Thyroid hormone transporters—functions and clinical implications

Abstract

The cellular influx and efflux of thyroid hormones are facilitated by transmembrane protein transporters. Of these transporters, monocarboxylate transporter 8 (MCT8) is the only one specific for the transport of thyroid hormones and some of their derivatives. Mutations in SLC16A2, the gene that encodes MCT8, lead to an X-linked syndrome with severe neurological impairment and altered concentrations of thyroid hormones. Histopathological analysis of brain tissue from patients who have impaired MCT8 function indicates that brain lesions start prenatally, and are most probably the result of cerebral hypothyroidism. A Slc16a2 knockout mouse model has revealed that Mct8 is an important mediator of thyroid hormone transport, especially T3, through the blood-brain barrier. However, unlike humans with an MCT8 deficiency, these mice do not have neurological impairment. One explanation for this discrepancy could be differences in expression of the T4 transporter OATP1C1 in the blood-brain barrier; OATP1C1 is more abundant in rodents than in primates and permits the passage of T4 in the absence of T3 transport, thus preventing full cerebral hypothyroidism. In this Review, we discuss the relevance of thyroid hormone transporters in health and disease, with a particular focus on the pathophysiology of MCT8 mutations.

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

“…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.…”

Thyroid hormone metabolism in innate immune cells

“…The other transporters are also capable of transporting additional substances including steroids and amino acids (Bernal et al 2015). Studies on transgenic mouse models and observations in patients with pathogenic mutations in TH transporters indicate that MCT8, MCT10 and OATP1C1 are the main transporters of (patho)physiological importance to TH transport in vivo (Bernal et al 2015, Visser 2016). MCT8 preferentially transports T 4 , whereas MCT10 preferentially transports T 3 (Visser 2016).…”

“…MCT8 preferentially transports T 4 , whereas MCT10 preferentially transports T 3 (Visser 2016). OATP1C1 transports T 3 , T 4 and rT 3 with high specificity; however, it has the lowest affinity for T 4 out of these transporters (Pizzagalli et al 2002, Bernal et al 2015, Visser 2016. Transporter expression is cell type-specific and differences in distribution have been observed between humans and rodents (Bernal et al 2015).…”

“…There are several families of TH transporters including organic anion transporter polypeptides (OATP), monocarboxylate transporters (MCT) and large neutral amino acid transporters (LAT) (Bernal et al 2015, Visser 2016. Of these transporters, MCT8 is the only one to transport TH exclusively.…”

Role of co-regulators in metabolic and transcriptional actions of thyroid hormone

“…Type 1 and type 2 5ʹ-deiodinases (DIO1 and DIO2) convert T 4 into active T 3 , and type 3 5ʹ-deiodinase (DIO3) inactivates T 4 and T 3 to form reverse T 3 and T 2 , respectively (Arrojo et al 2013, Charalambous & Hernandez 2013, Gereben et al 2008. Actions of deiodinases and transporters are crucial for normal maintenance of both intracellular and circulating TH levels, as well as function of HPT axis (Bernal et al 2015, Fonseca et al 2013, Hernandez et al 2007, Heuer & Visser 2013, Hoftijzer et al 2011, Schweizer & Kohrle 2013. Physiological effects of TH are largely mediated by regulation of gene transcription by TH receptors (TRs): ligand-dependent transcription factors that belong to the nuclear receptor (NR) superfamily.…”