Thyroid Hormone Transporters

Thyroid hormone is essential for the development of the brain and the nervous system. Cellular entry is required for conversion of thyroid hormones by the intracellular deiodinases and for binding of T3 to its nuclear receptors. Several transporters capable of thyroid hormone transport have been identified. Functional expression studies using Xenopus laevis oocytes have so far identified two categories of transporters involved in thyroid hormone uptake (i.e., organic anion transporters and amino acid transporters). Among the organic anion transporters, both Na+{plus 45 degree rule}taurocholate cotransporting polypeptide (NTCP) and various members of the organic anion transporting polypeptide (OATP) family mediate transport of iodothyronines. Because iodothyronines are a particular class of amino acids derived from tyrosine residues, it is no surprise that some amino acid transporters have been shown to be involved in thyroid hormone transport. We have characterized monocarboxylate transporter 8 (MCT8) as a very active and specific thyroid hormone transporter, the gene of which is located on the X chromosome. MCT8 is highly expressed in liver and brain but is also widely distributed in other tissues. MCT8 shows 50% amino acid identity with a system T amino acid transporter 1 (TAT1). TAT1, also called MCT10, has been characterized to transport aromatic amino acids but no iodothyronines. We have also found that mutations in MCT8 are associated with severe X-linked psychomotor retardation and strongly elevated serum T3 levels in young boys

In vitro and mouse studies support therapeutic utility of triiodothyroacetic acid in MCT8 deficiency

International audienceMCT8 transports thyroid hormone (TH) across the plasma membrane. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome (AHDS), comprising severe psychomotor retardation and elevated serum T3 levels. As the neurological symptoms are most likely caused by a lack of TH transport into the CNS, the administration of a TH analogue which does not require MCT8 for cellular uptake may represent a therapeutic strategy. Here, we investigated the therapeutic potential of the biologically active T3 metabolite Triac (TA3) by studying TA3 transport, metabolism and action both in vitro and in vivo. Incubation of SH-SY5Y neuroblastoma cells and MO3.13 oligodendrocytes with labeled substrates showed a time-dependent uptake of T3 and TA3. In intact SH-SY5Y cells, both T3 and TA3 were degraded by endogenous type 3 deiodinase, and they influenced gene expression to a similar extent. Fibroblasts from MCT8 patients showed an impaired T3 uptake compared to controls, whereas TA3 uptake was similar in patient and control fibroblasts. In transfected cells, TA3 did not show significant transport by MCT8. Most importantly, treatment of athyroid Pax8 knockout mice and Mct8/Oatp1c1 double knockout mice between postnatal day 1 and 12 with TA3 restored T3-dependent neural differentiation in the cerebral and cerebellar cortex indicating that TA3 can replace T3 in promoting brain development. In conclusion, we demonstrated uptake of TA3 in neuronal cells and in fibroblasts of MCT8 patients, and similar gene responses to T3 and TA3. This indicates that TA3 bypasses MCT8 and may be used to improve the neural status of MCT8 patients

Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability

Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis-Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tentatively identified as proteins with apparent molecular masses of 52 and 55 kDa. In different cells, such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblastoma cells, uptake of T4 and T3 appears to be mediated largely by system L or T amino acid transporters. Efflux of T3 from different cell types is saturable, but saturable efflux of T4 has not yet been demonstrated. Saturable uptake of T4 and T3 in the brain occurs both via the blood-brain barrier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several organic anion transporters and L type amino acid transporters have been shown to facilitate plasma membrane transport of thyroid hormone. Future research should be directed to elucidate which of these and possible other transporters are of physiological significance, and how they are regulated at the molecular level.</p

Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability

Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis-Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tentatively identified as proteins with apparent molecular masses of 52 and 55 kDa. In different cells, such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblastoma cells, uptake of T4 and T3 appears to be mediated largely by system L or T amino acid transporters. Efflux of T3 from different cell types is saturable, but saturable efflux of T4 has not yet been demonstrated. Saturable uptake of T4 and T3 in the brain occurs both via the blood-brain barrier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several organic anion transporters and L type amino acid transporters have been shown to facilitate plasma membrane transport of thyroid hormone. Future research should be directed to elucidate which of these and possible other transporters are of physiological significance, and how they are regulated at the molecular level

