Kawai Kotaro, Sasaki Shigekazu, Morita Hiroshi, Ito Takeshi, Suzuki Sadako, Misawa Hiroko, Nakamura Hirotoshi
Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
Endocrinology. 2004 Dec;145(12):5515-24. doi: 10.1210/en.2004-0382. Epub 2004 Aug 19.
The thyroid hormone receptor (TR) and liver X receptor (LXR)-alpha are members of the nuclear hormone receptor family and are ligand-dependent transcription factors. Among the promoter target genes, TR and LXR recognize the T3 response element and LXR response element (LXRE), respectively. Because T3 response elements and LXREs have similar configurations, referred to as direct repeat 4, we investigated the possibility of cross-talk between the two ligand-dependent signal transduction pathways. We found that TRbeta1, a major isoform of TR in the liver, binds and transactivates LXREs derived from the mouse mammary tumor virus long-terminal repeat and the promoter of the sterol regulatory element binding protein 1c. Moreover, unliganded TRbeta1 suppresses promoter activity driven by LXRalpha and its ligand, whereas transactivation by T3-bound TRbeta1 is not affected by LXRalpha in the presence or absence of oxysterols. Gel shift, mammalian two-hybrid, and glutathione S-transferase pull-down assays demonstrated the direct binding of TRbeta1 to these LXREs and revealed that the interaction between TRbeta1 and corepressors is important to the unliganded TR-mediated suppression of LXRalpha-transactivation. Our findings suggest that T3 and TR influence lipid metabolism regulated by oxysterol/LXRalpha at the transcriptional level.
甲状腺激素受体（TR）和肝脏X受体（LXR）-α是核激素受体家族的成员，属于配体依赖性转录因子。在启动子靶基因中，TR和LXR分别识别T3反应元件和LXR反应元件（LXRE）。由于T3反应元件和LXRE具有相似的结构，称为直接重复序列4，我们研究了这两种配体依赖性信号转导途径之间相互作用的可能性。我们发现，肝脏中TR的主要异构体TRβ1能够结合并反式激活源自小鼠乳腺肿瘤病毒长末端重复序列和固醇调节元件结合蛋白1c启动子的LXRE。此外，未结合配体的TRβ1会抑制由LXRα及其配体驱动的启动子活性，而在存在或不存在氧化固醇的情况下，结合T3的TRβ1的反式激活不受LXRα的影响。凝胶迁移、哺乳动物双杂交和谷胱甘肽S-转移酶下拉试验证明了TRβ1与这些LXRE的直接结合，并揭示了TRβ1与共抑制因子之间的相互作用对于未结合配体的TR介导的LXRα反式激活的抑制作用很重要。我们的研究结果表明，T3和TR在转录水平上影响由氧化固醇/LXRα调节的脂质代谢。
