Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

Müller, Julia; Mayerl, Steffen; Visser, Theo J.; Darras, Veerle; Boelen, Anita; Frappart, Lucien; Mariotta, Luca; Verrey, François; Heuer, Heike

doi:10.1210/en.2013-1800

Cited by 76 publications

(75 citation statements)

References 38 publications

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“…The values which we obtained were in general higher than those observed by investigators who used immunological methods [12,13,14,15,24,25,26,27], possibly due to the higher accuracy of the MS technique. Galton et al [28] reported similar or higher concentrations in kidney and liver, but in that study the homogenates were incubated with β-glucuronidase and therefore tissue concentrations also included glucuronide conjugates of THs.…”

Section: Discussioncontrasting

confidence: 86%

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Effect of Hypothyroidism and Hyperthyroidism on Tissue Thyroid Hormone Concentrations in Rat

Donzelli¹,

Colligiani²,

Kusmic³

et al. 2016

Eur Thyroid J

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Background and Objective: The present study was aimed at determining the effects of experimental hypothyroidism and hyperthyroidism on tissue thyroid hormones by a mass spectrometry-based technique. Methods: Rats were subjected to propylthiouracil treatment or administration of exogenous triiodothyronine (T₃) or thyroxine (T₄). Tissue T₃ and T₄ were measured by liquid chromatography tandem mass spectrometry in the heart, liver, kidney, visceral and subcutaneous adipose tissue, and brain. Results: Baseline tissue T₃ and T₄ concentrations ranged from 0.2 to 20 pmol ∙ g^-1 and from 3 to 125 pmol ∙ g^-1, respectively, with the highest values in the liver and kidney, and the lowest values in the adipose tissue. The T₃/T₄ ratio (expressed as a percentage) was in the 7-20% range in all tissues except the brain, where it averaged 75%. In hypothyroidism, tissue T₃ was more severely reduced than serum free T₃, averaging 1-6% of the baseline versus 30% of the baseline. The extent of tissue T₃ reduction, expressed as percentage of the baseline, was not homogeneous (p < 0.001), with liver = kidney > brain > heart > adipose tissue. The tissue T₃/T₄ ratio significantly increased in all organs except the kidney, averaging 330% in the brain and 50-90% in the other tissues. By contrast, exogenous T₃ and T₄ administration produced similar increases in serum free T₃ and in tissue T₃, and the relative changes were not significantly different between different tissues. Conclusions: While the response to increased thyroid hormones availability was similar in all tissues, decreased thyroid hormone availability induced compensatory responses, leading to a significant mismatch between changes in serum and in specific tissues.

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Section: Discussioncontrasting

confidence: 86%

“…As a matter of fact, complex changes in serum and tissue TH concentrations have recently been described in mice showing MCT8 and/or MCT10 deficiency [27], although it has been reported that the thyroid state had little effect on the transcription of T 4 transporters, at least in the liver [36]. …”

Section: Discussionmentioning

confidence: 99%

Effect of Hypothyroidism and Hyperthyroidism on Tissue Thyroid Hormone Concentrations in Rat

Donzelli¹,

Colligiani²,

Kusmic³

et al. 2016

Eur Thyroid J

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“…Previous studies on adult Mct8-knockout mice showed that T3 levels were elevated not only in the liver but also in the kidney (15,16). In agreement with the findings observed in mice treated chronically with T3, TRb expression was significantly decreased in the liver but not in the kidney in Mct8-knockout mice (Fig.…”

