Sub theme 1.4
Regulation of the bioactivity of thyroid hormone

Goals of research: general outline
Scientific achievements
Future plans: special goals and approach
Running projects
Associated staff

Workgroup leaders   Department
Dr.  E.B.  Baart   Obstetrics and Gynaecology
Dr.  J.S.E.  Laven   Obstetrics and Gynaecology
dr.  A.P.N.  Themmen   Internal Medicine

Goals of research: general outline

Thyroid hormone (TH) is essential for the development of virtually all tissues. The biological activity of TH is largely mediated by binding of the active hormone T3 to the nuclear T3 receptors TRα and TRβ. Three deiodinases (D1-3) and several TH transporters determine the availability of T3 for nuclear TRs. Defects in any of these proteins can have important consequences, as is illustrated by the severe psychomotor retardation in patients with inactivating mutations in MCT8, a TH transporter expressed in central neurons.

This subtheme concerns the characterization of the transporters, deiodinases and TH receptors involved, the study of their regulation in ageing and disease, and the consequences of genetic variation in these TH pathway genes.

Scientific achievements

a. (Patho)physiological role of thyroid hormone transporters

  • Identification of MCT8 as an active and specific TH transporter, facilitating both cellular TH uptake and efflux as well as intracellular TH metabolism
  • Demonstration that MCT8 is highly expressed in TH-sensitive neuron populations
  • Identification of mutations in MCT8 in patients with severe X-linked psychomotor retardation (Allan-Herndon-Dudley Syndrome, AHDS) and high serum T3 levels
  • Demonstration of the functional consequences of MCT8 mutations identified in AHDS patients with a clear genotype-phenotype relationship
  • Demonstration of beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8
  • Demonstration of abnormal TH metabolism in mice lacking MCT8
  • Demonstration of effective cellular uptake and efflux of TH by human MCT10
  • Demonstration that polymorphisms in the brain-specific TH transporter OATP1C1 are associated with fatigue and depression in hypothyroid patients
  • Demonstration that organic anion transporter OATP1B1 is an important factor in hepatic TH and estrogen transport and metabolism
  • Demonstration that the transporter OATP1C1 mediates transport of T4, T4S, and rT3 across the cell membrane and increases the availability of these substrates for intracellular deiodinases
  • Characterization of TH transport in human umbilical vein endothelial cells

b. Tissue-specific regulation of thyroid hormone bioactivity

  • Demonstration of major regulatory roles of iodothyronine deiodinases in different areas of the human developing brain
  • Demonstration of the importance of D1 in human metabolism, indicated by relations between genetic variations in D1 and circulating insulin-like growth factor I levels and body composition
  • Demonstration of the relation between serum TH in preterm infants and different indices of severity of intercurrent illness
  • Demonstration that polymorphisms in D2 are associated with circulating TH parameters
  • Demonstration that severe illness is associated with decreased expression of T3-generating D1 and increased expression of T3-degrading D3 in liver and muscle, both contributing to the low serum T3 (and high rT3) levels
  • Demonstration that serum rT3 and the T3/rT3 ratio are prognostic markers in critically ill patients
  • Demonstration that liver and muscle TH levels are decreased in critical illness
  • Demonstration that T4S levels are increased in critically ill patients as a result of a decreased hepatic D1 activity
  • Demonstration that low serum FT4 levels are associated with a better 4-yr survival in elderly subjects, suggesting an adaptive mechanism to prevent excessive catabolism
  • Demonstration that higher FT4 and rT3 levels are associated with brain atrophy on MRI in elderly subjects
  • Demonstration that substitution of serine for proline in the catalytic center of Xenopus D1 restores sensitivity to propylthiouracil inhibition
  • Demonstration that estradiol is one of the factors contributing to the induction of D3 activity in the pregnant uterus
  • Demonstration that genetic variation in the TSH receptor is associated with insulin resistance in elderly men
  • Demonstration that RXR receptor agonist bexarotene stimulates the peripheral metabolism of TH
  • Demonstration that serum TSH and a TSH receptor polymorphism are associated with femoral neck BMD in human subjects
  • Demonstration of a large induction of D3 expression after partial hepatectomy in the regenerating mouse and rat liver
  • Demonstration that high-normal thyroid function is associated with the risk of atrial fibrillation
  • Demonstration that a functional polymorphism in D1 is associated with enhanced potentiation of the antidepressant effect of sertraline by T3
  • Demonstration that human skeletal muscle D2 mRNA expression is modulated by fasting and insulin, but not by hypothyroidism
  • Demonstration that physiological TH levels regulate numerous skeletal muscle transcripts in humans
  • Demonstration that mutations in the iodotyrosine deiodinase gene result in hypothyroidism

