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.