Human type 1 Iodothyronine deiodinase (DIO1) mutations cause abnormal thyroid hormone metabolism

Thyroid hormone is essential for the normal function of virtually all tissues. The iodothyronine deiodinases catalyze the removal of an iodine residue from the pro-hormone thyroxine (T4) molecule, thus producing either the active form triiodothyronine (T3; activation) or inactive metabolites (reverse T3; inactivation). Type I deiodinase (D1) catalyzes both reactions. Over the last years, several studies have attempted to understand the mechanisms of D1 function, underlying its effects on normal thyroid hormone metabolism and pathological processes. Although peripheral D1-generated T3 production contributes to a portion of plasma T3 in euthyroid state, pathologically increased thyroidal D1 activity seems to be the main cause of the elevated T3 concentrations observed in hyperthyroid patients. On the other hand, D1-deficient mouse models show that, in the absence of D1, inactive and lesser iodothyronines are excreted in feces with the loss of associated iodine, demonstrating the scavenging function for D1 that might be particularly important in an iodine deficiency setting. Polymorphisms in the DIO1 gene have been associated with changes in serum thyroid hormone levels, whereas decreased D1 activity has been reported in the nonthyroid illness syndrome and in several human neoplasias. The current review aims at presenting an updated picture of the recent advances made in the biochemical and molecular properties of D1 as well as its role in human physiology.

Download Full-text

Lacking thyroid hormone receptor β gene does not influence alterations in peripheral thyroid hormone metabolism during acute illness

Journal of Endocrinology ◽

10.1677/joe-07-0601 ◽

2008 ◽

Vol 197 (1) ◽

pp. 151-158 ◽

Cited By ~ 20

Author(s):

J Kwakkel ◽

O Chassande ◽

H C van Beeren ◽

W M Wiersinga ◽

A Boelen

Keyword(s):

Thyroid Hormone ◽

Hormone Receptor ◽

Thyroid Hormone Receptor ◽

Hormone Metabolism ◽

Thyroid Hormone Metabolism ◽

Males And Females ◽

Induced Changes ◽

Thyroid Hormone Receptor Β

The downregulation of liver deiodinase type 1 (D1) is supposed to be one of the mechanisms behind the decrease in serum tri-iodothyronine (T3) observed during non-thyroidal illness (NTI). Liver D1 mRNA expression is positively regulated by T3, mainly via the thyroid hormone receptor (TR)β1. One might thus expect that lacking the TRβ gene would result in diminished downregulation of liver D1 expression and a smaller decrease in serum T3 during illness. In this study, we used TRβ−/− mice to evaluate the role of TRβ in lipopolysaccharide (LPS, a bacterial endotoxin)-induced changes in thyroid hormone metabolism. Our results show that the LPS-induced serum T3 and thyroxine and liver D1 decrease takes place despite the absence of TRβ. Furthermore, we observed basal differences in liver D1 mRNA and activity between TRβ−/− and wild-type mice and TRβ−/− males and females, which did not result in differences in serum T3. Serum T3 decreased rapidly after LPS administration, followed by decreased liver D1, indicating that the contribution of liver D1 during NTI may be limited with respect to decreased serum T3 levels. Muscle D2 mRNA did not compensate for the low basal liver D1 observed in TRβ−/− mice and increased in response to LPS in TRβ−/− and WT mice. Other (TRβ independent) mechanisms like decreased thyroidal secretion and decreased binding to thyroid hormone-binding proteins probably play a role in the early decrease in serum T3 observed in this study.

Download Full-text

Further Characterization of Thyroid Hormone Response Elements in the Human Type 1 Iodothyronine Deiodinase Gene1

Endocrinology ◽

10.1210/endo.139.3.5849 ◽

1998 ◽

Vol 139 (3) ◽

pp. 1156-1163 ◽

Cited By ~ 29

Author(s):

Chen-Yu Zhang ◽

Sungwoo Kim ◽

John W. Harney ◽

P. Reed Larsen

Keyword(s):

Thyroid Hormone ◽

Hormone Response ◽

Iodothyronine Deiodinase ◽

Response Elements ◽

Hormone Response Elements ◽

Human Type

Download Full-text

Effects of concomitant selenium and vitamin E administration on thyroid hormone metabolism in broilers

Journal of the Hellenic Veterinary Medical Society ◽

10.12681/jhvms.15490 ◽

2018 ◽

Vol 68 (3) ◽

pp. 355

Author(s):

A. C. PAPPAS ◽

B. M. KOTSAMPASI ◽

K. KALAMARAS ◽

K. FEGEROS ◽

G. ZERVAS ◽

...

