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Thyroid Hormone Disorders
(Released May 2001)

 
  by Jennifer A. Phillips  

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  1. Thyroid hormone action in mitochondria.

    Wrutniak-Cabello C; Casas F; Cabello G

    J Mol Endocrinol, 2001 Feb, 26(1):67-77

    Triiodothyronine (T3) is considered a major regulator of mitochondrial activity. In this review, we show evidence of the existence of a direct T3 mitochondrial pathway, and try to clarify the respective importance of the nuclear and mitochondrial pathways for organelle activity. Numerous studies have reported short-term and delayed T3 stimulation of mitochondrial oxygen consumption. Convincing data indicate that an early influence occurs through an extra-nuclear mechanism insensitive to inhibitors of protein synthesis. Although it has been shown that diiodothyronines could actually be T3 mediators of this short-term influence, the detection of specific T3-binding sites, probably corresponding to a 28 kDa c-Erb Aalpha1 protein of the inner membrane, also supports a direct T3 influence. The more delayed influence of thyroid hormone upon mitochondrial respiration probably results from mechanisms elicited at the nuclear level, including changes in phospholipid turnover and stimulation of uncoupling protein expression, leading to an increased inner membrane proton leak. However, the involvement of a direct mitochondrial T3 pathway leading to a rapid stimulation of mitochondrial protein synthesis has to be considered. Both pathways are obviously involved in the T3 stimulation of mitochondrial genome transcription. First, a 43 kDa c-Erb Aalpha1 protein located in the mitochondrial matrix (p43), acting as a potent T3-dependent transcription factor of the mitochondrial genome, induces early stimulation of organelle transcription. In addition, T3 increases mitochondrial TFA expression, a mitochondrial transcription factor encoded by a nuclear gene. Similarly, the stimulation of mitochondriogenesis by thyroid hormone probably involves both pathways. In particular, the c-erb Aalpha gene simultaneously encodes a nuclear and a mitochondrial T3 receptor (p43), thus ensuring coordination of the expression of the mitochondrial genome and of nuclear genes encoding mitochondrial proteins. Recent studies concerning the physiological importance of the direct mitochondrial T3 pathway involving p43 led to the conclusion that it is not only involved in the regulation of fuel metabolism, but also in the regulation of cell differentiation. As the processes leading to or resulting from differentiation are energy-consuming, p43 coordination of metabolism and differentiation could be of significant importance in the regulation of development.

  2. Regulation of mucin gene expression in human tracheobronchial epithelial cells by thyroid hormone.

    Gray T; Nettesheim P; Basbaum C; Koo J

    Biochem J, 2001 Feb 1, 353(Pt 3):727-34

    We reported previously that the expression of the gene encoding MUC5AC mucin in human airway epithelial cells is controlled by retinoic acid via the retinoic acid receptor (RAR)-alpha and that 3,3',5-tri-iodothyronine (T(3)) inhibits the expression of MUC5AC. The purpose of the present study was to identify mechanisms mediating the effect of T(3). T(3) has been shown to inhibit gene expression via several mechanisms, either by enhancing or repressing the transcription of target genes or by the regulation of post-transcriptional events. Results showed that T(3) strongly inhibited MUC5AC-driven luciferase activity in normal human tracheobronchial epithelial cells that had been transiently transfected with a MUC5AC-luciferase reporter construct; however, it did not affect MUC5AC mRNA stability. These results indicate that T(3) suppresses MUC5AC expression at the transcriptional level. An analysis of deletion constructs showed that deletion of the region downstream of 3 kb resulted in markedly decreased levels of MUC5AC transcription in the absence of T(3) (i.e. under control conditions) as well as a loss of responsiveness to the inhibitory effects of T(3). This suggests that this region might contain elements important for the activation as well as the repression of MUC5AC transcription. To determine whether T(3) modulates retinoic-acid-dependent MUC5AC transcription via an alteration in the abundance of retinoid receptor proteins, we examined the type and abundance of these receptors in nuclear extracts of airway epithelial cells grown in the presence or absence of T(3). Western blots showed that T(3) markedly decreased several types of retinoid receptor while not affecting T(3) receptor proteins. Consistent with this finding were gel-shift assays revealing a decrease in RAR-retinoic acid response element complexes obtained from T(3)-treated cells. We propose that T(3) might inhibit retinoid-dependent MUC5AC expression by decreasing retinoid receptor levels and thereby decreasing the transcriptional activation of this gene for mucins.

  3. Thyroid hormone activation in human vascular smooth muscle cells: expression of type II iodothyronine deiodinase.

    Mizuma H; Murakami M; Mori M

    Circ Res, 2001 Feb 16, 88(3):313-8

    Thyroid hormone has been reported to have significant effects on the peripheral vascular system, including relaxation of vascular smooth muscle cells and antiatherosclerotic effects. To exert its biological activity, thyroxine, which is a major secretory product of thyroid gland, needs to be converted to 3,5,3'-triiodothyronine (T(3)) by iodothyronine deiodinase. Type I iodothyronine deiodinase (DI) is widely distributed and maintains circulating T(3) level, whereas type II iodothyronine deiodinase (DII) is present in a limited number of tissues to provide local intracellular T(3). In the present study, we have identified iodothyronine deiodinase in cultured human coronary artery smooth muscle cells (hCASMCs) and human aortic smooth muscle cells (hASMCs). All of the characteristics of the deiodinating activity in hCASMCs and hASMCs were compatible with DII. Northern analysis demonstrated that DII mRNA was expressed in both hCASMCs and hASMCs, and DII mRNA levels as well as DII activities were rapidly increased by dibutyryl-cAMP or forskolin. These data demonstrate, for the first time, the expression of DII in human vascular smooth muscle cells, which is regulated by a cAMP-mediated mechanism. The present results suggest a previously unrecognized role of local T(3) production by DII in the pathophysiology of human vascular smooth muscle cells.

