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

Caterina Di Cosmo, Xiao H. Liao, Alexandra M. Dumitrescu, Roy E Weiss, Samuel Refetoff

Research output: Contribution to journalArticle

61 Citations (Scopus)

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 T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent.Wetested 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-T4. As expected, physiological doses of L-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 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.

Original languageEnglish (US)
Pages (from-to)4450-4458
Number of pages9
JournalEndocrinology
Volume150
Issue number9
DOIs
StatePublished - Sep 2009
Externally publishedYes

Fingerprint

Iodide Peroxidase
Thyroid Hormones
Liver
Brain
Acids
Thyroid Hormone Receptors
Mutation
Membrane Transport Proteins
X Chromosome
Neurologic Manifestations
Serum
Thyroid Gland
Genotype
Cell Membrane
Hormones
Phenotype

ASJC Scopus subject areas

  • Endocrinology

Cite this

A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport. / Di Cosmo, Caterina; Liao, Xiao H.; Dumitrescu, Alexandra M.; Weiss, Roy E; Refetoff, Samuel.

In: Endocrinology, Vol. 150, No. 9, 09.2009, p. 4450-4458.

Research output: Contribution to journalArticle

Di Cosmo, Caterina ; Liao, Xiao H. ; Dumitrescu, Alexandra M. ; Weiss, Roy E ; Refetoff, Samuel. / A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport. In: Endocrinology. 2009 ; Vol. 150, No. 9. pp. 4450-4458.
@article{6e8e4151183546cd986a6c874e2cb443,
title = "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 T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent.Wetested 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-T4. As expected, physiological doses of L-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 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.",
author = "{Di Cosmo}, Caterina and Liao, {Xiao H.} and Dumitrescu, {Alexandra M.} and Weiss, {Roy E} and Samuel Refetoff",
year = "2009",
month = "9",
doi = "10.1210/en.2009-0209",
language = "English (US)",
volume = "150",
pages = "4450--4458",
journal = "Endocrinology",
issn = "0013-7227",
publisher = "The Endocrine Society",
number = "9",

}

TY - JOUR

T1 - A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport

AU - Di Cosmo, Caterina

AU - Liao, Xiao H.

AU - Dumitrescu, Alexandra M.

AU - Weiss, Roy E

AU - Refetoff, Samuel

PY - 2009/9

Y1 - 2009/9

N2 - 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 T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent.Wetested 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-T4. As expected, physiological doses of L-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 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.

AB - 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 T3 content and high deiodinase 2 (D2) activity, reflecting TH deprivation. In contrast and as in serum, liver T3 content is high, resulting in increased deiodinase 1 (D1), suggesting that in this tissue TH entry is Mct8 independent.Wetested 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-T4. As expected, physiological doses of L-T4 normalized serum TSH, brain D2, and liver D1 in Wt mice but not the Mct8KO mice. The higher dose of T4 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.

UR - http://www.scopus.com/inward/record.url?scp=69249115321&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=69249115321&partnerID=8YFLogxK

U2 - 10.1210/en.2009-0209

DO - 10.1210/en.2009-0209

M3 - Article

VL - 150

SP - 4450

EP - 4458

JO - Endocrinology

JF - Endocrinology

SN - 0013-7227

IS - 9

ER -