Section: Adaptations During Hyperthyroidism and Withdrawal 855supporting

confidence: 89%

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

Ohba

Sinha

Singh

et al. 2017

Thyroid

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Background: Thyroid hormone (TH) has important roles in regulating hepatic metabolism. It was previously reported that most hepatic genes activated by a single triiodothyronine (T3) injection became desensitized after multiple injections, and that approximately 10% of target genes did not return to basal expression levels after T3 withdrawal, despite normalization of serum TH and thyrotropin (TSH) levels. To determine the possible mechanism(s) for desensitization and incomplete recovery of hepatic target gene transcription and their effects on metabolism, mRNA and/or protein expression levels of key regulators of TH action were measured, as well as metabolomic changes after chronic T3 treatment and withdrawal. Methods: Adult male mice were treated with daily injections of T3 (20 lg/100 g body weight) for 14 days followed by the cessation of T3 for 10 days. Livers were harvested at 6 hours, 24 hours, and 14 days after the first T3 injection, and at 10 days after withdrawal, and then analyzed by quantitative reverse transcription polymerase chain reaction, Western blotting, and metabolomics. Results: Although TH receptor (TRa and TRb) mRNAs decreased slightly after chronic T3 treatment, only TRb protein decreased before returning to basal expression level after withdrawal. The expression of other regulators of TH action was unchanged. TRb protein expression was also decreased in adult male monocarboxylate transporter-8 (Mct8)-knockout mice, an in vivo model of chronic intrahepatic hyperthyroidism. Previously, increased hepatic long-chain acylcarnitine levels were found after acute TH treatment. However, in this study, long-chain acylcarnitine levels were unchanged after chronic T3, and paradoxically increased after T3 withdrawal. Pathway analyses of the previous microarray results showed upregulation of lipogenic genes after acute T3 treatment and withdrawal. Phosphorylation of acetyl-CoA carboxylase also decreased after T3 withdrawal. Conclusions: Decreased hepatic TRb protein expression occurred after chronic T3 exposure in adult male wild-type and Mct8-knockout mice. Gene array pathway and metabolomics analyses showed abnormalities in hepatic lipogenic gene expression and acylcarnitine levels, respectively, after withdrawal, despite normalization of serum TSH and TH levels. These findings may help explain the variable clinical presentations of some patients during hyperthyroidism and recovery, since TRb protein, target gene expression, and metabolic adaptive changes can occur in individual tissues without necessarily being reflected by circulating TH and TSH concentrations.

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“…Mct8 has been reported to have a greater impact on TH efflux than influx in liver cells, as Mct8 -/y mice have higher T 3 content in liver and show upregulated Dio1 expression and activity [14][15][16] . Similarly Mct10 has been proposed to mediate TH efflux in liver tissue [16] . However, in our study the extent of regulation of both transporters remained in a significant range in livers of old mice only.…”

Section: Discussionmentioning

confidence: 99%

Differences in Mouse Hepatic Thyroid Hormone Transporter Expression with Age and Hyperthyroidism

et al. 2015

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Background: Clinical features of thyroid dysfunction vary with age, and an oligosymptomatic presentation of hyperthyroidism is frequently observed in the elderly. This suggests age modulation of thyroid hormone (TH) action, which may occur, for example, by alterations in TH production, metabolism and/or TH action in target organs. Objectives: In this paper, we address possible changes in TH transporter expression in liver tissues as a mechanism of age-dependent variation in TH action. Methods: Chronic hyperthyroidism was induced in 4- and 20-month-old C57BL6/NTac male mice (n = 8-10) by intraperitoneal injections of 1 µg/g body weight L-thyroxine (T₄) every 48 h over 7 weeks. Control animals were injected with PBS. Total RNA was isolated from liver samples for analysis of the TH transporter and TH-responsive gene expression. TH concentrations were determined in mice sera. Results: Baseline serum free T₄ (fT₄) concentrations were significantly higher in euthyroid young compared to old mice. T₄ treatment increased total T₄, fT₄ and free triiodothyronine to comparable concentrations in young and old mice. In the euthyroid state, TH transporter expression was significantly higher in old than in young mice, except for Mct8 and Oatp1a1 expression levels. Hyperthyroidism resulted in upregulation of Mct10, Lat1 and Lat2 in liver tissue, while Oatp1a1, Oatp1b2 and Oatp1a4 expression was downregulated. This effect was preserved in old animals. Conclusion: Here, we show age-dependent differences in TH transporter mRNA expression in the euthyroid and hyperthyroid state of mice focusing on the liver as a classical TH target organ.

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Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

Cited by 76 publications

References 38 publications

Effect of Hypothyroidism and Hyperthyroidism on Tissue Thyroid Hormone Concentrations in Rat

Effect of Hypothyroidism and Hyperthyroidism on Tissue Thyroid Hormone Concentrations in Rat

Changes in Hepatic TRβ Protein Expression, Lipogenic Gene Expression, and Long-Chain Acylcarnitine Levels During Chronic Hyperthyroidism and Triiodothyronine Withdrawal in a Mouse Model

Differences in Mouse Hepatic Thyroid Hormone Transporter Expression with Age and Hyperthyroidism

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