  4. A thyroid hormone receptor that is required for the development of green cone photoreceptors.

    Ng L; Hurley JB; Dierks B; Srinivas M; Salto C; Vennstrom B; Reh TA; Forrest D

    Nat Genet, 2001 Jan, 27(1):94-8

    Color vision is facilitated by distinct populations of cone photoreceptors in the retina. In rodents, cones expressing different opsin photopigments are sensitive to middle (M, 'green') and short (S, 'blue') wavelengths, and are differentially distributed across the retina. The mechanisms that control which opsin is expressed in a particular cone are poorly understood, but previous in vitro studies implicated thyroid hormone in cone differentiation. Thyroid hormone receptor beta 2 (TR beta 2) is a ligand-activated transcription factor that is expressed in the outer nuclear layer of the embryonic retina. Here we delete Thrb (encoding Tr beta 2) in mice, causing the selective loss of M-cones and a concomitant increase in S-opsin immunoreactive cones. Moreover, the gradient of cone distribution is disturbed, with S-cones becoming widespread across the retina. The results indicate that cone photoreceptors throughout the retina have the potential to follow a default S-cone pathway and reveal an essential role for Tr beta 2 in the commitment to an M-cone identity. Our findings raise the possibility that Thrb mutations may be associated with human cone disorders.

  5. Transcriptional regulation of the thyrotropin-releasing hormone gene by leptin and melanocortin signaling.

    Harris M; Aschkenasi C; Elias CF; Chandrankunnel A; Nillni EA; Bjoorbaek C; Elmquist JK; Flier JS; Hollenberg AN

    J Clin Invest, 2001 Jan, 107(1):111-20

    Starvation causes a rapid reduction in thyroid hormone levels in rodents. This adaptive response is caused by a reduction in thyrotropin-releasing hormone (TRH) expression that can be reversed by the administration of leptin. Here we examined hypothalamic signaling pathways engaged by leptin to upregulate TRH gene expression. As assessed by leptin-induced expression of suppressor of cytokine signaling-3 (SOCS-3) in fasted rats, TRH neurons in the paraventricular nucleus are activated directly by leptin. To a greater degree, they also contain melanocortin-4 receptors (MC4Rs), implying that leptin can act directly or indirectly by increasing the production of the MC4R ligand, alpha-melanocyte stimulating hormone (alpha-MSH), to regulate TRH expression. We further demonstrate that both pathways converge on the TRH promoter. The melanocortin system activates the TRH promoter through the phosphorylation and DNA binding of the cAMP response element binding protein (CREB), and leptin signaling directly regulates the TRH promoter through the phosphorylation of signal transducer and activator of transcription 3 (Stat3). Indeed, a novel Stat-response element in the TRH promoter is necessary for leptin's effect. Thus, the TRH promoter is an ideal target for further characterizing the integration of transcriptional pathways through which leptin acts.

  6. Effects of different activity and inactivity paradigms on myosin heavy chain gene expression in striated muscle.

    Baldwin KM; Haddad F

    J Appl Physiol, 2001 Jan, 90(1):345-57

    The goal of this mini-review is to summarize findings concerning the role that different models of muscular activity and inactivity play in altering gene expression of the myosin heavy chain (MHC) family of motor proteins in mammalian cardiac and skeletal muscle. This was done in the context of examining parallel findings concerning the role that thyroid hormone (T(3), 3,5,3'-triiodothyronine) plays in MHC expression. Findings show that both cardiac and skeletal muscles of experimental animals are initially undifferentiated at birth and then undergo a marked level of growth and differentiation in attaining the adult MHC phenotype in a T(3)/activity level-dependent fashion. Cardiac MHC expression in small mammals is highly sensitive to thyroid deficiency, diabetes, energy deprivation, and hypertension; each of these interventions induces upregulation of the beta-MHC isoform, which functions to economize circulatory function in the face of altered energy demand. In skeletal muscle, hyperthyroidism, as well as interventions that unload or reduce the weight-bearing activity of the muscle, causes slow to fast MHC conversions. Fast to slow conversions, however, are seen under hypothyroidism or when the muscles either become chronically overloaded or subjected to intermittent loading as occurs during resistance training and endurance exercise. The regulation of MHC gene expression by T(3) or mechanical stimuli appears to be strongly regulated by transcriptional events, based on recent findings on transgenic models and animals transfected with promoter-reporter constructs. However, the mechanisms by which T(3) and mechanical stimuli exert their control on transcriptional processes appear to be different. Additional findings show that individual skeletal muscle fibers have the genetic machinery to express simultaneously all of the adult MHCs, e.g., slow type I and fast IIa, IIx, and IIb, in unique combinations under certain experimental conditions. This degree of heterogeneity among the individual fibers would ensure a large functional diversity in performing complex movement patterns. Future studies must now focus on 1) the signaling pathways and the underlying mechanisms governing the transcriptional/translational machinery that control this marked degree of plasticity and 2) the morphological organization and functional implications of the muscle fiber's capacity to express such a diversity of motor proteins.

  7. Thyroid Hormone Response Element Sequence and the Recruitment of Retinoid X Receptors for Thyroid Hormone Responsiveness

    Wu, Y; Xu, B; Koenig, RJ

    Journal of Biological Chemistry [J. Biol. Chem.], vol. 276, no. 6, pp. 3929-3936, 9 Feb 2001

    Thyroid hormone receptors (TRs) are transcription factors that bind to thyroid hormone response elements (TREs) in the regulatory regions of target genes. TRs are thought to activate transcription primarily as heterodimers with retinoid X receptors (RXRs), with RXR binding upstream to the two directly repeated half-sites in a typical TRE. However, given that TRs and RXRs prefer to bind to different DNA sequences (T(A/G)AGGTCA and GGGGTCA), we postulate that only certain TREs require RXR-TR heterodimerization, depending on the TRE sequence. We have tested this hypothesis by comparing in Saccharomyces cerevisiae the functional activity of TR plus or minus RXR on 10 naturally occurring mammalian TREs. S. cerevisiae was used as a model system because yeast lack endogenous nuclear receptors and thus can be manipulated to express TRs and/or RXRs. We first studied ligand-independent reporter gene activation, which reflects the activity of the activator function 1 (AF-1) domain. The 10 TREs formed a continuous spectrum from being fully dependent on RXR for TR AF-1 activity to being essentially independent of RXR. Relative independence of RXR generally was seen when the TRE upstream half-site has a TA or TG 5' to the core hexamer. Gel mobility shift assays revealed that functional independence of RXR correlates with the strong binding of TR alone, whereas more RXR dependence correlates with higher binding of RXR-TR heterodimers. Restoration of ligand-dependent (AF-2 domain) reporter gene activation was achieved by expression of the coactivator TIF2. This ligand-induced stimulation was stronger in the presence of TR alone than with RXR plus TR, suggesting a preference for TIF2 activation of TR homodimers. Overall the data support the notion that the TRE sequence plays an important role in determining the nuclear hormone receptor and coactivator requirements for TR action.

