Farnesoid X Receptor Induces GLUT4 Expression Through FXR Response Element in the GLUT4 Promoter
Farnesoid X Receptor Induces GLUT4 Expression Through FXR Response Element in the GLUT4 Promoter
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DOI：
10.1159/000149779
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发表时间：
2008-07
影响因子：
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通讯作者：
Hong Shen;Yu Zhang;H. Ding;Xu Wang;Li-li Chen;Hualiang Jiang;Xu Shen
中科院分区：
文献类型：
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作者：
Hong Shen;Yu Zhang;H. Ding;Xu Wang;Li-li Chen;Hualiang Jiang;Xu Shen
GLUT 4是胰岛素应答的主要葡萄糖转运蛋白，在维持全身葡萄糖稳态中起关键作用，并受到复杂的代谢调节。GLUT 4表达异常可能导致胰岛素抵抗，GLUT 4的过度表达已被证实可改善糖尿病。本文报道了法尼醇X受体（FXR）及其激动剂鹅去氧胆酸（CDCA）可诱导3 T3-L1和HepG 2细胞中GLUT 4的转录。CDCA还能增加C57 BL/6 J小鼠GLUT 4蛋白的表达，且具有性别依赖性。随后进行的5“-缺失分析和位点突变研究进一步表明，FXR可通过GLUT 4启动子中的FXR应答元件（FXRE）诱导GLUT 4表达。EMSA和类维生素A X受体（RXR）的敲低表明，FXR作为单体与GLUT 4-FXRE结合，RXR不参与FXR刺激GLUT 4表达。此外，我们证明FXR不干扰胰岛素诱导的GLUT 4转运到质膜。所有这些数据表明FXR是GLUT 4的一个新的转录因子，进一步阐明了FXR在葡萄糖代谢中的潜在作用。
GLUT4, the main insulin-responsive glucose transporter, plays a critical role in maintaining systemic glucose homeostasis and is subject to complicated metabolic regulation. GLUT4 expression disorder might cause insulin resistance, and over-expression of GLUT4 has been confirmed to ameliorate diabetes. Here, we reported that farnesoid X receptor (FXR) and its agonist chenodeoxycholic acid (CDCA) could induce GLUT4 transcription in 3T3-L1 and HepG2 cells. Furthermore, CDCA could increase the GLUT4 protein amount in C57BL/6J mice sex-dependently. The following progressive 5''-deletion analysis and site-mutation investigation further suggested that FXR could induce GLUT4 expression through FXR response element (FXRE) in the GLUT4 promoter. EMSA and knock-down of retinoid X receptor (RXR) indicated that FXR binds to the GLUT4-FXRE as a monomer and RXR does not participate in the FXR stimulation of GLUT4 expression. In addition, we demonstrated that FXR does not interfere with insulin-induced GLUT4 translocation to plasma membrane. All these data thereby implied that FXR is a new transcription factor of GLUT4, further elucidating the potential role for FXR in glucose metabolism.