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Thyroid Hormone Receptor-Dependent Transcriptional Regulation of Fibrinogen and Coagulation Proteins

Department of Biochemistry (C.-h.S., S.-L.C., C.-C.Y., Y.-H.H., C.-d.C., K.-h.L.), Graduate Institute of Clinical Medicine (Y.-S.L.), Chang-Gung University, Taoyuan, Taiwan 333, Republic of China

Address all correspondence and requests for reprints to: Dr. Kwang-huei Lin, Department of Biochemistry, Chang-Gung University, 259 Wen-hwa 1 Road, Taoyuan, Taiwan 333, Republic of China. E-mail: khlin{at}mail.cgu.edu.tw.

Thyroid hormone (T₃) regulates growth, development, and differentiation. These activities are mediated by the nuclear thyroid hormone receptors (TRs), which belong to the steroid/TR superfamily of ligand-dependent transcription factors. The effect of T₃ treatment on target gene regulation was investigated in a TR-overexpressing hepatoma cell line (HepG2-TR), by performing cDNA microarrays. We demonstrate that 148 of the 7597 genes represented were up-regulated by T₃, including fibrinogen and several other components of the coagulation factor system. To confirm the microarray results, fibrinogen and a small number of the blood clotting components were further investigated using quantitative RT-PCR. The T₃-induction ratios observed with quantitative RT-PCR for factors such as thrombin (8-fold), coagulation factor X (4.9-fold), and hepatoglobin (30-fold) were similar to those observed by the cDNA microarray analysis. Further investigation, using HepG2-TR (cell lines, revealed a 2- to 3-fold induction of fibrinogen transcription after 24 h of T₃ treatment. In addition, T₃ treatment increased the level of fibrinogen protein expression 2.5- to 6-fold at 48 h. The protein synthesis inhibitor, cycloheximide, did not inhibit the induction of fibrinogen by T₃, indicating that this regulation was direct. Furthermore, transcription run-on experiments indicate that the induction of fibrinogen by T₃ is regulated largely at the level of transcription. Similar observations were made on the regulation of fibrinogen by T₃ using rats that received surgical thyroidectomy (TX) as an in vivo model. These results suggest that T₃ plays an important role in the process of blood coagulation and inflammation and may contribute to the understanding of the association between thyroid diseases and the misregulation of the inflammatory and clotting profile evident in the circulatory system of these patients.

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