  8. Autoinduction of nuclear hormone receptors during metamorphosis and its significance

    Tata, JR

    Insect Biochemistry and Molecular Biology [Insect Biochem. Mol. Biol.], vol. 30, no. 8-9, pp. 645-651, 1 Sep 2000

    Metamorphosis is a most dramatic example of hormonally regulated genetic reprogramming during postembryonic development. The initiation and sustenance of the process are under the control of ecdysteroids in invertebrates and thyroid hormone, 3,3',5-triiodothyronine, in oviparous vertebrates. Their actions are inhibited or potentiated by other endogenous or exogenous hormones --- juvenile hormone in invertebrates and prolactin and glucocorticoids in vertebrates. The nuclear receptors for ecdysteroids and thyroid hormone are the most closely related members of the steroid/retinoid/thyroid hormone receptor supergene family. In many pre-metamorphic amphibia and insects, the onset of natural metamorphosis and the administration of the exogenous hormones to the early larvae are characterized by a substantial and rapid autoinduction of the respective nuclear receptors. This review will largely deal with the phenomenon of receptor autoinduction during amphibian metamorphosis, although many of its features resemble those in insect metamorphosis. In the frog Xenopus, thyroid hormone receptor autoinduction has been shown to be brought about by the direct interaction between the receptor protein and the thyroid-responsive elements in the promoter of its own gene. Three lines of evidence point towards the involvement of receptor autoinduction in the process of initiation of amphibian metamorphosis: (1) a close association between the extent of inhibition or potentiation by prolactin and glucocorticoid, respectively, and metamorphic response in whole tadpoles and in organ and cell cultures; (2) thyroid hormone fails to upregulate the expression of its own receptor in obligatorily neotenic amphibia but does so in facultatively neotenic amphibia; and (3) dominant-negative receptors known to block hormonal response prevent the autoinduction of wild-type Xenopus receptors in vivo and in cell lines. Autoinduction is not restricted to insect and amphibian metamorphic hormones but is also a characteristic of other nuclear receptors (e.g., retinoid, sex steroids, vitamin D sub(3) receptors) where the ligand is involved in a postembryonic developmental function. A wider significance of such receptor autoregulation is that the process may also be important for mammalian postembryonic development.

  9. Association of some potential hormone response elements in human genes with the Alu family repeats

    Babich, V; Aksenov, N; Alexeenko, V; Oei, SL; Buchlow, G; Tomilin, N*

    Gene, vol. 239, no. 2, pp. 341-349, 1 Nov 1999

    Short interspersed repeats of the Alu family located in promoters of some human genes contain high-affinity binding sites for thyroid hormone receptor, retinoic acid receptor and estrogen receptor. The standard binding sites for the receptors represent variants of duplicated AGGTCA motif with different spacing and orientation (direct, DR, or inverted, IR), and Alu sequences were found to have functional DR-4, DR-2 or variant IR-3/IR-17 elements. In this study we analyzed distribution and abundance of the elements in a set of human genomic sequences from GenBank and their association with Alu repeats. Our results indicate that a major fraction of potentially active DR-4, DR-2 and variant IR-3/IR-17 elements in the genes is located within Alu repeats. Alu-associated DR-2 elements are conserved in primate evolution. However, very few Alu have potential DR-3 glucocorticoid-response elements. Gel-shift experiments with the probe (AUB) corresponding to the consensus Alu sequence just upstream of the RNA polymerase III promoter B-box and containing duplicated AGGTCA motif indicate that the probe interacts in a sequence-specific manner with human nuclear proteins which bind to standard IR-0, DR-1, DR-4 or DR-5 elements. The AUB sequence was also able to promote thyroid hormone-dependent trans-activation of a reporter gene. The results support the view that Alu retroposons played an important role in evolution of regulation of the primate gene expression by nuclear hormone receptors.

  10. Regulation of gene expression by nuclear hormone receptors

    METHODOLOGY IN RECEPTOR RESEARCH., pp. 319-335; vol. 17, no. 1-3, May 1997

    Steroids and thyroid hormones, as well as vitamin D, retinoids and some nutrient metabolites (fatty acids, prostaglandins, farnesol metabolites) act by binding to members of the zinc-finger containing superfamily of nuclear hormone receptors. These receptor proteins bind directly to specific DNA recognition sequences (hormone response elements) in the promoter region of target genes, resulting in the alteration of the transcription initiation rate. While the principle of action of these receptors appears to be quite simple, the promiscuous behavior of some members of this family as well as cross-talk with other signaling systems result in an intricate regulatory network with distinct particularities for each receptor type. Specific areas of current interest in nuclear receptor research are: (i) the mechanisms for target gene specificity, which occur at the level of receptor expression, ligand metabolism and/or DNA sequence; (ii) cross-talk with other signaling systems resulting in the modulation of the transcriptional activity of the ligand-activated receptor through phosphorylation and/or heterodimerization with shared nuclear factors; and (iii) the discovery of novel agonistic and antagonistic ligands for established and orphan nuclear receptors. Recent insights through screening strategies for putative ligands, the cloning of co-activator proteins, as well as the characterization of human and animal models with germline and somatic mutations in nuclear receptors have resulted in important insights into some of the above questions, which are fundamental for a better understanding of the role of these hormone-activated transcription factors during development and cell differentiation.

  11. "Spot 14" protein functions at the pretranslational level in the regulation of hepatic metabolism by thyroid hormone and glucose

    Brown, SB; Maloney, M; Kinlaw, WB*

    Journal of Biological Chemistry [J. Biol. Chem.], vol. 272, no. 4, pp. 2163-2166, Jan 1997

    "Spot 14" protein appears rapidly in nuclei of hepatocytes exposed to glucose and thyroid hormone. Exposure of glucose- and T sub(3)-treated hepatocytes to a spot 14 antisense oligonucleotide inhibited induction of mRNAs encoding malic enzyme, ATP citrate-lyase, fatty acid synthase, liver-type pyruvate kinase, phosphoenolpyruvate carboxykinase, and type I deiodinase but not hydroxymethylglutaryl-CoA reductase, cytochrome c, and actin mRNAs. Induction of spot 14, ATP citrate-lyase, and fatty acid synthase polypeptides, but not propionyl-CoA carboxylase and mitochondrial pyruvate carboxylase, was inhibited. Antisense treatment of hepatocytes transfected with a reporter controlled by a glucose- and T sub(3)-inducible fragment of the pyruvate kinase gene promoter inhibited reporter activity, as did cotransfection of the reporter and a spot 14 antisense plasmid. Spot 14 protein acts in the induction of mRNAs coding for key lipogenic (malic enzyme, ATP citrate-lyase, fatty acid synthase), glycolytic (pyruvate kinase), and gluconeogenic enzymes (phosphoenolpyruvate carboxykinase), as well as the diet-responsive type I deiodinase, but not those involved in mitochondrial respiration (cytochrome c) or cholesterol synthesis (hydroxymethylglutaryl-CoA reductase). Transfection experiments indicated that these effects are mediated at the transcriptional level. The protein functions in the activation of genes involved in metabolic switching between the fasted and fed states in liver.