Plasma membrane transport of thyroid hormones and its role in thyroid hormone metabolism and bioavailability

Although it was originally believed that thyroid hormones enter target cells by passive diffusion, it is now clear that cellular uptake is effected by carrier-mediated processes. Two stereospecific binding sites for each T4 and T3 have been detected in cell membranes and on intact cells from humans and other species. The apparent Michaelis-Menten values of the high-affinity, low-capacity binding sites for T4 and T3 are in the nanomolar range, whereas the apparent Michaelis-Menten values of the low-affinity, high-capacity binding sites are usually in the lower micromolar range. Cellular uptake of T4 and T3 by the high-affinity sites is energy, temperature, and often Na+ dependent and represents the translocation of thyroid hormone over the plasma membrane. Uptake by the low-affinity sites is not dependent on energy, temperature, and Na+ and represents binding of thyroid hormone to proteins associated with the plasma membrane. In rat erythrocytes and hepatocytes, T3 plasma membrane carriers have been tentatively identified as proteins with apparent molecular masses of 52 and 55 kDa. In different cells, such as rat erythrocytes, pituitary cells, astrocytes, and mouse neuroblastoma cells, uptake of T4 and T3 appears to be mediated largely by system L or T amino acid transporters. Efflux of T3 from different cell types is saturable, but saturable efflux of T4 has not yet been demonstrated. Saturable uptake of T4 and T3 in the brain occurs both via the blood-brain barrier and the choroid plexus-cerebrospinal fluid barrier. Thyroid hormone uptake in the intact rat and human liver is ATP dependent and rate limiting for subsequent iodothyronine metabolism. In starvation and nonthyroidal illness in man, T4 uptake in the liver is decreased, resulting in lowered plasma T3 production. Inhibition of liver T4 uptake in these conditions is explained by liver ATP depletion and increased concentrations of circulating inhibitors, such as 3-carboxy-4-methyl-5-propyl-2-furan-propanoic acid, indoxyl sulfate, nonesterified fatty acids, and bilirubin. Recently, several organic anion transporters and L type amino acid transporters have been shown to facilitate plasma membrane transport of thyroid hormone. Future research should be directed to elucidate which of these and possible other transporters are of physiological significance, and how they are regulated at the molecular level.</p

Multiple effects of cold exposure on livers of male mice

Cold exposure of mice is a common method to stimulate brown adipose tissue (BAT) activity and induce browning of white adipose tissue (WAT) that has beneficial effects on whole-body lipid metabolism, including reduced plasma triglyceride (TG) concentrations. The liver is a key regulatory organ in lipid metabolism as it can take up as well as oxidize fatty acids. The liver can also synthesize, store and secrete TGs in VLDL particles. The effects of cold exposure on murine hepatic lipid metabolism have not been addressed. Here, we report the effects of 24-h exposure to 4°C on parameters of hepatic lipid metabolism of male C57BL/6J mice. Cold exposure increased hepatic TG concentrations by 2-fold (P < 0.05) but reduced hepatic lipogenic gene expression. Hepatic expression of genes encoding proteins involved in cholesterol synthesis and uptake such as the LDL receptor (LDLR) was significantly increased upon cold exposure. Hepatic expression of Cyp7a1 encoding the rate-limiting enzyme in the classical bile acid (BA) synthesis pathway was increased by 4.3-fold (P < 0.05). Hepatic BA concentrations and fecal BA excretion were increased by 2.8- and 1.3-fold, respectively (P < 0.05 for both). VLDL-TG secretion was reduced by approximately 50% after 24 h of cold exposure (P < 0.05). In conclusion, cold exposure has various, likely intertwined effects on the liver that should be taken into account when studying the effects of cold exposure on wholebody metabolism.</p