Schnellverweise

Expression of the selenoprotein Type III 5-Deiodinase Type is altered in hemangioma and other diseases

DEIODINASE, IODOTHYRONINE, TYPE III; DIO3; THYROXINE DEIODINASE, TYPE III; TXDI3;
IODOTHYRONINE DEIODINASE, PLACENTAL TYPE

Thyroid hormone is critical to the normal development of the human central nervous system. Salvatore et al. (1995) noted that, despite the presence of thyroxine (T4) and thyroid follicles in the fetal thyroid by 10 to 12 weeks of gestation, as well as the potential availability of maternal thyroid hormone, the free concentration of the active thyroid hormone T3 is less than half that of maternal levels up to the time of delivery. The physiologic rationale for this circumstance is not well understood, but the authors suggested that it is possible that 'normal' circulating T3 concentrations could have deleterious effects on immature tissues or could enhance the metabolic requirements of the fetus. There are 2 principal mechanisms by which the circulating fetal T3 concentration is maintained at low levels. One is that the type I iodothyronine deiodinase in fetal liver is expressed at lower levels relative to those in adult life. This reduces the extra thyroidal T3 supply from this source. The second important factor in maintaining low serum T3 concentrations is the expression of high levels of the type III deiodinase in placenta of all species examined. Type III iodothyronine deiodinase catalyzes the conversion of T4 and T3 to inactive metabolites. Salvatore et al. (1995) cloned human placental type III iodothyronine deiodinase (which they referred to as D3). It is a selenoenzyme, as evidenced by (1) the presence of an in-frame UGA codon at position 144; (2) the synthesis of a 32-kD (75)Se-labeled protein in D3 cDNA transfected cells; and (3) the presence of a selenocysteine insertion sequence element in the 3-prime untranslated region of an mRNA that is required for its expression. The authors stated that the D3 selenocysteine insertion sequence element is more potent than that found in the type I deiodinase or glutathione peroxidase gene, suggesting a high priority for selenocysteine incorporation into this enzyme. The conservation of this enzyme from Xenopus laevis tadpoles to humans implies an essential role for regulation of thyroid hormone inactivation during embryologic development.
Huang et al. (2000) reported the case of a 3-month-old infant with massive hepatic hemangiomas and primary hypothyroidism who needed very high doses of thyroid hormone to restore euthyroidism and normal thyrotropin secretion. This finding suggested that the rate of degradation of thyroid hormone was accelerated. They subsequently identified high levels of type III iodothyronine deiodinase activity in the hemangioma tissue. Normally present in the brain and placenta, this selenoenzyme catalyzes the conversion of thyroxine to reverse triiodothyronine and the conversion of triiodothyronine to 3,3-prime-diiodothyronine, both of which are biologically inactive. They then retrospectively analyzed other patients with hemangiomas and identified additional patients with similar histories and other hemangiomas with type III iodothyronine deiodinase activity.

By FISH, Hernandez et al. (1998) mapped the human DIO3 gene to 14q32 and the mouse Dio3 gene to 12F1.
See also DIO1 and DIO2.

References:
1. Hernandez, A.; Park, J. P.; Lyon, G. J.; Mohandas, T. K.; St. Germain, D. L.: Localization of the type 3 iodothyronine deiodinase (DIO3) gene to human chromosome 14q32 and mouse chromosome 12F1. Genomics 53: 119-121, 1998.
2. Huang, S. A.; Tu, H. M.; Harney, J. W.; Venihaki, M.; Butte, A. J.; Kozakewich, H. P. W.; Fishman, S. J.; Larsen, P. R.: Severe hypothyroidism caused by type 3 iodothyronine deiodinase in infantile hemangiomas. New Eng. J. Med. 343: 185-189, 2000.
3. Salvatore, D.; Low, S. C.; Berry, M.; Maia, A. L.; Harney, J. W.; Croteau, W.; St. German, D. L.; Larsen, P. R.: Type 3 iodothyronine deiodinase: cloning, in vitro expression, and functional analysis of the placental selenoenzyme. J. Clin. Invest. 96: 2421-2430, 1995

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Reduced activation and increased inactivation of thyroid hormone in tissues of critically ill patients

Peeters RP, Wouters PJ, Kaptein E, van Toor H, Visser TJ, Van den Berghe G.
Department of Internal Medicine, Erasmus University Medical Center, 3015 GE; Rotterdam, The Netherlands.
Clin Endocrinol Metab. 2003 Jul;88(7):3202-11.