Future plans: special goals and approach

a. (Patho)physiological role of thyroid hormone transporters

  • Characterization of thyroid state in a large cohort (~950 subjects) of patients with psychomotor retardation
  • Identification of mutations in candidate genes (D2, D3, MCT8, MCT10, OATP1C1, OATP1C1, etc) in patients with abnormal serum thyroid parameters
  • Study of the importance of different TH transporters for intracellular hormone availability
  • Localization of MCT8 expression in the human brain; importance of the long and short MCT8 protein variants
  • Study of the regulation of MCT8 expression in human cell lines
  • Development of strategies for the treatment of patients with MCT8 mutations
  • Development of tissue-specific TH agonists and antagonists based on the specificity of iodothyronine transporters in different tissues
  • Characterization of TH transport and metabolism in mice with single or combined inactivation of MCT8, MCT10 and OATP1C1

a. (Patho)physiological role of thyroid hormone transporters

  • Identification of patients with mutations in the alpha T3 receptor (TRa) by sequencing different groups of candidate patients
  • Demonstration of the role of TRa in vivo, using a genetic approach
  • Studying the importance of TRa for brain development, using different knock out mouse models
  • Studying the regulation of TRa in vitro
  • Further analysis of the tissue-specific regulation of the expression of the different deiodinases, TH receptors and transporters during development, illness and other (patho)physiological conditions
  • Identification of new TH pathway genes using genome wide association studies

Most recent publications

1.      Friesema ECH, Grueters A, Biebermann H, Krude H, von Moers A, Reeser M, Barrett TG, Mancilla EE, Svensson J, Kester MHA, Kuiper GGJM, Balkassmi S, Uitterlinden AG, Koehrle J, Rodien P, Halestrap AP, Visser TJ. Severe X-linked psychomotor retardation caused by mutations in a thyroid hormone transporter. Lancet 2004; 364: 1435-1437. (IF: 28.41)

2.      Peeters RP, van den Beld AW, Uitterlinden AG, Janssen JA, Lamberts SWJ, Visser TJ. A polymorphism in type I deiodinase (D1) is associated with circulating free IGF-I levels and body composition in humans. J Clin Endocrinol Metab 2005; 90: 256-263. (IF: 6.33)

3.      Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G. Serum rT3 and T3/rT3 are early prognostic markers in critically ill patients and are associated with post-mortem tissue deiodinase activities. J Clin Endocrinol Metab 2005 90:4559-4565. (IF: 6.33)

4.      Peeters RP, van der Geyten S, Wouters P, van Toor H, Kaptein E, Visser TJ, Van den Berghe G. Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 2005; 90: 6498-6507. (IF: 6.33)

5.      Jansen J, Friesema EC, Kester MH, Milici C, Reeser M, Gruters A, Barrett TG, Mancilla EE, Svensson J, Wemeau JL, Busi da Silva Canalli MH, Lundgren J, McEntagart ME, Hopper N, Arts WF, Visser TJ. Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine. J Clin Endocrinol Metab 2007; 92: 2378-2381. (IF: 6.33)

6.      van der Deure WM, Friesema ECH, de Jong FJ, de Rijke, de Jong FH, Uitterlinden AG, Breteler MM, Peeters RP, Visser TJ. Organic Anion Transporter 1B1: An Important Factor in Hepatic Thyroid Hormone and Estrogen Transport and Metabolism. Endocrinology 2008; 149:4695-4701. (IF: 4.95)

7.      Van der Deure WM, Hansen PS, Peeters RP, Kyvik KO, Friesema ECH, Hegeds L, Visser TJ. Thyroid hormone transport and metabolism by OATP1C1 and consequences of genetic variation. Endocrinology 2008; 149: 5307-5314. (IF: 4.95)

8.      Friesema ECH, Jansen J, Jachtenberg JW, Visser WE, Kester MHA, Visser TJ. Effective cellular uptake and efflux of thyroid hormone by human monocarboxylate transporter 10 (MCT10). Mol Endocrinol 2008; 22: 1357-1369. (IF: 5.39)

9.      Moreno JC, Klootwijk W, van Toor H, Gestel D, Pinto G, D'Alessandro M, Lger A, Goudie D, Polak M, Grters A, Visser TJ. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Eng J Med 358: 1811-1818 (2008). (IF: 50.02)

10.  Kester MHA, Toussaint MJM, Punt CA, Matondo R, Aarnio AA, Darras VM, Everts ME, de Bruin A, Visser TJ. Large induction of type III deiodinase expression after partial hepatectomy in the regenerating mouse and rat liver. Endocrinology 2009; 150: 540-545.