Tributyltin chloride induces ABCA1 expression and apolipoprotein A-I-mediated cellular cholesterol efflux by activating LXRalpha/RXR
Tributyltin chloride induces ABCA1 expression and apolipoprotein A-I-mediated cellular cholesterol efflux by activating LXRalpha/RXR
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DOI：
10.1016/j.bcp.2010.12.023
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发表时间：
2011-03-15
影响因子：
5.8
通讯作者：
Nishimaki-Mogami, Tomoko
中科院分区：
文献类型：
--
作者：
Cui, Hongyan;Okuhira, Keiichiro;Nishimaki-Mogami, Tomoko
包括三丁基氯化锡（TBTC）在内的有机锡广泛应用于农业和化学工业，并造成持续和广泛的污染。 TBTC 已被证明可以通过与 RXR 相互作用来激活核受体视黄醇 X 受体 (RXR)/PPAR gamma 信号传导，从而调节脂肪生成。然而，TBTC 是否影响肝脏 X 受体 (LXR)/RXR 活性以及随后胆固醇动员基因的表达尚不清楚。在本研究中，我们评估了 TBTC 激活 LXR/RXR 和 ABC 转运蛋白 A1 (ABCA1) 表达的能力。 ABCA1 在 HDL 生成、维持胆固醇稳态以及胆固醇积累诱发的疾病（如动脉粥样硬化和胰岛功能障碍）中发挥着关键作用。在报告基因检测中，TBTC 激活 LXR α/RXR，但不激活 LXR β/RXR。在小鼠巨噬细胞 RAW264 细胞中，TBTC 以 LXR 响应元件依赖性方式激活 ABCA1 启动子，并增加 ABCA1 mRNA 表达。 TBTC 增强了 ABCA1 蛋白水平和载脂蛋白 A-I 依赖性细胞胆固醇流出（HDL 生成）。 TBTC 暴露也增加了 LXR 靶标脂肪酸合酶和 Spa mRNA 水平。我们得出结论，TBTC 能够激活许可的 LXR α/RXR 信号传导，从而调节细胞胆固醇流出。 (C) 2011 Elsevier Inc. 保留所有权利。
Organotins, including tri-butyltin chloride (TBTC), are widely used in agricultural and chemical industries and cause persistent and widespread pollution. TBTC has been shown to activate nuclear receptor retinoid X receptor (RXR)/PPAR gamma signaling by interacting with RXR to modulate adipogenesis. However, whether TBTC affects liver X receptor (LXR)/RXR activity and subsequently the expression of cholesterol mobilizing genes is not known. In this study, we evaluated the ability of TBTC to activate LXR/RXR and ABC transporter A1 (ABCA1) expression. ABCA1 plays a critical role in HDL generation, maintaining cholesterol homeostasis, and cholesterol accumulation-induced diseases, such as atherosclerosis and pancreatic islet dysfunction. In a reporter gene assay, TBTC activated LXR alpha/RXR but not LXR beta/RXR. In mouse macrophage RAW264 cells, TBTC activated the ABCA1 promoter in an LXR-responsive element dependent manner and increased ABCA1 mRNA expression. TBTC augmented ABCA1 protein levels and apolipoprotein A-I-dependent cellular cholesterol efflux (HDL generation). The LXR-target fatty acid synthase and Spa mRNA levels were also increased by TBTC exposure. We conclude that TBTC has the ability to activate permissive LXR alpha/RXR signaling and thereby modulate cellular cholesterol efflux. (C) 2011 Elsevier Inc. All rights reserved.