Critical illness is often associated with reduced TSH and thyroid hormone secretion as well as marked changes in peripheral thyroid hormone metabolism, resulting in low serum T(3) and high rT(3) levels. To study the mechanism(s) of the latter changes, we determined serum thyroid hormone levels and the expression of the type 1, 2, and 3 iodothyronine deiodinases (D1, D2, and D3) in liver and skeletal muscle from deceased intensive care patients. To study mechanisms underlying these changes, 65 blood samples, 65 liver, and 66 skeletal muscle biopsies were obtained within minutes after death from 80 intensive care unit patients randomized for intensive or conventional insulin treatment. Serum thyroid parameters and the expression of tissue D1-D3 were determined. Serum TSH, T(4), T(3), and the T(3)/rT(3) ratio were lower, whereas serum rT(3) was higher than in normal subjects (P < 0.0001). Liver D1 activity was down-regulated and D3 activity was induced in liver and skeletal muscle. Serum T(3)/rT(3) ratio correlated positively with liver D1 activity (P < 0.001) and negatively with liver D3 activity (ns). These parameters were independent of the type of insulin treatment. Liver D1 and serum T(3)/rT(3) were highest in patients who died from severe brain damage, intermediate in those who died from sepsis or excessive inflammation, and lowest in patients who died from cardiovascular collapse (P < 0.01). Liver D3 showed an opposite relationship. Acute renal failure requiring dialysis and need of inotropes were associated with low liver D1 activity (P < 0.01 and P = 0.06) and high liver D3 (P < 0.01) and skeletal muscle D3 (P < 0.05) activity. Liver D1 activity was negatively correlated with plasma urea (P = 0.002), creatinine (P = 0.06), and bilirubin (P < 0.0001). D1 and D3 mRNA levels corresponded with enzyme activities (both P < 0.001), suggesting regulation of the expression of both deiodinases at the pretranslational level. This is the first study relating tissue deiodinase activities with serum thyroid hormone levels and clinical parameters in a large group of critically ill patients. Liver D1 is down-regulated and D3 (which is not present in liver and skeletal muscle of healthy individuals) is induced, particularly in disease states associated with poor tissue perfusion. These observed changes, in correlation with a low T(3)/rT(3) ratio, may represent tissue-specific ways to reduce thyroid hormone bioactivity during cellular hypoxia and contribute to the low T(3) syndrome of severe illness.

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New volume 347 of Methods in Enzymology (2002)

edited by L. Packer and H. Sies

contains up to date reviews on recent developments in the field of selenoprotein research:
VOLUME 347 Protein Sensors and Reactive Oxygen Species, Part A: Selenoproteins and Thioredoxin
Edited by Helmut Sies and Lester Packer
574 pp./ISBN: 0121822486

Several authors of the DFG Priority Programme Selenoproteins 1087 contributed to this new volume !

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New Link between selenoprotein and diabetes:

see: Diabetes 2002 Mar;51(3):880-3

Association between a novel variant of the human type 2 deiodinase gene Thr92Ala and insulin resistance: evidence of interaction with the Trp64Arg variant of the beta-3-adrenergic receptor.

by Mentuccia D, Proietti-Pannunzi L, Tanner K, Bacci V, Pollin TI, Poehlman ET, Shuldiner AR, Celi FS.
Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland, Baltimore, Maryland 21201, USA

Type I I 5'-deiodinase, a human selenoprotein is one of the key enzymes in thyroid hormone metabolism and activation of the prohormone L-thyroxine (T4) to the active hormone T3.
Thyroid hormone action is an important determinant of energy and glucose metabolism. T4 metabolism is regulated by the deiodinases of which type 2 5'-deiodinase is expressed in humans in skeletal muscle and brown adipose tissue, where its transcription is stimulated by the beta-3 adrenergic pathway.
The first human variant of the Type I I 5'-deiodinase strongly associates with insulin resistance and, in subjects with the Trp64Arg ADRB3 variant, an increased BMI, suggesting an interaction between these two common gene variants.

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New book on Trace Elements, Minerals and Vitamins

Hans Konrad Biesalski, Josef Köhrle, Klaus Schümann (Hrsg.)

Vitamine, Spurenelemente und Mineralstoffe - Prävention und Therapie mit Mikronährstoffen

2002, 820 Seiten, 250 Abbildungen,
ISBN 3131293713
Georg Thieme Verlag, Stuttgart & New York

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