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Unliganded Thyroid Hormone Receptor-ß1 Represses Liver X Receptor /Oxysterol-Dependent Transactivation

Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka 431-3192, Japan

Address all correspondence and requests for reprints to: Shigekazu Sasaki, M.D., Ph.D., Second Division, Department of Internal Medicine, Hamamatsu University School of Medicine, 1-20-1 Handayama, Hamamatsu, Shizuoka 431-3192, Japan. E-mail: sasakis{at}hama-med.ac.jp.

The thyroid hormone receptor (TR) and liver X receptor (LXR)- 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 TRß1, 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 TRß1 suppresses promoter activity driven by LXR and its ligand, whereas transactivation by T₃-bound TRß1 is not affected by LXR in the presence or absence of oxysterols. Gel shift, mammalian two-hybrid, and glutathione S-transferase pull-down assays demonstrated the direct binding of TRß1 to these LXREs and revealed that the interaction between TRß1 and corepressors is important to the unliganded TR-mediated suppression of LXR-transactivation. Our findings suggest that T₃ and TR influence lipid metabolism regulated by oxysterol/LXR at the transcriptional level.

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