  12. Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with levothyroxine

    Sherman, SI; Ringel, MD; Smith, MJ; Kopelen, HA; Zoghbi, WA; Ladenson, PW

    Journal of Clinical Endocrinology and Metabolism [J. Clin. Endocrinol. Metab.], vol. 82, no. 7, pp. 2153-2158, 1997

    A thyroid hormone analog with organ-selective effects could have therapeutic application for disorders such as hyperlipidemia and osteoporosis. We performed a randomized clinical trial to determine the specific thyromimetic effects of tiratricol. Twenty-four athyreotic patients underwent detailed metabolic and physiological evaluation after a 2-month baseline period, taking TSH-suppressive doses of L-T sub(4). They were then randomized to blinded treatment with either tiratricol (24 mu g/kg twice daily) or L-T sub(4) (1.9 mu g /kg daily). The dose of hormone was increased until the TSH level was less than 0.1 mU/L, and the metabolic and physiological testing was repeated. Comparing the change from baseline to the study drug periods, when serum TSH levels were equivalently suppressed, there were no significant differences between the two groups in resting metabolic rate, weight, urea nitrogen excretion, or symptom score. Plasma total and low density lipoprotein cholesterol levels declined 13 plus or minus 4% and 23 plus or minus 6% in the tiratricol group compared with 2 plus or minus 2% and 5 plus or minus 3% in the L-T sub(4) group (P = 0.015 and P = 0.0066, respectively). Serum sex hormone-binding globulin levels increased 55 plus or minus 13% with tiratricol compared with a 1.7 plus or minus 4% decline with L-T sub(4) (P = 0.0006), indicating an augmented hepatic response to tiratricol. Skeletal metabolic activity was enhanced, with increased levels of serum osteocalcin and urinary excretion of calcium and pyridinium cross-links. Tiratricol and L-T sub(4) had comparable effects on cardiovascular function. Tiratricol has distinct augmented hepatic and skeletal thyromimetic actions of potential therapeutic value.

  13. Thyroid Hormone Deficiency Before the Onset of Hearing Causes Irreversible Damage to Peripheral and Central Auditory Systems

    Knipper, M; Zinn, C; Maier, H; Praetorius, M; Rohbock, K; Koepschall, I; Zimmermann, U

    Journal of Neurophysiology [J. Neurophysiol.], vol. 83, no. 5, pp. 3101-3112, May 2000

    Both a genetic or acquired neonatal thyroid hormone (TH) deficiency may result in a profound mental disability that is often accompanied by deafness. The existence of various TH-sensitive periods during inner ear development and general success of delayed, corrective TH treatment was investigated by treating pregnant and lactating rats with the goitrogen methimazole (MMI). We observed that for the establishment of normal hearing ability, maternal TH, before fetal thyroid gland function on estrus days 17-18, is obviously not required. Within a crucial time between the onset of fetal thyroid gland function and the onset of hearing at postnatal day 12 (P12), any postponement in the rise of TH-plasma levels, as can be brought about by treating lactating mothers with MMI, leads to permanent hearing defects of the adult offspring. The severity of hearing defects that were measured in 3- to 9-mo-old offspring could be increased with each additional day of TH deficiency during this critical period. Unexpectedly, the active cochlear process, assayed by distortion product otoacoustic emissions (DPOAE) measurements, and speed of auditory brain stem responses, which both until now were not thought to be controlled by TH, proved to be TH-dependent processes that were damaged by a delay of TH supply within this critical time. In contrast, no significant differences in the gross morphology and innervation of the organ of Corti or myelin gene expression in the auditory system, detected as myelin basic protein (MBP) and proteolipid protein (PLP) mRNA using Northern blot approach, were observed when TH supply was delayed for few days. These classical TH-dependent processes, however, were damaged when TH supply was delayed for several weeks. These surprising results may suggest the existence of different TH-dependent processes in the auditory system: those that respond to corrective TH supply (e.g., innervation and morphogenesis of the organ of Corti) and those that do not, but require T3 activity during a very tight time window (e.g., active cochlear process, central processes).

  14. Thyroid hormone receptor beta -dependent expression of a potassium conductance in inner hair cells at the onset of hearing

    Ruesch, A; Erway, LC; Oliver, D; Vennstroem, B; Forrest, D

    Proceedings of the National Academy of Sciences, USA [Proc. Natl. Acad. Sci. USA], vol. 95, no. 26, pp. 15758-15762, 22 Dec 1998

    To elucidate the role of thyroid hormone receptors (TRs) alpha 1 and beta in the development of hearing, cochlear functions have been investigated in mice lacking TR alpha 1 or TR beta . TRs are ligand-dependent transcription factors expressed in the developing organ of Corti, and loss of TR beta is known to impair hearing in mice and in humans. Here TR alpha 1-deficient (TR alpha 1 super(-/-)) mice are shown to display a normal auditory-evoked brainstem response, indicating that only TR beta and not TR alpha 1, is essential for hearing. Because cochlear morphology was normal in TR beta super(-/-) mice, we postulated that TR beta regulates functional rather than morphological development of the cochlea. At the onset of hearing, inner hair cells (IHCs) in wild-type mice express a fast-activating potassium conductance I sub(K,f), that transforms the immature IHC from a regenerative, spiking pacemaker to a high- frequency signal transmitter. Expression of I sub(K,f) was significantly retarded in TR beta super(-/-) mice, whereas the development of the endocochlear potential and other cochlear functions including mechanoelectrical transduction in hair cells, progressed normally. TR alpha 1 super(-/-) mice expressed I sub(K,f) normally, in accord with their normal auditory-evoked brainstem response. These results establish that the physiological differentiation of IHCs depends on a TR beta -mediated pathway. When defective, this may contribute to deafness in congenital thyroid diseases.

