Follicular thyroglobulin suppresses iodide uptake by suppressing expression of the sodium/iodide symporter gene

A major function of the thyrocyte is to take up and concentrate iodide. Thi s is needed for thyroid hormone synthesis and is accomplished by the sodium iodide symporter (NIS), whose expression and activity are up-regulated by TSH. Recently, we reported that follicular thyroglobulin (TG) is a potent s uppressor of thyroid-specific gene expression and can overcome TSH-increase d gene expression. We suggested this might be a negative feedback, autoregu latory mechanism that counterbalanced TSH stimulation of follicular functio n. In this report, we support this hypothesis by coordinately evaluating TG regulation of NIS gene expression and iodide transport. We show that physi ological concentrations of TG similarly and significantly suppress TSH-incr eased NIS promoter activity, NIS protein, and NIS-dependent iodide uptake a s well as RNA levels. We show, in vivo, that TG accumulation at the apical membrane of a thyrocyte facing the follicular lumen is associated with decr eased uptake of radioiodide. It is likely, therefore, that TG suppresses NI S-dependent iodide uptake and NIS gene expression in vivo, as is the case i n vitro. RNA levels of NIS and vascular endothelial growth factor/vascular permeability factor, which has been reported to be TSH regulated and possib ly associated with TSH-increased iodide uptake, are coordinately decreased by follicular TG as a function of concentration and time. Also, removal of follicular TG from the medium, but not TSH, coordinately returns NIS and va scular endothelial growth factor/vascular permeability factor RNA levels to their TSH-stimulated state. TG accumulated in the follicular lumen appears , therefore, to be a negative feedback regulator of critical TSH-increased follicular functions, iodide uptake, and vascular permeability.