Thyroid hormone dependent regulation of target genes and their physiological significance.

Thyroid hormone (T3) regulates growth, development and differentiation. These activities are mediated by nuclear thyroid hormone receptors (TRs), which belong to the steroid/thyroid hormone receptor superfamily of ligand-dependent transcription factors. In an effort to study the mechanism of target genes regulation and their physiological significance after T3 treatment in a TR alpha-overexpressing hepatoma cell line (HepG2-TR alpha), c-DNA microarrays were performed. The data demonstrated that approximately 149 genes represented were positively regulated by T3, including fibrinogen, transferrin, fibronectin (FN), androgen receptor (AR)-associated protein (ARA70), and dehydroepiandrosterone sulfotransferase family 1A member 2 (SULT2A1). To further confirm the microarray results, a quantitative-reverse transcription polymerase chain reaction (Q-RT-PCR) was applied. The protein synthesis inhibitor, cycloheximide was used to determine whether the regulation was direct or indirect. A promoter assay further showed that T3 regulation was largely at the level of transcription. Although those genes were isolated from a human tumor cell line, they are regulated similarly in rats and humans. These results indicate that T3 might play an important role in the process of blood coagulation, inflammation, metabolism and cell proliferation. This may help to explain the association between thyroid diseases and the mis-regulation of the inflammatory and clotting profiles evident in the circulatory systems of these patients.