  15. Thyroxine replacement increases central 5-hydroxytryptamine activity and reduces depressive symptoms in hypothyroidism

    Cleare, AJ; McGregor, A; Chambers, SM; Dawling, S; O'Keane, V

    Neuroendocrinology, vol. 64, no. 1, pp. 65-69, 1996

    Hypothyroidism is associated with both reduced central 5-HT function and an increased incidence of depression. This study tested the hypothesis that the reduced 5-HT function returns to normal with thyroxine replacement therapy. Seven hypothyroid patients were tested before and after adequate thyroxine replacement. Cortisol and prolactin responses to d-fenfluramine, a centrally acting 5-HT-releasing agent, were used as an index of central (hypothalamic) 5-HT responsiveness. 5-HT-mediated cortisol responses were significantly higher after thyroxine replacement. Basal prolactin levels were reduced, but 5-HT-mediated prolactin responses were not significantly higher after treatment, perhaps due to the pre-treatment responses being elevated by the direct stimulatory effects of hypothyroidism itself on pituitary prolactin secretion. Depressive symptomatology improved with thyroxine. TSH levels were positively related to depressive symptomatology, and inversely to cortisol responses. Depressive symptomatology was inversely related to cortisol responses. These findings thus provide further support that central 5-HT neurotransmission is affected by hypothyroidism. They also suggest that the reduction in 5-HT responsiveness is reversible with thyroxine replacement therapy.

  16. Effects of contractile activity and hypothyroidism on nuclear hormone receptor mRNA isoforms in rat skeletal muscle

    Schuler, MJ; Buehler, S; Pette, D*

    European Journal of Biochemistry [Eur. J. Biochem.], vol. 264, no. 3, pp. 982-988, Sep 1999

    Absolute molecule numbers of thyroid hormone receptor isoforms T3R alpha 1, T3R alpha 2, T3R beta 1, and the 9-cis retinoic acid receptor gamma were measured in adult fast extensor digitorum longus (EDL) and slow soleus (SOL) muscles of rat by competitive reverse transcriptase (RT)-PCR. The nuclear hormone receptor corepressor (NCoR) mRNA was quantified by noncompetitive RT-PCR in the same muscles. T3R beta 1 mRNA was the most abundant isoform in both muscle types. All nuclear hormone receptor (NHR) mRNAs were found at lower molecule numbers in fast than in slow muscle. No differences existed with regard to NCoR mRNA. With the exception of T3R alpha 1 in the EDL, hypothyroidism led to decreases in NHR mRNAs, especially in SOL, but did not significantly affect the level of NCoR mRNA. Enhanced neuromuscular activity of the fast EDL muscle, as induced by chronic low-frequency stimulation, transiently increased NHR mRNAs, but decreased NCoR mRNA. These chronic-low-frequency-stimulation-induced changes were attenuated by hypothyroidism.

  17. Screening for hypothyroidism in sleep apnea.

    Skjodt NM; Atkar R; Easton PA

    Am J Respir Crit Care Med, 1999 Aug, 160(2):732-5

    Primary sleep apnea-hypopnea syndrome (obstructive sleep apnea [OSA]) and hypothyroidism have many signs and symptoms in common. The overlap in clinical presentation, and the sleep-disordered breathing that can accompany hypothyroidism, create a significant risk of misdiagnosis of sleep apnea among patients referred to sleep clinic who have undiagnosed hypothyroidism. We determined the point prevalence of hypothyroidism in our sleep clinic patients with newly diagnosed sleep-disordered breathing. Of 290 sequential patients referred to sleep clinic, 200 (69%) patients judged at high risk for OSA underwent polysomnography (PSG) and biochemical screening for hypothyroidism. Of these, 124 (62%) were judged to have sleep apnea. This included three patients (1.5% of patients undergoing PSG or 2. 4% of those judged to have OSA) who were also discovered to have previously undiagnosed hypothyroidism. These three patients with "secondary" sleep apnea were treated with thyroxine therapy alone, and followed with sequential sleep studies and serum thyroid hormone assays; symptoms, sleep-disordered breathing, nocturnal hypoxia, and thyroid deficiency resolved simultaneously. We conclude that biochemical screening for hypothyroidism is required to prevent inadvertent misdiagnosis of hypothyroid sleep-disordered breathing as primary sleep apnea, and that it is a cost-effective component of the investigation of sleep apnea.

  18. [Coma in myxedema--a rare complication of hypothyroidism. Possible iatrogenic factors should be taken into account]

    Hehrmann R

    Fortschr Med, 1996 Dec 10, 114(34):474-8

    Myxedema coma is the most severe form of hypothyroidism and is characterized by extreme hypothermia, bradycardia, central hypoventilation and hypoxia. Common causes are intercurrent diseases, interruption of thyroid hormone treatment, or an overdose of sleeping pills or sedatives. The diagnosis is usually readily established on the basis of very high serum TSH and low T4 levels. Consideration must also be given to an extra-thyroidal influence on the hormone levels. Intensive care treatment involving intravenous high-dose L-thyroxine and the reversal of hypoxia improve the prognosis of the serious disease.

  19. Effect of nicotine on type 2 deiodinase activity in cultured rat glial cells.

    Gondou A; Toyoda N; Nishikawa M; Yonemoto T; Sakaguchi N; Tokoro T; Inada M

    Endocr J, 1999 Feb, 46(1):107-12

    Intracellular generation of triiodothyronine (T3) from thyroxine (T4) by type 2 deiodinase (D2) in the mammalian brain, plays a key role in thyroid hormone action. The presence of D2 in rat astrocytes suggests the importance of glial cells in the regulation of intracellular T3 levels in the rat central nervous system (CNS). To analyze further the factors that regulate D2 activity in the CNS, we investigated the effects of nicotine and of mecamylamine, which inhibits the binding of nicotine with nicotinic acetylcholine receptors, on D2 activity in cultured mixed glial cells of the rat brain. We incubated cultured mixed glial cells obtained from neonatal Wistar rats in the presence of 10 mM dithiothreitol, 2 nM [125I] reverse T3 and 1 mM 6-N-propyl-2-thiouracil for 2 h at 37 degrees C, and the released 125I- was counted in a gamma counter. D2 activity of cultured cells was dependent on the temperature and the amount of protein. The basal D2 activity of rat mixed glial cells was 1.9 +/- 0.2 fmol of I- released/mg protein/h (mean +/- SEM). The addition of 10(-11), 2 x 10(-11), 10(-10), and 10(-9) M nicotine significantly increased D2 activity to approximately 2.2-, 2.4, 3.5- and 2.9-fold the basal level, respectively. D2 activity stimulated by 10(-8) M nicotine (2.5-fold) reached a peak after 9 h incubation. The stimulatory effect of nicotine was completely blocked by 10(-6) M mecamylamine. In conclusion, nicotine increases D2 activity probably via nicotinic acetylcholine receptors, and may influence brain function, at least in part, by affecting thyroid hormone metabolism.

