The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

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Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

Thyroid hormones require transport across cell membranes to carry out their biological functions. The importance of transport for thyroid hormone signaling was highlighted by the discovery that inactivating mutations in the human monocarboxylate transporter-8 (MCT8) (SLC16A2) cause severe psychomotor retardation due to thyroid hormone deficiency in the central nervous system. It has been reported that Mct8 expression in the mouse brain is restricted to neurons, leading to the model that organic ion transporter polypeptide-14 (OATP14, also known as OATP1C1/SLCO1C1) is the primary thyroid hormone transporter at the blood-brain barrier, whereas MCT8 mediates thyroid hormone uptake into neurons. In contrast to these reports, we report here that in addition to neuronal expression, MCT8 mRNA and protein are expressed in cerebral microvessels in human, mouse, and rat. In addition, OATP14 mRNA and protein are strongly enriched in mouse and rat cerebral microvessels but not in human microvessels. In rat, Mct8 and ...

/pdf/expression-of-the-thyroid-hormone-transporters-4cm2t9a5h0.pdf

Expression of the Thyroid Hormone Transporters Monocarboxylate Transporter-8 (SLC16A2) and Organic Ion Transporter-14 (SLCO1C1) at the Blood-Brain Barrier

The syndromes of reduced sensitivity to thyroid hormone.

Thyroid hormone transport into cells requires plasma membrane transport proteins. Mutations in one of these, monocarboxylate transporter 8 (MCT8), have been identified as underlying cause for the Allan-Herndon-Dudley syndrome, an X-linked mental retardation in which the patients also present with abnormally high 3',3,5-triiodothyronine (T(3)) plasma levels. Mice deficient in Mct8 replicate the thyroid hormone abnormalities observed in the human condition. However, no neurological deficits have been described in mice lacking Mct8. Therefore, we subjected Mct8-deficient mice to a comprehensive immunohistochemical, neurological, and behavioral screen. Several behavioral abnormalities were found in the mutants. Interestingly, some of these behavioral changes are compatible with hypothyroidism, whereas others rather indicate hyperthyroidism. We thus hypothesized that neurons exclusively dependent on Mct8 are in a hypothyroid state, whereas neurons expressing other T(3) transporters become hyperthyroid, if they are exposed directly to the high plasma T(3). The majority of T(3) uptake in primary cortical neurons is mediated by Mct8, but pharmacological inhibition suggested functional expression of additional T(3) transporter classes. mRNAs encoding six T(3) transporters, including L-type amino acid transporters (LATs), were coexpressed with Mct8 in isolated neurons. We then demonstrated Lat2 expression in cultured neurons and throughout murine brain development. In contrast, LAT2 is expressed in microglia in the developing human brain during gestation, but not in neurons. We suggest that lack of functional complementation by alternative thyroid hormone transporters in developing human neurons precipitates the devastating neurodevelopmental phenotype in MCT8-deficient patients, whereas Mct8-deficient mouse neurons are functionally complemented by other transporters, for possibly Lat2.

https://www.jneurosci.org/content/jneuro/29/30/9439.full.pdf

Neuronal 3′,3,5-Triiodothyronine (T3) Uptake and Behavioral Phenotype of Mice Deficient in Mct8, the Neuronal T3 Transporter Mutated in Allan–Herndon–Dudley Syndrome

The thyroid hormone (TH) plays a significant role in diverse processes related to growth, development, differentiation, and metabolism. TH signaling modulates energy expenditure through both central and peripheral pathways. At the cellular level, the TH exerts its effects after concerted mechanisms facilitate binding to the TH receptor. In the hypothalamus, signals from a range of metabolic pathways, including appetite, temperature, afferent stimuli via the autonomic nervous system, availability of energy substrates, hormones, and other biologically active molecules, converge to maintain plasma TH at the appropriate level to preserve energy homeostasis. At the tissue level, TH actions on metabolism are controlled by transmembrane transporters, deiodinases, and TH receptors. In the modern environment, humans are susceptible to an energy surplus, which has resulted in an obesity epidemic and, thus, understanding the contribution of the TH to cellular and organism metabolism is increasingly relevant.

Thyroid hormone signaling in energy homeostasis and energy metabolism.

Context: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct X-linked phenotype of severe psychomotor retardation and consistently elevated T3 levels. Lack of MCT8 transport of T3 in neurons could explain the neurological phenotype. Objective: Our objective was to determine whether the high T3 levels could also contribute to some critical features observed in these patients. Results: A 16-yr-old boy with severe psychomotor retardation and hypotonia was hospitalized for malnutrition (body weight = 25 kg) and delayed puberty. He had tachycardia (104 beats/min), high SHBG level (261 nmol/liter), and elevated serum free T3 (FT3) level (11.3 pmol/liter), without FT4 and TSH abnormalities. A missense mutation of the MCT8 gene was present. Oral overfeeding was unsuccessful. The therapeutic effect of propylthiouracil (PTU) and then PTU plus levothyroxine (LT4) was tested. After PTU (200 mg/d), serum FT4 was undetectable, FT3 was reduced (3.1 pmol/liter) with high TSH levels (50.1 mU/li...

Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8.

Autoimmune and inflammatory thyroid diseases (Graves’ disease, subacute thyroiditis, chronic autoimmune thyroiditis) have been reported following SARS-CoV-2 vaccines but Graves’ orbitopathy (GO) post-COVID-19 vaccination is uncommon. We describe six new patients seen in Endocrinology Departments with Outpatient Clinics for GO following SARS-CoV-2 vaccines in France. After COVID-19 vaccination, GO was observed in six patients (three men, three women, mean age 53 ± 6 years) with a personal past history of Graves’ disease (5/6) or orbitopathy (4/6). New-onset (n = 2) or recurrence (n = 4) of GO was observed following mRNA vaccines after the first (3/6) or second (3/6) dose, with the mean time from vaccination to GO at 23.8 ± 10.4 days. In one patient, thyrotoxicosis was confirmed by increased free T4 and low TSH concentrations while others had normal TSH levels, during chronic levothyroxine treatment in three patients. Four patients had significant anti-TSH receptor antibodies levels. According to the severity and activity of GO, the patients were treated using selenium (n = 2), intravenous glucocorticoids (n = 2), teprotumumab (n = 1), tocilizumab (n = 2) and orbital decompression (n = 1) with a significant improvement in GO signs and symptoms observed by most patients. In this study, we report the main data from six new patients with GO following SARS-CoV-2 vaccines. Clinicians need to be aware of the risk of new-onset or recurrent GO in predisposed patients with autoimmune thyroid diseases after COVID-19 vaccination. This study should not raise any concerns regarding SARS-CoV-2 vaccination since the risk of COVID-19 undoubtedly outweighs the incidence of uncommon GO after SARS-CoV-2 vaccination. 

https://link.springer.com/content/pdf/10.1007/s40618-022-01955-8.pdf

M. Ladsous

Papers

Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8.

Graves’ orbitopathy post-SARS-CoV-2 vaccines: report on six patients