Distinct Tissue-Specific Roles for Thyroid Hormone Receptors β and α1 in Regulation of Type 1 Deiodinase Expression
Open accessAbstract
Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to control levels of T3, the active ligand for thyroid hormone receptors (TR). The D1 gene is itself T3-inducible and here, the regulation of D1 expression by TRα1 and TRβ, which act as T3-dependent transcription factors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TRβ−/− but not TRα1−/− mice. Liver D1 remained weakly T3 inducible in TRβ–/– mice whereas induction was abolished in double mutant TRα1–/–TRβ–/– mice. This indicates that TRβ is primarily responsible for regulating D1 expression whereas TRα1 has only a minor role. In kidney, despite the expression of both TRα1 and TRβ, regulation relied solely on TRβ, thus revealing a marked tissue restriction in TR isotype utilization. Although TRβ and TRα1 mediate similar functions in vitro, these results demonstrate differential roles in regulating D1 expression in vivo and suggest that tissue-specific factors and structural distinctions between TR isotypes contribute to functional specificity. Remarkably, there was an obligatory requirement for a TR, whether TRβ or TRα1, for any detectable D1 expression in liver. This suggests a novel paradigm of gene regulation in which the TR sets both basal expression and the spectrum of induced states. Physiologically, these findings suggest a critical role for TRβ in regulating the thyroid hormone status through D1-mediated metabolism.
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Decreased TR or/and reduced RXR expression may play a role in the downregulation of hepatic DIO1 during NTIS.
“The Dio1 gene is positively regulated via a TR/RXR heterodimer which suggests that decreased TR or/and reduced RXR expression may play a role in the downregulation of hepatic DIO1 during NTIS [76].”
From An update on non-thyroidal illness syndrome (2021) · cites this paper as [76]
The TR Gene Expression section identifies TR–RXR complexes bound to DNA, and the D1 Abnormalities section reports markedly reduced hepatic D1 expression in TR-deficient mice (page numbers unavailable). These findings support the proposed role of TR in hepatic D1 regulation, but the paper does not test reduced RXR expression or downregulation during NTIS. (LLM, conf=0.87)
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- Authors
- Amma, L. L., Campos-Barros, A., Wang, Z., Vennström, B., & Forrest, D.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Department of Human Genetics (L.L.A., A.C.-B., Z.W., D.F.) Mount Sinai School of Medicine New York, New York 10029
- Laboratory of Developmental Biology (B.V.) CMB, Karolinska Institute Stockholm, S-17 177, Sweden
- Venue
- Molecular Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2001-03-01
- Volume
- 15
- Issue
- 3
- Pages
- 467-475
- ISSN
- 0888-8809 (ISSN-L)
- 1944-9917
- OpenAlex
- W2052640431
- Cited by
- 94
- References
- 1
- Citations by year
- 2023: 1 · 2022: 1 · 2021: 4 · 2020: 1 · 2019: 1 · 2018: 3 · 2017: 5 · 2016: 3 · 2015: 3 · 2014: 1 · 2013: 3 · 2012: 6
- FWCI
- 4.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Molecular Endocrinology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- March of Dimes Foundation
- Swedish Cancer Foundation
- National Institutes of Health
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007105)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Estrogen and related hormone effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Cancer Diagnosis and Treatment
- Keywords
- thyroid hormone receptor beta, thyroid hormone receptor alpha 1, type I deiodinase, liver, kidney, thyroid hormone metabolism, basal gene expression
- MeSH terms
- Animals, Body Weight, Female, Hyperthyroidism, Hypothyroidism, Iodide Peroxidase, Kidney, Liver, Male, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Inbred Strains, Mice, Mutant Strains, Organ Specificity, Receptors, Thyroid Hormone, Triiodothyronine, Gene Expression Regulation, Enzymologic, Mice
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