Peripheral Action of Thyroid Hormones

The major effects of thyroid hormone action occur through the intranuclear action of T3, with T4 being largely a prohormone.29 It remains controversial as to whether T4 might also regulate non-nuclear biologic responses in some contexts, for instance, the activation of certain mitochondrial or cellmembrane enzymes.29 In the 1960s, Tata and associates observed that T3 treatment resulted in the rapid synthesis of nuclear RNA, which preceded increases in protein synthesis and mitochondrial oxygen consumption.30 Subsequently, subcellular fractionation demonstrated specific nuclear binding sites for T3 and identified the anterior pituitary, liver, brain, and heart as having high binding capacity for T3.31 Thus, the current concept of thyroid hormone action is that its nuclear receptor binds to specific regulatory regions in target genes and regulates gene transcription in response to T3.32-34

Thyroid hormone receptors (TRs) are members of the steroid hormone receptor superfamily. There are two TR genes, a and (J, located on chromosomes 17 and 3, respectively, and differential splicing of both these genes yields a total of four isoforms, denoted as 77?«7, 77?«2, TR/31, and 77?j32 (Fig. 1-4).32 The expression of the various TR isoforms is both developmentally regulated and tissue specific, such that TRa is widely expressed at all stages of development, preceding the appearance of endogenous thyroid hormone, whereas TRp begins to be expressed as thyroid hormone-dependent processes occur.29 An aminoterminal splice variant of the TRfi receptor, TR(i2 is specifically expressed in the hypothalamus and pituitary and may therefore be the critical subtype involved in negative-feedback effects of T3.32 In the adult, TRal may be the predominant isoform in myocardium, skeletal muscle, and fat, whereas TRpl and TR(i2 predominate in the pituitary and liver.32 TRa2 does not bind ligand and its function is poorly understood, although it may function as an inhibitor of thyroid hormone action in some contexts.32

TRs bind to specific regulatory DNA sequences usually within gene promoters.35 A consensus regulatory binding site, termed the thyroid hormone response element (TRE), consists of a pair of hexanucleotide half-sites. Natural TREs present in gene promoters are commonly degenerate variations of these consensus sequences. Biochemical evidence suggests that on many TREs, the receptor complex is most active when bound to DNA as a heterodimer with the retinoid X receptor.36

TRcd

TRa2

TRcd

FIGURE 1-4. Multiple human thyroid hormone receptor (TR) isoforms. TRa and TRP receptors are transcribed from different genes on chromosomes 17 and 3, respectively. Different isoforms are then generated from differential splicing of the primary messenger RNA transcripts in each case, such that TRal and TRa2 isoforms differ in their carboxytermini, whereas TRpi and TR(52 isoforms differ in their aminotermini, as shown. (Adapted from Lazar MA. Thyroid hormone receptors: Multiple forms, multiple possibilities. EndocrRev 1993;14:184.)

The clinical manifestations of thyroid hormone action are the net result of the actions of the products of the various genes whose expression is regulated by T3. For example, thyroid hormones affect cardiac contractility by affecting the transcription of, and subsequent relative proportions of, the various myosin heavy chains in cardiac muscle.37 38 In the pituitary, T3 regulates the transcription of the genes for both a and P subunits of TSH, thus affecting the level of TSH secretion.39

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