A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport

Abstract

Mutations of the thyroid hormone (TH) cell membrane transporter MCT8, on chromosome-X, produce severe mental and neurological impairment in men. We generated a Mct8-deficient mouse (Mct8KO) manifesting the human thyroid phenotype. Although these mice have no neurological manifestations, they have decreased brain T(3) content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T(3) content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent. We tested the effect of 3,5-diiodothyropropionic acid (DITPA), a TH receptor agonist, for its dependence on Mct8 in Mct8KO and wild-type (Wt) mice tissues. After depletion of endogenous TH, mice were given three different doses of DITPA. Effects were compared with treatment with two doses of l-T(4). As expected, physiological doses of l-T(4) normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T(4) suppressed TSH in the Wt mice, normalized TSH and brain D2 in Mct8KO mice, but produced a thyrotoxic effect on liver D1 in both genotypes. In contrast DITPA produced similar effects on TSH, D2, and D1 in both Wt and Mct8KO mice. The higher dose fully normalized all measurements and other parameters of TH action. Thus, DITPA is relatively MCT8 independent for entry into the brain and corrects the TH deficit in Mct8KO mice without causing thyrotoxic effect in liver. The potential clinical utility of this analog to patients with MCT8 mutations requires further studies.

Figure 1

Comparison of the effect of T₄, T₃, and DITPA on serum TSH of Wt and Mct8KO mice. Doses are indicated in the abscissae. Data are expressed as mean ± se. The shaded area represents the normal range for Wt animals. Statistical differences between Wt and Mct8KO mice for each treatment group are indicated above the Mct8KO bars. Bars just below the range of normal and not showing se indicate TSH values suppressed bellow limits of the assay sensitivity. Treatment with LoI/MMI/ClO₄ is simply indicated as methimazole (MMI) on the abscissa.

Figure 2

Brain D2, Hr, and Dio3 at baseline and during treatment with l-T₄ and DITPA. Data are expressed as mean ± se. Statistical differences between Wt and Mct8KO mice for each treatment group are indicated above the Mct8KO bars. Lack of statistical difference from the values in Wt mice at baseline are indicated below each value bar as NS (not significant). Treatment with LoI/MMI/ClO₄ is simply indicated as methimazole (MMI) on the abscissa.

Figure 3

Liver D1 and Gstα2 and serum cholesterol at baseline and during treatment with l-T₄ and DITPA. Data are expressed as mean ± se. Statistical differences between Wt and Mct8KO mice for each treatment group are indicated above the Mct8KO bars. Lack of statistical difference from the values in Wt mice at baseline are indicated below each value bar as NS (not significant). Treatment with LoI/MMI/ClO₄ is simply indicated as minimum maintenance dose of thiamazole (MMI) on the abscissa. Serum cholesterol was measured only in animals that received the higher dose of l-T₄ and DITPA. Note that the higher dose of l-T₄, which partially corrected the TH deprivation of brain in Mct8KO mice, caused thyrotoxic effects in the liver of mice of both genotypes. DITPA, however, corrected the effects of TH deprivation in brain of Mct8KO mice without causing thyrotoxicity.

Figure 4

Effect of DITPA in mice without prior depletion of endogenous TH assessed by measurement of D2 and D1 enzymatic activity in brain (A) and liver (B), respectively. Data are expressed as mean ± SE. Lack of statistical difference from the values in Wt mice at baseline are indicated below each value bar as NS (not significant). The higher dose corrected the effect of TH deficiency on D2 in brain of Mct8KO mice and corrected the thyrotoxic effect on D1 in Mct8KO mice.

Figure 5

Effect of DITPA on suppression of endogenous T₄ and TSH in untreated mice. Data are expressed as mean ± se. Statistical differences between Wt and Mct8KO mice for each treatment group are indicated above the Mct8KO bars. Lack of statistical difference from the values in Wt mice at baseline are indicated below each value bar as NS (not significant). At baseline serum T₄ was lower in Mct8KO than Wt mice. T₄ and TSH declined with the administration of DITPA in both genotypes. The absolute value of TSH reached was not statistically different between the two genotypes.