  20. The effect of nicotine on thyroid function in rats.

    Colzani R; Fang SL; Alex S; Braverman LE

    Metabolism, 1998 Feb, 47(2):154-7

    Very recently, it has been reported that subclinical hypothyroidism is more severe and peripheral markers of hypothyroidism are more pronounced in women with subclinical or overt hypothyroidism who smoke. Increased concentrations of the known goitrogen thiocyanate, generated from cigarette smoke, have been the major explanation for the decreased thyroid function in these women but do not explain the reported increased peripheral markers of hypothyroidism. There are no data on the effect of the other major product of cigarettes, nicotine, on thyroid function in vivo. The present studies were therefore performed to determine the effects of large doses of nicotine infused for 7 days on thyroid function, outer-ring 5'deiodinase activity (5'D-I), and hepatic malic enzyme activity (a measure of thyroid hormone action) in euthyroid, subclinically hypothyroid (hemithyroidectomized), and L-thyroxine (L-T4)-treated thyroidectomized rats. Nicotine infusion had no effect on serum T4, triiodothyronine (T3), thyrotropin (TSH), and cholesterol concentrations, intrathyroidal metabolism of 125I, liver and kidney 5'D-I activity, and hepatic malic enzyme activity in euthyroid and subclinically hypothyroid rats. Nicotine administration also did not affect serum T3, TSH, or cholesterol concentrations, liver and kidney 5'D-I activity, and hepatic malic enzyme activity in L-T4-treated thyroidectomized rats. These studies provide strong evidence that nicotine is not responsible for the observed adverse effects of smoking on the thyroid in humans.

  21. Effects of acute administration of ethanol and the mu -opiate agonist etonitazene on thyroid hormone metabolism in rat brain

    Baumgartner, A; Pinna, G; Hiedra, L; Bauer, F; Wolf, J; Eravci, M; Prengel, H; Broedel, O; Schmidt, G; Meinhold, H

    Psychopharmacology, vol. 135, no. 1, pp. 63-69, Jan 1998

    The effects of acute, low-dose administration of ethanol (1 g/kg bodyweight) and the mu -opioid receptor agonist etonitazene (30 mu g/kg bodyweight) on the activities of the iodothyronine deiodinase isoenzymes were investigated in nine regions of the rat brain. The experiments were performed at three different times of the 24-h cycle (1300, 2100 and 0500 hours) and the rats were decapitated 30 and 120 min after administration of the respective drugs. Interest was focused on changes in the two enzymes that catalyze 1) 5'-deiodination of thyroxine (T sub(4)) to the biologically active triiodothyronine (T sub(3)), i.e. type II 5'-deiodinase (5'D-II) and 2) 5 (or inner-ring) deiodination of T sub(3) to the biologically inactive 3'3-T sub(2), i.e. type III deiodinase (5D-III). 120 min after administration of ethanol and etonitazene 5D-III activity was selectively inhibited in the frontal cortex (at 1300 and 1700 hours) and the amygdala (at all three measuring times). The 5'D-II activity was significantly enhanced 30 min after administration of etonitazene in the frontal cortex, amygdala and limbic forebrain, and after administration of ethanol in the amygdala alone. These effects on 5'D-II activity were seen at 2100 hours only. In conclusion, the two different addictive drugs both reduced the inactivation of the physiologically active thyroid hormone T sub(3) and enhanced its production. These effects occurred almost exclusively in the brain regions which were most likely to be involved in the rewarding properties of addictive drugs. As thyroid hormones have stimulating and mood-elevating properties, an involvement of these hormones in the reinforcing effects of addictive drugs seems conceivable.

  22. The stressful condition as a nutritionally dependent adaptive dichotomy.

    Ingenbleek Y; Bernstein L

    Nutrition, 1999 Apr, 15(4):305-20

    The injured body manifests a cascade of cytokine-induced metabolic events aimed at developing defense mechanisms and tissue repair. Rising concentrations of counterregulatory hormones work in concert with cytokines to generate overall insulin and insulin-like growth factor 1 (IGF-1), postreceptor resistance and energy requirements grounded on lipid dependency. Salient features are self-sustained hypercortisolemia persisting as long as cytokines are oversecreted and down-regulation of the hypothalamo-pituitary-thyroid axis stabilized at low basal levels. Inhibition of thyroxine 5'-deiodinating activity (5'-DA) accounts for the depressed T3 values associated with the sparing of both N and energy-consuming processes. Both the liver and damaged territories adapt to stressful signals along up-regulated pathways disconnected from the central and peripheral control systems. Cytokines stimulate liver 5'-DA and suppress the synthesis of transthyretin (TTR), causing the drop of retinol-binding protein (RBP) and the leakage of increased amounts of T4 and retinol in free form. TTR and RBP thus work as prohormonal reservoirs of precursor molecules which need to be converted into bioactive derivatives (T3 and retinoic acids) to reach transcriptional efficiency. The converting steps (5'-DA and cellular retinol-binding protein-I) are activated by T4 and retinol, themselves operating as limiting factors of positive feedback loops. Healthy adults with normal macrophage functioning and liver parenchymal integrity, who submitted to a stress of medium severity, are characterized by TTR-RBP plasma levels reduced by half and an estimated ten-fold increase in free ligand disposal to target cells during the days ensuing injury. This transient hyperthyroid and hyperretinoid climate creates a second defense line strengthening and fine-tuning the effects primarily initiated by cytokines. The suicidal behavior of thyroxine-binding globulin (TBG), corticosteroid-binding globulin (CBG), and IGFBP-3 allows the occurrence of peak endocrine and mitogenic influences at the site of inflammation. The production rate of TTR by the liver is the main determinant of both the hepatic release and blood transport of holoRBP, which explains why poor nutritional status concomitantly impairs thyroid- and retinoid-dependent acute-phase responses, hindering the stressed body to appropriately face the survival crisis. The prognostic significance of low TT4 blood levels may be assigned to the exhaustion of extrathyroidal hormonal pools normally stored in liver and plasma but markedly shrunken in protein-depleted states. These data offer new insights into the mechanisms whereby preexisting malnutrition and stressful complications are interrelated, emphasizing the pivotal role played by TTR in that context.

