Paradoxical triiodothyronine suppression of S14 transcription in permanent hepatic cell lines.

Both in vivo and in primary rat hepatocyte culture, carbohydrate and triiodothyronine (T(3)) rapidly induce transcription of the rat S14 gene. To determine if regulation of this gene by T(3) is similar in human liver cells, we transfected the S14 upstream region into HepG2 cells. We chose this cell line because many others have used this cell line to study the effect of thyroid hormone on hepatic gene expression. We found that changing media glucose concentration did not affect S14 transcription. Furthermore, addition of T(3) to HepG2 cells caused a marked reduction of rat S14 transcription. This paradoxical reduction was dependent on cotransfection of the T(3) receptor. We obtained similar results in the other human hepatoma cell lines, HuH-7 and Hep3B. The paradoxical response was not limited to human cells. We found a similar response in the nonmalignant permanent mouse liver cell line, AML-12. This paradoxical response was specific to the S14 gene because transfection of all the cell lines with a CAT or luciferase reporter driven by a mouse mammary tumor virus promoter containing 1 or 4 copies of a palindromic thyroid hormone response element (TRE) showed marked induction by T(3). Our results show that T(3) abnormally regulates the S14 gene in proliferating liver cell lines of diverse origins. This paradoxical regulation by T(3) is caused by an interaction between T(3) and the thyroid hormone receptor. The factors that lead to this paradoxical response are not active in primary hepatocytes and normal intact liver.