Majdalawieh Amin, Ro Hyo-Sung
Department of Biochemistry and Molecular Biology, Faculty of Medicine, Sir Charles Tupper Medical Building, Dalhousie University, Halifax, Nova Scotia, Canada.
Int J Biochem Cell Biol. 2009 Jul;41(7):1518-25. doi: 10.1016/j.biocel.2009.01.003. Epub 2009 Jan 8.
Macrophages facilitate clearance of cholesterol from the body via reverse cholesterol transport (RCT). The first event in RCT is internalization of modified low density lipoprotein by macrophages, upon which PPARgamma1 and LXRalpha signaling pathways are turned on, leading to the transactivation of a cascade of genes (e.g. ABCA1 and ABCG1), whose products promote macrophage cholesterol efflux. Down-regulation of macrophage cholesterol efflux mediators leads to an imbalance in cholesterol homeostasis, promoting foam cell formation. Lipopolysaccharide (LPS) has been shown to suppress PPARgamma1 and its downstream target genes in macrophages, inducing foam cell formation; a key mechanism proposed to underlie bacterial infection-induced atherosclerosis. Herein, we show that adipocyte enhancer-binding protein 1 (AEBP1) is up-regulated during monocyte differentiation. Moreover, we provide experimental evidence suggesting that AEBP1 expression is induced by LPS, and that LPS-induced down-regulation of pivotal macrophage cholesterol efflux mediators, leading to foam cell formation, is largely mediated by AEBP1. Although AEBP1-independent pathways seem to contribute to these LPS effects, such pathways can only mediate lesser and delayed effects of LPS on macrophage cholesterol efflux and development of foam cells. We speculate that AEBP1 may serve as a potential therapeutic target for the prevention/treatment of bacterial infection-induced atherosclerosis.
巨噬细胞通过逆向胆固醇转运（RCT）促进体内胆固醇的清除。RCT的首个事件是巨噬细胞内化修饰的低密度脂蛋白，在此过程中PPARγ1和LXRα信号通路被激活，导致一系列基因（如ABCA1和ABCG1）的反式激活，其产物促进巨噬细胞胆固醇外流。巨噬细胞胆固醇外流介质的下调导致胆固醇稳态失衡，促进泡沫细胞形成。脂多糖（LPS）已被证明可抑制巨噬细胞中的PPARγ1及其下游靶基因，诱导泡沫细胞形成；这是提出的细菌感染诱导动脉粥样硬化的关键机制。在此，我们表明脂肪细胞增强子结合蛋白1（AEBP1）在单核细胞分化过程中上调。此外，我们提供的实验证据表明，AEBP1的表达由LPS诱导，并且LPS诱导的关键巨噬细胞胆固醇外流介质的下调导致泡沫细胞形成，这在很大程度上由AEBP1介导。尽管不依赖AEBP1的途径似乎对这些LPS效应有贡献，但此类途径只能介导LPS对巨噬细胞胆固醇外流和泡沫细胞形成的较小且延迟的效应。我们推测AEBP1可能作为预防/治疗细菌感染诱导的动脉粥样硬化的潜在治疗靶点。
