Thyroid hormone action
- Gregory A Brent, MD
Gregory A Brent, MD
- Professor of Medicine and Physiology
- David Geffen School of Medicine at UCLA
Thyroid hormones are critical determinants of brain and somatic development in infants and of metabolic activity in adults; they also affect the function of virtually every organ system. Thyroid hormones must be constantly available to perform these functions. To maintain their availability, there are large stores of thyroid hormone in the thyroid gland. Furthermore, thyroid hormone biosynthesis and secretion are maintained within narrow limits by a regulatory mechanism that is very sensitive to small changes in circulating hormone concentrations.
Thyroid hormone, in the form of triiodothyronine (T3), acts by modifying gene transcription in virtually all tissues to alter rates of protein synthesis and substrate turnover [1,2]. These actions are the net result of the presence of T3 and of multiple other factors that amplify or reduce its action (figure 1A-B). The actions of T3 will be reviewed here. The production of T3 and its precursor thyroxine (T4) and how their production is regulated are discussed elsewhere (see "Thyroid hormone synthesis and physiology"). Extranuclear actions of T4 and T3 have been increasingly recognized and are mediated by interactions with membranes receptors, organelles, and components of the signal transduction system [3,4].
DETERMINANTS OF T3 ACTION
The nuclear actions of triiodothyronine (T3) are dependent upon four factors: the availability of the hormone, thyroid hormone nuclear receptors (TRs), receptor cofactors, and DNA regulatory elements.
Ligand availability — Thyroid hormone synthesis and secretion from the thyroid gland are regulated by pituitary thyroid-stimulating hormone (TSH) (see "Thyroid hormone synthesis and physiology"). Circulating thyroxine (T4) and T3 enter cells by diffusion and, in some tissues, such as the thyroid and brain, by active transport . An inherited defect in the MCT8 thyroid transporter has been associated with alterations of circulating thyroid hormone levels, due to reduced transport of thyroid hormone out of the thyroid , and severely impaired neurologic development in boys, due to reduced transport of T3 into neurons .
T3 is also available to cells because it is produced from T4 within them. The locally produced T3, some of which leaves the cells, provides much of the T3 that is bound to T3 nuclear receptors in many tissues. Overall, about 80 percent of circulating T3 in humans is derived from extrathyroidal conversion of T4 to T3, and about 20 percent from direct thyroidal secretion .
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- DETERMINANTS OF T3 ACTION
- Ligand availability
- Thyroid hormone nuclear receptors
- Receptor cofactors
- DNA regulatory elements
- THYROID HORMONE ACTIONS DURING DEVELOPMENT
- Ligand availability during fetal development
- Expression pattern of TR isoforms
- TISSUE-SPECIFIC THYROID HORMONE ACTION
- Tissue-specific expression of TR isoforms
- TR cofactors
- DNA response elements
- Tissue-specific expression of thyroid hormone deiodinases
- THYROID HORMONE ACTION IN BONE, HEART, AND REGULATION OF METABOLISM
- Bone and bone development
- Cardiac gene expression
- Regulation of metabolism
- AGENTS THAT MAY INTERFERE WITH THYROID HORMONE ACTION
- CLINICAL APPLICATIONS
- Clinical markers of thyroid hormone action
- Selective thyroid hormone analogs