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

Key points Expression of the Na+/I− symporter (NIS) at the apical surface of the epithelium of the small intestine is key to I− absorption, the first step in I− metabolism. Intracellular I− at high concentrations in enterocytes decreases its own NIS‐mediated uptake by a newly discovered mechanism, downregulating NIS expression at the plasma membrane, increasing NIS protein degradation and decreasing NIS mRNA levels by reducing NIS mRNA stability, involving the NIS 3′‐untranslated region. In conclusion, we have uncovered that I− regulates intestinal NIS expression, and thus its own intestinal absorption, by a complex array of post‐transcriptional mechanisms. 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.