  23. Thyrotropin receptors in brown adipose tissue: thyrotropin stimulates type II iodothyronine deiodinase and uncoupling protein-1 in brown adipocytes.

    Murakami M; Kamiya Y; Morimura T; Araki O; Imamura M; Ogiwara T; Mizuma H; Mori M

    Endocrinology, 2001 Mar, 142(3):1195-201

    It has been demonstrated that TSH receptors are expressed not only in thyroid gland but also in extrathyroidal tissues. Brown adipose tissue of guinea pig has been reported to express TSH receptor messenger RNA (mRNA), but the physiological roles of TSH receptors in brown adipose tissue have not been understood. We studied the expression and function of TSH receptors in rat brown adipose tissue and cultured rat brown adipocytes. Northern analysis demonstrated the expression of TSH receptor mRNA in rat brown adipose tissue and cultured rat brown adipocytes. TSH receptor mRNA in rat brown adipose tissue was decreased by cold exposure of the rat, and its mRNA in cultured rat brown adipocytes was also decreased by incubation with TSH or (Bu)(2)cAMP. TSH increased the intracellular cAMP concentration in cultured rat brown adipocytes in a dose dependent manner. Type II iodothyronine deiodinase mRNA, its activity, and uncoupling protein-1 mRNA in cultured rat brown adipocytes were significantly increased by incubation with TSH in a dose-dependent manner. These results suggest the expression of functional TSH receptors in brown adipose tissue, which may be involved in regulation of the expression of type II iodothyronine deiodinase and uncoupling protein-1.

  24. PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors.

    Mathur M; Tucker PW; Samuels HH

    Mol Cell Biol, 2001 Apr, 21(7):2298-311

    Members of the type II nuclear hormone receptor subfamily (e.g., thyroid hormone receptors [TRs], retinoic acid receptors, retinoid X receptors [RXRs], vitamin D receptor, and the peroxisome proliferator-activated receptors) bind to their response sequences with or without ligand. In the absence of ligand, these DNA-bound receptors mediate different degrees of repression or silencing of gene expression which is thought to result from the association of their ligand binding domains (LBDs) with corepressors. Two related corepressors, N-CoR and SMRT, interact to various degrees with the LBDs of these type II receptors in the absence of their cognate ligands. N-CoR and SMRT have been proposed to act by recruiting class I histone deacetylases (HDAC I) through an association with Sin3, although they have also been shown to recruit class II HDACs through a Sin3-independent mechanism. In this study, we used a biochemical approach to identify novel nuclear factors that interact with unliganded full-length TR and RXR. We found that the DNA binding domains (DBDs) of TR and RXR associate with two proteins which we identified as PSF (polypyrimidine tract-binding protein-associated splicing factor) and NonO/p54(nrb). Our studies indicate that PSF is a novel repressor which interacts with Sin3A and mediates silencing through the recruitment of HDACs to the receptor DBD. In vivo studies with TR showed that although N-CoR fully dissociates in the presence of ligand, the levels of TR-bound PSF and Sin3A appear to remain unchanged, indicating that Sin3A can be recruited to the receptor independent of N-CoR or SMRT. RXR was not detected to bind N-CoR although it bound PSF and Sin3A as effectively as TR, and this association with RXR did not change with ligand. Our studies point to a novel PSF/Sin3-mediated pathway for nuclear hormone receptors, and possibly other transcription factors, which may fine-tune the transcriptional response as well as play an important role in mediating the repressive effects of those type II receptors which only weakly interact with N-CoR and SMRT.

  25. The expression of thyrotropin receptor in the brain.

    Crisanti P; Omri B; Hughes E; Meduri G; Hery C; Clauser E; Jacquemin C; Saunier B

    Endocrinology, 2001 Feb, 142(2):812-22

    The regulation of the thyroid gland by TSH is mediated by a heterotrimeric G protein-coupled receptor. Nonthyroid effects of TSH have been reported, and expression of its receptor has been described in adipocytes and lymphocytes. We have previously reported the existence of specific and saturable binding sites of TSH and specific TSH effects in primary cultured rat brain astroglial cells. We now report expression of the TSH receptor gene in these cells; the coding sequence of the corresponding complementary DNA is identical to that previously established in thyroid. Using specific antisense RNA probe, expression of this gene was detected in some isolated or clustered glial fibrillary acidic protein-positive primary cultured cells by in situ hybridization. With this technique, we further detected TSH receptor messenger RNA (mRNA) expression in rat brain cryoslices in both neuronal cells and astrocytes. Its presence predominated in neuron-rich areas (pyriform and postcingulate cortex, hippocampus, and hypothalamic nuclei) and was mostly colocalized with neuron-specific enolase. In astrocytes, this mRNA was detected in the ependymal cell layer and the subependymal zone, and several isolated cells were also found in the brain parenchyma. We also detected TSH receptor mRNA and protein in primary cultured human astrocytes. The protein was detected as well in both rat and human brain cryoslices. Together, these findings clearly demonstrate the expression of the TSH receptor gene in the brain in both neuronal cells and astrocytes.

  26. PSF is a novel corepressor that mediates its effect through Sin3A and the DNA binding domain of nuclear hormone receptors.

    Mathur M; Tucker PW; Samuels HH

    Mol Cell Biol, 2001 Apr, 21(7):2298-311

    Members of the type II nuclear hormone receptor subfamily (e.g., thyroid hormone receptors [TRs], retinoic acid receptors, retinoid X receptors [RXRs], vitamin D receptor, and the peroxisome proliferator-activated receptors) bind to their response sequences with or without ligand. In the absence of ligand, these DNA-bound receptors mediate different degrees of repression or silencing of gene expression which is thought to result from the association of their ligand binding domains (LBDs) with corepressors. Two related corepressors, N-CoR and SMRT, interact to various degrees with the LBDs of these type II receptors in the absence of their cognate ligands. N-CoR and SMRT have been proposed to act by recruiting class I histone deacetylases (HDAC I) through an association with Sin3, although they have also been shown to recruit class II HDACs through a Sin3-independent mechanism. In this study, we used a biochemical approach to identify novel nuclear factors that interact with unliganded full-length TR and RXR. We found that the DNA binding domains (DBDs) of TR and RXR associate with two proteins which we identified as PSF (polypyrimidine tract-binding protein-associated splicing factor) and NonO/p54(nrb). Our studies indicate that PSF is a novel repressor which interacts with Sin3A and mediates silencing through the recruitment of HDACs to the receptor DBD. In vivo studies with TR showed that although N-CoR fully dissociates in the presence of ligand, the levels of TR-bound PSF and Sin3A appear to remain unchanged, indicating that Sin3A can be recruited to the receptor independent of N-CoR or SMRT. RXR was not detected to bind N-CoR although it bound PSF and Sin3A as effectively as TR, and this association with RXR did not change with ligand. Our studies point to a novel PSF/Sin3-mediated pathway for nuclear hormone receptors, and possibly other transcription factors, which may fine-tune the transcriptional response as well as play an important role in mediating the repressive effects of those type II receptors which only weakly interact with N-CoR and SMRT.