Keyword(s):

Vitamin E ◽

Thyroid Hormone ◽

Control Diet ◽

Dietary Treatment ◽

Tocopheryl Acetate ◽

Type I ◽

Hormone Metabolism ◽

Iodothyronine Deiodinase ◽

Thyroid Hormone Metabolism ◽

Diet Control

A total of 400, as hatched, broilers were used to investigate the effect of selenium (Se) and vitamin E supplementation on thyroid hormones metabolism. There were 5 replicates of 4 dietary treatments namely: control (C), a soybean meal maize basal diet with adequate Se and vitamin E (0.3 mg Se per kg diet and 80 mg vitamin E per kg diet), control diet with Se added (Se+, with an additional 1 mg of Se per kg of diet), control diet with vitamin E added (E+, with an additional 350 mg of vitamin E per kg of diet) and Se+E+ (with additional 1 mg of Se and 350 mg of vitamin E per kg of diet). Diets were isonitrogenous and isocaloric. Zinc L-selenomethionine complex was used to increase Se content and dl-α-tocopheryl acetate to increase vitamin E content. The experiment lasted 42 days. Plasma Se concentration increased in Se+ groups, while whole blood glutathione peroxidase (GPx) activity increased in Se+, E+ and Se+E+ groups compared to control. Hepatic type I iodothyronine deiodinase (ID-I) and thyroid hormone concentrations were unaffected by any dietary treatment. It is concluded that supplementation with Se or vitamin Ε alone or in combination above animal’s requirements does not affect thyroid hormone metabolism and liver ID-I activity under the conditions examined.

Download Full-text

Inhibition of type I and type II iodothyronine deiodinase activity in rat liver, kidney and brain produced by selenium deficiency

Biochemical Journal ◽

10.1042/bj2590887 ◽

1989 ◽

Vol 259 (3) ◽

pp. 887-892 ◽

Cited By ~ 75

Author(s):

G J Beckett ◽

D A MacDougall ◽

F Nicol ◽

J R Arthur

Keyword(s):

Body Weight ◽

Thyroid Hormone ◽

Feedback Inhibition ◽

Selenium Deficiency ◽

Stress Factors ◽

Type I ◽

Type Ii ◽

Hormone Metabolism ◽

Iodothyronine Deiodinase ◽

Thyroid Hormone Metabolism

Selenium deficiency for periods of 5 or 6 weeks in rats produced an inhibition of tri-iodothyronine (T3) production from added thyroxine (T4) in brain, liver and kidney homogenate. This inhibition was reflected in plasma T4 and T3 concentrations, which were respectively increased and decreased in selenium-deficient animals. Although plasma T4 levels increased in selenium-deficient animals, this did not produce the normal feedback inhibition on thyrotropin release from the pituitary. Selenium deficiency was confirmed in the animals by decreased selenium-dependent glutathione peroxidase (Se-GSH-Px) activity in all of these tissues. Administration of selenium, as a single intraperitoneal injection of 200 micrograms of selenium (as Na2SeO3)/kg body weight completely reversed the effects of selenium deficiency on thyroid-hormone metabolism and partly restored the activity of Se-GSH-Px. Selenium administration at 10 micrograms/kg body weight had no significant effect on thyroid-hormone metabolism or on Se-GSH-Px activity in any of the tissues studied. The characteristic changes in plasma thyroid-hormone levels that occurred in selenium deficiency appeared not to be due to non-specific stress factors, since food restriction to 75% of normal intake or vitamin E deficiency produced no significant changes in plasma T4 or T3 concentration. These data are consistent with the view that the Type I and Type II iodothyronine deiodinase enzymes are seleno-enzymes or require selenium-containing cofactors for activity.

Download Full-text