{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Type I iodothyronine deiodinase (DIO1) is a selenoenzyme that plays a central role in thyroid hormone metabolism by catalyzing the outer‐ring deiodination of thyroxine (T4) to generate the biologically active triiodothyronine (T3), thereby contributing significantly to the circulating T3 pool as well as to local T3 production in peripheral tissues (see, for example."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In human hepatocytes and other target cells, DIO1 expression is regulated at the pretranslational level by thyroid hormone itself and by additional factors such as retinoids and glucocorticoids; its promoter harbors specific T3‐responsive elements that facilitate autoregulation and cross‐talk with nuclear receptor pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Nutritional factors, particularly selenium availability, are critical for optimal DIO1 activity because the enzyme requires the rare amino acid selenocysteine in its active site, with deficiencies (or alterations in zinc or manganese status) resulting in diminished enzyme activity and altered thyroid hormone homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, DIO1 is subject to modulation by post‐translational mechanisms such as tyrosine phosphorylation, and its activity can be affected by pro‐inflammatory cytokines and environmental toxins; for instance, altered phosphorylation state, exposure to dioxins like TCDD, and changes in cytokine milieu in disease conditions such as nonthyroidal illness or hepatic cancers can lead to reduced DIO1 activity and thereby contribute to an abnormal T3/T4 profile."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " In addition, studies in both human and animal models indicate that pharmacological agents such as dexamethasone can enhance DIO1 mRNA expression via increased levels of its heterodimer partner RXRα, ultimately impacting T3 production"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and changes in circulating T3 levels in thyroidectomized rats have been shown to closely parallel hepatic DIO1 activity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these findings underscore the multifaceted regulation of DIO1—the enzyme not only activates thyroid hormone but is itself modulated by nutritional, endocrine, inflammatory, and environmental cues—highlighting its pivotal role in maintaining thyroid hormone balance and metabolic homeostasis.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J Köhrle "}, {"type": "b", "children": [{"type": "t", "text": "Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Acta Med Austriaca (1996)"}]}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "8767511"}], "href": "https://pubmed.ncbi.nlm.nih.gov/8767511"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "J Köhrle "}, {"type": "b", "children": [{"type": "t", "text": "Local activation and inactivation of thyroid hormones: the deiodinase family."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Endocrinol (1999)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0303-7207(99)00040-4"}], "href": "https://doi.org/10.1016/s0303-7207(99"}, {"type": "t", "text": "00040-4) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "10411325"}], "href": "https://pubmed.ncbi.nlm.nih.gov/10411325"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Madesh Belakavadi, Joseph D Fondell "}, {"type": "b", "children": [{"type": "t", "text": "Cyclin-dependent kinase 8 positively cooperates with Mediator to promote thyroid hormone receptor-dependent transcriptional activation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01541-09"}], "href": "https://doi.org/10.1128/MCB.01541-09"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20231357"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20231357"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "T C Jakobs, C Schmutzler, J Meissner, et al. 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