  27. Flavonoids as hormones. A perspective from an analysis of molecular fossils.

    Baker ME

    Adv Exp Med Biol, 1998, 439:249-67

    Although for centuries plants have been known to have hormone-like actions in humans, the mechanism(s) by which plant-derived compounds act in humans is still being elucidated, a goal that has assumed more importance due to interest in the protective actions of fruits and vegetables in diseases such as cancer. Here I use the "molecular fossil record" of amino acid sequences of proteins involved in regulating the actions steroids, retinoids, thyroid hormone and prostaglandins to propose some mechanisms by which flavonoids in fruits and vegetables can have hormone-like actions in humans. I focus on: i) hormone receptors that bind to DNA and regulate gene transcription and ii) the enzymes that regulate the concentrations of these hormones. Comparative analyses of amino acid sequences show that nuclear receptors for steroids, retinoids, thyroid hormone and prostaglandins in humans and insects are descended from a common ancestor. Similar analyses of dehydrogenases that regulate the concentrations of steroids, retinoids and prostaglandins reveal strong sequence similarity to enzymes in plants, insects, fungi, and bacteria. The similarity is sufficient to suggest that some compounds that bind receptors or enzymes in invertebrates, plants or unicellular organisms may also bind to mammalian homologs that are involved in endocrine physiology. Among the phytochemicals that are candidates for such activity are flavonoids because they are involved in plant-insect and plant-bacteria interactions and have some structural and chemical similarities to steroids, retinoids, thyroid hormone, prostaglandins and fatty acids. These similarities and the kinship of human, plant, insect and bacterial proteins involved in signal transduction provide a conceptual framework for investigating flavonoids for hormone-like actions in humans. Understanding these modes of action may be useful in developing protocols for preventing hormone-dependent diseases such as breast and prostate cancer.

  28. Examination of antithyroid effects of smoking products in cultured thyroid follicles: only thiocyanate is a potent antithyroid agent.

    Fukayama H; Nasu M; Murakami S; Sugawara M

    Acta Endocrinol (Copenh), 1992 Dec, 127(6):520-5

    We studied the antithyroid action of cigarette smoking products (nicotine, cotinine, and thiocyanate) in the physiological culture system of porcine thyroid follicles. Iodide uptake, iodine organification, de novo thyroid hormone formation, and iodide efflux were measured in the presence of 0-200 mumol/l nicotine, cotinine, or potassium thiocyanate. Nicotine and cotinine did not inhibit iodide transport or thyroid hormone formation. Thiocyanate concentrations equivalent to serum levels of smokers showed three independent antithyroid actions: (i) inhibition of iodide transport, (ii) inhibition of iodine organification, and (iii) increased iodide efflux. Inhibition of iodide transport by thiocyanate was competitive with iodide and independent of TSH concentration. Thiocyanate did not inhibit TSH mediated cAMP production or Na+K+ ATPase activity, a sodium pump for iodide transport. When 50 mumol/l thiocyanate was added 2 h after incubation with iodide or when 1 mumol/l thiocyanate was added from the beginning of incubation, iodine organification was inhibited without changing iodide transport. De novo thyroid hormone formation was clearly inhibited by 50 mumol/l thiocyanate. Thiocyanate increased iodide efflux although the degrees of iodide efflux by 10 mumol/l and 100 mumol/l thiocyanate did not differ significantly. In summary, thiocyanate, a product of smoking, has three independent antithyroid activities. The data of iodide transport kinetics suggest that thiocyanate can be an antithyroid agent particularly in iodine deficiency.

  29. Thyrotropin releasing hormone decreases alcohol intake and preference in rats

    Kulkosky, PJ; Allison, CT; Mattson, BJ

    Alcohol, vol. 20, no. 1, pp. 87-91, Jan 2000

    Thyrotropin releasing hormone (TRH) has been reported to reduce stress- and deprivation-induced eating, hypothetically by induction of satiation. Early work demonstrated thyroid extracts reduced alcohol intake, and recent research shows a TRH analog specifically inhibits alcohol preference. We determined whether parenteral administration of TRH reduces alcohol consumption and choice in a manner consistent with a satiation effect. Water-restricted ad lib fed female and male rats (n = 12) were given access to 5% w/v ethanol 0 or 30 minutes after intraperitoneal (i.p.) injection of TRH. TRH (20-40 mg/kg) inhibited alcohol intake only if injected immediately before alcohol access. Inhibition of alcohol intake was reliably accompanied by increased production of fecal boli but not by reliably decreased food intake. Rats given a choice of 2% w/v ethanol and water decreased alcohol preference after TRH (20 mg/kg) but did not reduce total fluid intake. Results are partially consistent with the hypothesis of TRH as one of several functional elements in the integrative neuropeptide control of alcohol consumption via short-term satiation.

  30. Retinoic acid activation and thyroid hormone repression of the human alcohol dehydrogenase gene ADH3.

    Harding, PP; Duester, G

    Journal of Biological Chemistry [J. BIOL. CHEM.], vol. 267, no. 20, pp. 14145-150, 1992

    We dissected the ADH3 RARE and determined that receptor binding as well as transactivation are dependent upon only the two downstream AGGTCA motifs separated by 5 base pairs, a structure noticed previously for a RARE in the promoter for the retinoic acid receptor beta (RAR beta ) gene. ADH3 and RAR beta RAREs functioned similarly in transfection assays, suggesting that the feedback mechanisms controlling ADH3 and RAR beta utilize a common RARE. We also found that the normal functioning of the ADH3 RARE was abrogated by thyroid hormone receptor in the presence of thyroid hormone. A negative thyroid hormone response element in the human ADH3 promoter was found to colocalize with the RARE. Since ADH production in rat liver is known to be repressed by thyroid hormone, these findings suggest that human ADH production may also be subject to thyroid hormone repression and that the mechanism involves an interference with retinoic acid induction.