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Division of Endocrinology, Diabetes and Metabolism Departments of Medicine and Genetics and The Penn Diabetes Center University of Pennsylvania School of Medicine Philadelphia, Pennsylvania 19104
Address all correspondence and requests for reprints to: Mitchell A. Lazar, M.D., Ph.D., University of Pennsylvania School of Medicine, 611 CRB, 415 Curie Boulevard, Philadelphia, Pennsylvania 19104-6149. E-mail: lazar{at}mail.med.upenn.edu
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Introduction |
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Desirable biological effects of pharmacological doses of thyroid hormone include increased metabolic rate and lowering of serum low density lipoprotein-cholesterol. The availability and easy delivery of thyroid hormones make them a potentially attractive therapeutic modality. However, the pharmacological utility of natural thyroid hormones L-thyroxine and triiodothyronine (T3) has been limited, especially by cardiac toxicity that can include tachycardia, atrial fibrillation, and heart failure (1). Despite initial enthusiasm for the treatment of hypercholesterolemia, the enantiomer D-thyroxine (2) as well as putative liver-selective thyroid hormone analogues (3) have not been successful in the clinic. Indeed, at the present time thyroid hormone therapy is limited to physiological replacement in cases of hypothyroidism, and the use of thyroid hormone to suppress TSH levels in patients with thyroid cancer (4).
An understanding of the molecular mechanism of thyroid hormone action has the potential to rationally guide development of tissue-specific thyromimetics. Many actions of thyroid hormones are mediated by intranuclear receptors (5). Thyroid hormone receptors are members of a superfamily of nuclear hormone receptors that also includes receptors for classical hormones such as steroid hormones, vitamins A and D, xenobiotics, and metabolites including eicosanoids, bile acids, and oxysterols (6). These receptors all function as transcription factors that selectively recognize a subset of genes whose expression is then modulated in a ligand-dependent manner. In each case, the carboxyl terminus of the protein is necessary and sufficient for ligand binding.
It has long been recognized that the thyroid hormone receptor
concentration influences the magnitude of the cellular response to
thyroid hormone (7, 8). The cloning and characterization
of the receptors revealed the existence of multiple, distinct thyroid
hormone receptors (TRs) and TR variants (9). These are the
products of two genes, termed 
and ß. They include three different
receptors that regulate gene expression in response to thyroid
hormone (TR1, TRß1, and TRß2) and two variant molecules
(TR2, TR3) that do not bind thyroid hormone but are likely to
modify the actions of the true receptors.
Each TR has a characteristic tissue expression. TRß1 is expressed
widely and at high levels in liver and kidney; TRß2 is particularly
abundant in the pituitary and hypothalamus; and TR1 is rather
ubiquitous with high levels in the heart (9). This pattern
of expression is likely to explain why patients with mutant TRß
alleles have abnormal regulation of thyroid stimulating hormone in the
pituitary, resulting in elevated serum-free thyroid hormone levels
(10). Organs with high levels of TRß relative to TR,
such as the liver, display evidence of tissue hypothyroidism. On the
other hand, the cardiac function of patients with TRß mutations is
often suggestive of hyperthyroidism. This is thought to be due to the
predominance of TR in this organ. Experimental studies in mice
support the concept that TRß predominates in pituitary and liver,
whereas TR is the major thyroid receptor in the heart. Mice lacking
TRß have elevated TSH, elevated thyroid hormone levels, and hepatic
abnormalities consistent with hypothyroidism (11). By
contrast, mice lacking TR have a quite different phenotype, with
evidence of cardiac hypothyroidism (12).
At the molecular level, TRß1 and TRß2 have identical C-terminal
ligand binding domains (LBDs), suggesting that it will be difficult to
develop molecules that differentially interact with or regulate the
activity of these two TRs, which from this point on will be referred to
collectively as TRß. TR and TRß have very similar C-terminal
LBDs, but enough differences that it is reasonable to imagine the
development of small molecules that distinguish TR from TRß. One
such candidate is a recently described TRß-specific high-affinity
agonist, GC-1 (13). In this issue of
Endocrinology, Trost et al. show that GC-1 was
equally or more effective than T3 in lowering
cholesterol and triglycerides, presumably due to its actions on TRß
in liver (14). It also potently decreased TSH levels,
probably via TRß2 in pituitary (15). However, GC-1 was a
less potent regulator of thyroid hormone action in the heart as
assessed by physiological parameters of heart rate and inotropy as well
as by molecular analysis of thyroid-responsive genes. These results are
consistent with a relative sparing of TR by this thyromimetic
compound in vivo. Of note, the authors also found that GC-1
preferentially accumulated in the liver, suggesting a second mechanism
of tissue selectivity that is probably unrelated to the TRß
selectivity of this compound. Nevertheless, the beneficial effects of
GC-1 without overt cardiac toxicity support the authors’ optimism
about the potential to use receptor- and/or tissue-selective
thyromimetic compounds to treat diseases other than hypothyroidism.
When bound by natural thyroid hormones such as
T3, TR and TRß both assume conformations
that display increased affinity for molecules called coactivators,
which communicate a positive signal to the transcriptional
machinery leading to gene activation (16).
Interactions between TR and opposing coregulators, called corepressors,
are reciprocally destabilized by binding of T3
(17). It is not yet known whether the GC-1 bound TRß
interacts with the same range of coactivators as the TR bound to
T3 or, for that matter, whether GC-1 binding
causes corepressor to dissociate from TR. Specificity at the level of
coregulator recruitment could be a determinant of unique properties of
GC-1 or, possibly, future tissue-specific thyromimetics. Indeed, is
now recognized that selective estrogen receptor modulators work in part
by inducing a ligand-bound conformation that facilitates corepressor
but not coactivator binding to the estrogen receptor (18, 19).
GC-1 is an example of a thyromimetic whose tissue specificity is at
least in part due to differential binding to TR and TRß. The
search for additional receptor-specific compounds will be aided not
only by using GC-1 as a lead, but by taking advantage of rapidly
emerging structural information. The three-dimensional structure of
ligand-bound TR LBD is already available (20), and it
seems a certainty that the structures of liganded TRß and the
unliganded TRs will be forthcoming. Comparison of the structures of
T3-bound TR and TRß with that of
GC-1-occupied TRß will be particularly useful in determining the
basis of TR vs. TRß selectivity at the atomic
level.
It may also be possible for chemists to create molecules that
distinguish between TR and TRß not at the level of binding
affinity but, rather, by the complement of coactivators and
corepressors that are recruited to the ligand-bound TRs. Structural
information about the role of ligand in creating or stabilizing the
coregulator binding site should be a useful guide to the development of
such compounds (21). It will then be the role of
biologists to empirically determine whether novel combinations of
thyromimetic receptor binding and coregulator recruitment can be
correlated with a desired pharmacological effect, and whether this can
be dissociated from the toxicities associated with high levels of
thyroid hormone. Now that we have a sense of the underlying
complexity and multiplicity of thyroid hormone receptors and their
coregulators, it seems likely that promising new therapeutics could
emerge from this line of investigation.
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Footnotes |
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Received July 13, 2000.
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References |
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TopIntroductionReferences |
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1. EMBO J 17:455–461[CrossRef][Medline]
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