Adaptive changes in transmembrane transport and metabolism of triiodothyronine in perfused livers of fed and fasted hypothyroid and hyperthyroid rats

Jong, Marion de; Docter, R.; Hoek, Hans van der; Krenning, Eric P.; Hennemann, G

doi:10.1016/0026-0495(94)90027-2

Cited by 9 publications

(5 citation statements)

References 38 publications

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“…Previous observations with the use of isolated perfused rat liver indicate that hepatic uptake of T 3 is decreased in hyperthyroid animals (7), whereas the present findings suggest no effect of hyperthyroidism on hepatic T 4 uptake. A different regulation of hepatic uptake of T 4 and T 3 is consistent with the existence of separate transporters for T 4 and T 3 (22,29).…”

Section: Discussioncontrasting

confidence: 85%

“…Both in humans and in rats, the liver plays a major role in plasma T 3 production (13). Previous experiments in our laboratory have shown that liver uptake of T 3 is decreased in hyperthyroid rats (7). The aim of this study was to investigate whether thyroid state influences the mRNA levels for hepatic T 4 transporter(s) by use of the X. laevis oocyte expression system.…”

Section: Discussionmentioning

confidence: 99%

“…Most publications point to the Na ϩ gradient, temperature, and energy dependence of the transport mechanisms and their inhibition by thyroid hormone analogs (11,13,(21)(22)(23)27). Because the hepatic T 3 production depends on the intracellular T 4 concentration, regulation of T 4 transport is potentially important in the determination of plasma T 3 production in addition to changes in D1 activity during pathophysiological circumstances (7,13,(21)(22)(23).…”

mentioning

confidence: 99%

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Effects of thyroid state on the expression of hepatic thyroid hormone transporters in rats

Peeters¹,

Friesema²,

Docter³

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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Liver uptake of thyroxine (T4) is mediated by transporters and is rate limiting for hepatic 3,3',5-triiodothyronine (T3) production. We investigated whether hepatic mRNA for T4 transporters is regulated by thyroid state using Xenopus laevis oocytes as an expression system. Because X. laevis oocytes show high endogenous uptake of T4, T4 sulfamate (T4NS) was used as an alternative ligand for the hepatic T4 transporters. Oocytes were injected with 23 ng liver mRNA from euthyroid, hypothyroid, or hyperthyroid rats, and after 3-4 days uptake was determined by incubation of injected and uninjected oocytes for 1 h at 25 degrees C or for 4 h at 18 degrees C with 10 nM [125I]T4NS. Expression of type I deiodinase (D1), which is regulated by thyroid state, was studied in the oocytes as an internal control. Uptake of T4NS showed similar approximately fourfold increases after injection of liver mRNA from euthyroid, hypothyroid, or hyperthyroid rats. A similar lack of effect of thyroid state was observed using reverse T3 as ligand. In contrast, D1 activity induced by liver mRNA from hyperthyroid and hypothyroid rats in the oocytes was 2.4-fold higher and 2.7-fold lower, respectively, compared with euthyroid rats. Studies have shown that uptake of iodothyronines in rat liver is mediated in part by several organic anion transporters, such as the Na+/taurocholate-cotransporting polypeptide (rNTCP) and the Na-independent organic anion-transporting polypeptide (rOATP1). Therefore, the effects of thyroid state on rNTCP, rOATP1, and D1 mRNA levels in rat liver were also determined. Northern analysis showed no differences in rNTCP or rOATP1 mRNA levels between hyperthyroid and hypothyroid rats, whereas D1 mRNA levels varied widely as expected. These results suggest little effect of thyroid state on the levels of mRNA coding for T4 transporters in rat liver, including rNTCP and rOATP1. However, they do not exclude regulation of hepatic T4 transporters by thyroid hormone at the translational and posttranslational level.

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Section: Discussioncontrasting

confidence: 85%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Effects of thyroid state on the expression of hepatic thyroid hormone transporters in rats

Peeters¹,

Friesema²,

Docter³

et al. 2002

American Journal of Physiology-Endocrinology and Metabolism

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“…These data suggest an adaptation mechanism at the cellular level to maintain tissue T3 levels when T3 supply is abnormal (198). When expression of mRNA of thyroid hormone transporters in rat liver was studied, using Xenopus laevis oocytes as expression system, no thyroid state-dependent differences were seen in the expression of these transporters, not excluding, however, any regulation of transporter activity at the translational or post-translational level (199).…”

Section: Plasma Membrane Transport Is Subject To Regulationmentioning

confidence: 87%

Thyroid hormone transporters

Friesema

Jansen

Visser

2005

Biochemical Society Transactions

106

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Thyroid hormone is important for development of various tissues, in particular brain, and for regulation of metabolic processes throughout life. The follicular cells of the thyroid gland produce predominantly T4 (thyroxine), but the biological activity of thyroid hormone is largely exerted by T3 (3,3',5-tri-iodothyronine). The deiodinases involved in T4-to-T3 conversion or T4 and T3 degradation, as well as the T3 receptors, are located intracellularly. Therefore the action and metabolism of thyroid hormone require transport of iodothyronines across the cell membrane via specific transporters. Recently, a number of transporters capable of cellular uptake of iodothyronines have been identified. The most specific transporters identified so far are OATP1C1 and MCT8, which appear to be involved in T4 transport across the blood-brain barrier, and in T3 transport into brain neurons, respectively. The MCT8 gene is located on human chromosome Xq13, and mutations in MCT8 are associated with X-linked severe psychomotor retardation and elevated serum T3 levels.

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“…In livers of hyperthyroid rats, uptake of T 3 was decreased and T 3 metabolism was increased. These data suggest an adaptation mechanism at the cellular level to maintain tissue T 3 levels when T 3 supply is abnormal (198). When expression of mRNA of thyroid hormone transporters in rat liver was studied, using Xenopus laevis oocytes as the expression system, no thyroid state-dependent differences were seen in the expression of these transporters, not excluding, however, any regulation of transporter activity at the translational or posttranslational level (199).…”

Section: Plasma Membrane Transport Is Subject To Regulationmentioning

confidence: 87%

Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability

et al. 2001

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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-furanpropanoic 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.

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Adaptive changes in transmembrane transport and metabolism of triiodothyronine in perfused livers of fed and fasted hypothyroid and hyperthyroid rats

Cited by 9 publications

References 38 publications

Effects of thyroid state on the expression of hepatic thyroid hormone transporters in rats

Effects of thyroid state on the expression of hepatic thyroid hormone transporters in rats

Thyroid hormone transporters

Plasma Membrane Transport of Thyroid Hormones and Its Role in Thyroid Hormone Metabolism and Bioavailability

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