEBP1的转基因巨噬细胞胆固醇外流减少，而与野生型（AEBP1+/+）巨噬细胞相比，敲除AEBP1（AEBP1-/-）的巨噬细胞胆固醇外流增强。我们的体外和体内实验数据强烈表明，AEBP1在巨噬细胞胆固醇稳态、泡沫细胞形成和促炎过程中起关键调节作用。因此，我们推测AEBP1可能与动脉粥样硬化的发展密切相关，它可能成为开发抗炎、抗动脉粥样硬化治疗方法的分子靶点。
