Dietary iodide controls its own absorption through post-transcriptional regulation of the intestinal Na+/I- symporter

Abstract

Dietary I- absorption in the gastrointestinal tract is the first step in I- metabolism. Given that I- is an essential constituent of the thyroid hormones, its concentrating mechanism is of significant physiological importance. We recently described the expression of the Na+/I- symporter (NIS) on the apical surface of the intestinal epithelium as a central component of the I- absorption system and reported reduced intestinal NIS expression in response to an I--rich diet in vivo. Here, we evaluated the mechanism involved in the regulation of NIS expression by I- itself in enterocytes. Excess I- reduced NIS-mediated I- uptake in IEC-6 cells in a dose- and time-dependent fashion, which was correlated with a reduction of NIS expression at the plasma membrane. Perchlorate, a competitive inhibitor of NIS, prevented these effects, indicating that an increase in intracellular I- regulates NIS. Iodide induced rapid intracellular recruitment of plasma membrane NIS molecules and NIS protein degradation. Lower NIS mRNA levels were detected in response to I- treatment, although no transcriptional effect was observed. Interestingly, I- decreased NIS mRNA stability, affecting NIS translation. Heterologous green fluorescent protein-based reporter constructs revealed a significant repressive effect of the I--targeting NIS mRNA 3′ untranslated region. In conclusion, excess I- downregulates NIS expression in enterocytes by virtue of a complex mechanism. Our data suggest that I- regulates intestinal NIS mRNA expression at the post-transcriptional level as part of an autoregulatory effect of I- on its own metabolism. © 2012 The Authors. The Journal of Physiology © 2012 The Physiological Society.