Mechanism Of Thyroid Hormone Action

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As must already be obvious, virtually all cells appear to require optimal amounts of thyroid hormone for normal operation, even though different aspects of cellular function may be affected in different cells. Thyroid hormones are quite hydrophobic and may either diffuse across the cell membrane or enter target cells by a carrier-mediated transport process. T3 formed within the target cell by deiodination of T4 appears to mix freely with T3 taken up from the plasma and to enter the nucleus, where it binds to specific receptors (see Chapter 2). Thyroid hormone receptors are members of the large family of nuclear hormone receptors and bind to specific nucleotide sequences (thyroid response elements or TREs) in the genes they regulate. Unlike most other nuclear receptors, thyroid hormone receptors bind to their response elements in the absence of hormone. They bind as monomers or as homodimers composed either of two thyroid hormone receptors, or they may form heterodimers with other nuclear receptor family members, usually the receptor for an isomer of retinoic acid. In the absence of T3, the unoccupied receptor, in conjunction with a corepressor protein, inhibits T3-dependent gene expression by maintaining the DNA in a tightly coiled configuration that bars access of transcription activators or RNA poly-merase. Upon binding T3, the configuration of the receptor is modified in a way that causes it to release the corepressor and bind instead to a coactivator. Although T3 acts in an analogous way to suppress expression of some genes, the underlying mechanism for negative control of gene expression is not understood.

Nuclear receptors for T3 are encoded in two genes, designated TRa and TR^. The TRa gene resides on chromosome 17 and gives rise to two isoforms, TRa1 and TRa2, as a result of alternate splicing that deletes the T3 binding site from the TRa2 isoform. The TRa2 isoform, therefore, cannot act as a hormone receptor, but it nevertheless plays a vital physiologic role (see later discussion). The TR^ gene maps to chromosome 3 and also gives rise to two alternately spliced products, TR^1 and TRy82. TRa1 and TR^1 are widely distributed throughout the body and are present in different ratios in the nuclei of all target tissues examined, but TR^2

thyrotrope thyrotrope

FIGURE 13 Effects of TRH, T3, and T4 on the thyrotrope. T3 down-regulates expression of genes for TRH receptors and both subunits of TSH (dashed arrows). TRH effects (shown in blue) include up-regulation of TSH gene expression, enhanced TSH glycosylation, and accelerated secretion. ( + ), increase; (—), decrease.

FIGURE 13 Effects of TRH, T3, and T4 on the thyrotrope. T3 down-regulates expression of genes for TRH receptors and both subunits of TSH (dashed arrows). TRH effects (shown in blue) include up-regulation of TSH gene expression, enhanced TSH glycosylation, and accelerated secretion. ( + ), increase; (—), decrease.

appears to be expressed primarily in the anterior pituitary gland and the brain.

Efforts to determine which T3 responses are mediated by each form of the T3 receptor have been greatly advanced by the advent of technology that permits disruption or "knock out'' of individual genes in mouse embryos. Mice lacking both TR^ isoforms have no development deficiencies, are fertile, and exhibit no obvious behavioral abnormalities. However, these animals have abnormally high rates of TSH, T4, and T3 secretion presumably because the TR^2 mediates the negative feedback action of T3. These symptoms are remarkably similar to those seen in a rare genetic disease that is characterized by resistance to thyroid hormone. Like the knockout mice, patients exhibit few abnormalities but have increased circulating levels of TSH, T4, and T3. They have enlarged thyroid glands (goiter) stemming from increased TSH levels, but exhibit none of the consequences of T4 hypersecretion. This disease typically results from mutations in the TR^ gene.

No effects on life span or fertility result from manipulation of TRa gene so that it encodes only the TRa2 isoform that cannot bind T3. However, animals that lack the TRa1 isoform have low heart rates and low body temperature. When the TRa gene was knocked out so that neither the a1 nor a2 isoform could be expressed, the animals stopped growing after about 2 weeks and died shortly after weaning with apparent failure of intestinal development. Thus although few symptoms of hypothyroidism result from knock out of any of the thyroid hormone receptors that are capable of binding T3, loss of the a2 isoform produced devastating effects, suggesting that it plays a critical, though perhaps T3-independent, role in gene transcription. The combined absence of TRa1, TR^1, and TR^2 produces more symptoms of hypothyroidism than lack of either TRa1 or TRy8, suggesting that these receptors have redundant or overlapping functions. However, the hypothyroid symptoms are mild compared to those seen when the complement of TRs is normal but thyroid hormone is absent. Unoccupied TRs that repress gene expression may therefore produce harmful effects. Consistent with this idea, a mutation of the TR^ gene that prevents it from binding T3 produced severe defects in neurologic development similar to those seen in hypothyroid mice even though T3 was abundant. Thus at least one of the physiologic roles of T3 may be to counteract the consequences of T3 receptor silencing of some genes.

Although extensive evidence indicates that T3 and T4 produce the majority of their actions through nuclear

FIGURE 14 Effect of treatment with thyroid hormones for 3-4 weeks on TSH secretion in normal young men in response to an intravenous injection of TRH. Six normal subjects received 25 mg of TRH indicated by the arrow. Values are expressed as means ± SEM. (From Snyder PJ, Utiger RD. Inhibition of thyrotropin response to thyrotropin-releasing hormone by small quantities of thyroid hormones. J Clin Invest 1972;52:2077.)

FIGURE 14 Effect of treatment with thyroid hormones for 3-4 weeks on TSH secretion in normal young men in response to an intravenous injection of TRH. Six normal subjects received 25 mg of TRH indicated by the arrow. Values are expressed as means ± SEM. (From Snyder PJ, Utiger RD. Inhibition of thyrotropin response to thyrotropin-releasing hormone by small quantities of thyroid hormones. J Clin Invest 1972;52:2077.)

receptors, extranuclear specific binding proteins for thyroid hormones have also been found in the cytosol and mitochondria. The function, if any, of these proteins is not known. In addition, some rapid effects ofT3 and T4 that may not involve the genome have also been described. It is highly likely that T3 and T4 have physiologically important actions that are not dependent on nuclear events, but detailed understanding will require further research.

Suggested Reading

Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid, 8th ed. Philadelphia: Lippincott Williams and Wilkins, 2000. (This book provides excellent coverage of a broad range of basic and clinical topics.)

De La Vieja A, Dohan O, Levy O, Carrasco N. Molecular analysis of the sodium/iodide symporter: Impact on thyroid and extrathyroid pathophysiology. Physiol Rev 2000;80:1083-1105.

Gershengorn MC, Osman R. Molecular and cellular biology of thyro-tropin-releasing hormone receptors. Physiol Rev 1996;76:175-191.

Kohrle J. Local activation and inactivation of thyroid hormones: The deiodinase family. Mol Cell Endocrinol 1999;151:103-119.

Rapoport B, Chazenbalk D, Jaume JC, McLachlan, SM. The thyrotropin (TSH) receptor: Interactions with TSH and auto-antibodies. Endocr Rev 1998;19:673-716.

Vassart G, Dumont J. The thyrotropin receptor and the regulation of thyrocyte function and growth. Endocr Rev 1992;13:596-611.

Yen PM. Physiologic and molecular basis of thyroid hormone action. Physiol Rev 2001;81:1097-1142.

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