Abstract
Deiodination is an important metabolic pathway for iodothyronines and their sulfates that takes place intracellularly. Therefore, transport of (sulfated) iodothyronines across the plasma membrane is required. Only a few proteins are reported to facilitate these processes, of which rat Na+/taurocholate cotransporting polypeptide (Ntcp; SLC10a1) has been identified as an important transporter protein. We demonstrate that among the 7 members of the SLC10 family, exclusively human SLC10A1 transports the iodothyronine T4 and the sulfated iodothyronines T3S and T4S. Taurocholate and sulfated iodothyronines, which are both transported by SLC10A1, reciprocally inhibit each others uptake. In contrast to SLC10A2-7, cells co-expressing SLC10A1 and the deiodinase D1 results in a dramatic increase of T3S and T4S metabolism, indicating that SLC10A1 facilitates intracellular metabolism of sulfated iodothyronines. Furthermore, several experiments indicate that CRYM, a well-known intracellular iodothyronine-binding protein, is also capable of binding sulfated iodothyronines. This suggests an additional role of CRYM as a binding protein for sulfated iodothyronines, possibly directing the sulfated iodothyronines to intracellular targets. The present findings indicate that SLC10A1, which is specifically expressed in liver, transports (sulfated) iodothyronines, thereby increasing their intracellular availability. Therefore, SLC10A1 may fulfill a critical step in providing liver D1 with sulfated iodothyronines for rapid degradation. Our observations that taurocholate and sulfated iodothyronines are transported by the same transporter and reciprocally inhibit each others uptake may have physiological implications. If serum bile acids concentrations increase, uptake of sulfated iodothyronines by SLC10A1 will diminish, thereby preventing hepatic clearance of sulfated iodothyronines. As a consequence, increased serum concentrations of sulfated iodothyronines are available for extrahepatic desulfation, resulting in increased biologically active thyroid hormone levels. Our findings may add a new dimension to the recently identified connection between bile acids and thyroid hormone in the control of energy expenditure.