Abstract
Thyroid hormones influence gene expression in virtually all vertebrate tissues. Precise regulation of the active endogenous ligand, 3,5,3'-triiodothyronine (T3), is achieved by the sequential removal of iodine moieties from the thyroid hormone molecule. Type III iodothyronine deiodinase (D3) is the major inactivating enzyme terminating the action of T3 and preventing activation of the prohormone, thyroxine (T4). Recent studies have revealed the induction of high D3 activity in diverse animal models of tissue injury including starvation, cryolesion, cardiac hypertrophy, infarction, and chronic inflammation. By analyzing serum and tissues taken from hospitalized patients at the time of death, investigators have also documented the robust induction of D3 activity in several human tissues that normally have none, including the liver and skeletal muscle, and shown clinically relevant consequences to systemic thyroid status. These studies reveal a novel role of D3 in the tissue response to injury and in the derangement of thyroid hormone homeostasis commonly observed during critical illness.
Key Points
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The low-T3 syndrome is multifactorial, with evidence that decreased glandular secretion, decreased T4 activation, and increased thyroid hormone inactivation all contribute
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Type III iodothyronine deiodinase (D3) is normally undetectable in mature tissues, but its expression is re-activated in diverse cell types in response to injury
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D3 re-activation during illness is associated with a fall in serum T3 levels
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Additional studies are required to identify the molecular mechanisms that regulate the re-activation of D3 during illness and the functional consequence of D3-mediated local hypothyroidism to injured tissues
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Acknowledgements
The authors are supported by grants DK58538, DK65055, DK77148, and DK76099 from the National Institutes of Health, and the Doris Duke Clinical Scientist Development Award from the Doris Duke Charitable Foundation. We thank Scott Ribich for his helpful comments and the design of Figure 1.
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Huang, S., Bianco, A. Reawakened interest in type III iodothyronine deiodinase in critical illness and injury. Nat Rev Endocrinol 4, 148–155 (2008). https://doi.org/10.1038/ncpendmet0727
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DOI: https://doi.org/10.1038/ncpendmet0727
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