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 .
- Brent GA. Mechanisms of thyroid hormone action. J Clin Invest 2012; 122:3035.
- Cheng SY, Leonard JL, Davis PJ. Molecular aspects of thyroid hormone actions. Endocr Rev 2010; 31:139.
- Liu YY, Brent GA. Thyroid hormone crosstalk with nuclear receptor signaling in metabolic regulation. Trends Endocrinol Metab 2010; 21:166.
- Lin HY, Cody V, Davis FB, et al. Identification and functions of the plasma membrane receptor for thyroid hormone analogues. Discov Med 2011; 11:337.
- Bernal J, Guadaño-Ferraz A, Morte B. Thyroid hormone transporters--functions and clinical implications. Nat Rev Endocrinol 2015; 11:406.
- Di Cosmo C, Liao XH, Dumitrescu AM, et al. Mice deficient in MCT8 reveal a mechanism regulating thyroid hormone secretion. J Clin Invest 2010; 120:3377.
- Marsili A, Zavacki AM, Harney JW, Larsen PR. Physiological role and regulation of iodothyronine deiodinases: a 2011 update. J Endocrinol Invest 2011; 34:395.
- Gereben B, Zavacki AM, Ribich S, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008; 29:898.
- Shulman AI, Mangelsdorf DJ. Retinoid x receptor heterodimers in the metabolic syndrome. N Engl J Med 2005; 353:604.
- Chatonnet F, Picou F, Fauquier T, Flamant F. Thyroid hormone action in cerebellum and cerebral cortex development. J Thyroid Res 2011; 2011:145762.
- Stagnaro-Green A, Abalovich M, Alexander E, et al. Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and postpartum. Thyroid 2011; 21:1081.
- Moran C, Chatterjee K. Resistance to thyroid hormone due to defective thyroid receptor alpha. Best Pract Res Clin Endocrinol Metab 2015; 29:647.
- Astapova I, Hollenberg AN. The in vivo role of nuclear receptor corepressors in thyroid hormone action. Biochim Biophys Acta 2013; 1830:3876.
- Vennström B, Mittag J, Wallis K. Severe psychomotor and metabolic damages caused by a mutant thyroid hormone receptor alpha 1 in mice: can patients with a similar mutation be found and treated? Acta Paediatr 2008; 97:1605.
- Göthe S, Wang Z, Ng L, et al. Mice devoid of all known thyroid hormone receptors are viable but exhibit disorders of the pituitary-thyroid axis, growth, and bone maturation. Genes Dev 1999; 13:1329.
- Reutrakul S, Sadow PM, Pannain S, et al. Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor beta or alpha genes. J Clin Endocrinol Metab 2000; 85:3609.
- Hernandez A, Martinez ME, Fiering S, et al. Type 3 deiodinase is critical for the maturation and function of the thyroid axis. J Clin Invest 2006; 116:476.
- Weiss RE, Refetoff S. Effect of thyroid hormone on growth. Lessons from the syndrome of resistance to thyroid hormone. Endocrinol Metab Clin North Am 1996; 25:719.
- Bassett JH, Williams GR. Critical role of the hypothalamic-pituitary-thyroid axis in bone. Bone 2008; 43:418.
- Wojcicka A, Bassett JH, Williams GR. Mechanisms of action of thyroid hormones in the skeleton. Biochim Biophys Acta 2013; 1830:3979.
- Grais IM, Sowers JR. Thyroid and the heart. Am J Med 2014; 127:691.
- Brenta G, Danzi S, Klein I. Potential therapeutic applications of thyroid hormone analogs. Nat Clin Pract Endocrinol Metab 2007; 3:632.
- Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev 2014; 94:355.
- Mitchell CS, Savage DB, Dufour S, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest 2010; 120:1345.
- Haluzik M, Nedvidkova J, Bartak V, et al. Effects of hypo- and hyperthyroidism on noradrenergic activity and glycerol concentrations in human subcutaneous abdominal adipose tissue assessed with microdialysis. J Clin Endocrinol Metab 2003; 88:5605.
- Chidakel A, Mentuccia D, Celi FS. Peripheral metabolism of thyroid hormone and glucose homeostasis. Thyroid 2005; 15:899.
- Crunkhorn S, Patti ME. Links between thyroid hormone action, oxidative metabolism, and diabetes risk? Thyroid 2008; 18:227.
- Surks MI, Sievert R. Drugs and thyroid function. N Engl J Med 1995; 333:1688.
- Sherman SI, Gopal J, Haugen BR, et al. Central hypothyroidism associated with retinoid X receptor-selective ligands. N Engl J Med 1999; 340:1075.
- Müller B, Zulewski H, Huber P, et al. Impaired action of thyroid hormone associated with smoking in women with hypothyroidism. N Engl J Med 1995; 333:964.
- Kogai T, Brent GA. The sodium iodide symporter (NIS): regulation and approaches to targeting for cancer therapeutics. Pharmacol Ther 2012; 135:355.
- Portulano C, Paroder-Belenitsky M, Carrasco N. The Na+/I- symporter (NIS): mechanism and medical impact. Endocr Rev 2014; 35:106.
- Hershman JM. Perchlorate and thyroid function: what are the environmental issues? Thyroid 2005; 15:427.
- Messina M, Redmond G. Effects of soy protein and soybean isoflavones on thyroid function in healthy adults and hypothyroid patients: a review of the relevant literature. Thyroid 2006; 16:249.
- Cable EE, Finn PD, Stebbins JW, et al. Reduction of hepatic steatosis in rats and mice after treatment with a liver-targeted thyroid hormone receptor agonist. Hepatology 2009; 49:407.
- Baxter JD, Webb P. Thyroid hormone mimetics: potential applications in atherosclerosis, obesity and type 2 diabetes. Nat Rev Drug Discov 2009; 8:308.
- Safer JD, Crawford TM, Holick MF. Topical thyroid hormone accelerates wound healing in mice. Endocrinology 2005; 146:4425.
- Sherman SI, Ringel MD, Smith MJ, et al. Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with levothyroxine. J Clin Endocrinol Metab 1997; 82:2153.
- Freitas FR, Moriscot AS, Jorgetti V, et al. Spared bone mass in rats treated with thyroid hormone receptor TR beta-selective compound GC-1. Am J Physiol Endocrinol Metab 2003; 285:E1135.
- Grover GJ, Mellström K, Ye L, et al. Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc Natl Acad Sci U S A 2003; 100:10067.
- Lin JZ, Martagón AJ, Cimini SL, et al. Pharmacological Activation of Thyroid Hormone Receptors Elicits a Functional Conversion of White to Brown Fat. Cell Rep 2015; 13:1528.
- Ladenson PW, Kristensen JD, Ridgway EC, et al. Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N Engl J Med 2010; 362:906.
- Sabatino L, Colantuoni A, Iervasi G. Is the vascular system a main target for thyroid hormones? From molecular and biochemical findings to clinical perspectives. Curr Vasc Pharmacol 2005; 3:133.
- Goldman S, McCarren M, Morkin E, et al. DITPA (3,5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation 2009; 119:3093.
- Ladenson PW, McCarren M, Morkin E, et al. Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: a pilot prospective, randomized, controlled study. J Clin Endocrinol Metab 2010; 95:1349.
- Di Cosmo C, Liao XH, Dumitrescu AM, et al. A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport. Endocrinology 2009; 150:4450.
- Verge CF, Konrad D, Cohen M, et al. Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J Clin Endocrinol Metab 2012; 97:4515.
- 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