Effects of thyroid state on the expression of hepatic thyroid hormone transporters in rats

Departments of 1 Internal Medicine and 2 Nuclear Medicine, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands Liver uptake of thyroxine (T 4 ) is mediated by transporters and is rate limiting for hepatic 3,3',5-triiodothyronine (T 3 ) production. We investigated whether hepatic mRNA for T 4 transporters is regulated by thyroid state using Xenopus laevis oocytes as an expression system. Because X. laevis oocytes show high endogenous uptake of T 4 , T 4 sulfamate (T 4 NS) was used as an alternative ligand for the hepatic T 4 transporters. Oocytes were injected with 23 ng liver mRNA from euthyroid, hypothyroid, or hyperthyroid rats, and after 3-4 days uptake was determined by incubation of injected and uninjected oocytes for 1 h at 25°C or for 4 h at 18°C with 10 nM [ 125 I]T 4 NS. Expression of type I deiodinase (D1), which is regulated by thyroid state, was studied in the oocytes as an internal control. Uptake of T 4 NS showed similar approximately fourfold increases after injection of liver mRNA from euthyroid, hypothyroid, or hyperthyroid rats. A similar lack of effect of thyroid state was observed using reverse T 3 as ligand. In contrast, D1 activity induced by liver mRNA from hyperthyroid and hypothyroid rats in the oocytes was 2.4-fold higher and 2.7-fold lower, respectively, compared with euthyroid rats. Studies have shown that uptake of iodothyronines in rat liver is mediated in part by several organic anion transporters, such as the Na + /taurocholate-cotransporting polypeptide (rNTCP) and the Na-independent organic anion-transporting polypeptide (rOATP1). Therefore, the effects of thyroid state on rNTCP, rOATP1, and D1 mRNA levels in rat liver were also determined. Northern analysis showed no differences in rNTCP or rOATP1 mRNA levels between hyperthyroid and hypothyroid rats, whereas D1 mRNA levels varied widely as expected. These results suggest little effect of thyroid state on the levels of mRNA coding for T 4 transporters in rat liver, including rNTCP and rOATP1. However, they do not exclude regulation of hepatic T 4 transporters by thyroid hormone at the translational and posttranslational level. iodothyronines; thyroid state; hypothyroidism; hyperthyroidism; rat; liver; plasma membrane