Thyroid hormone regulation of heme synthesis in rat liver

Thyroid hormone alters the rate of heme degradation and the levels of cytochrome P450 in rat liver. These studies report the effects of thyroid status on the activity of hepatic delta-aminolevulinate synthase (ALAS), the initial and rate-limiting enzyme in heme synthesis. Thyroidectomized male Sprague-Dawley rats received sc injections of diluent or hormones. T3 was found to stimulate ALAS activity in the liver in doses which rendered the animals euthyroid (0.3 microgram/100 g BW.day). Higher doses failed to enhance enzyme activity further. T4 had similar effects but was less potent; rT3 had no effect on ALAS activity. The administration of a large single dose of T3 (50 micrograms/100 g BW) produced a significant (P less than 0.001) increase in ALAS activity 72 h later. Allylisopropylacetamide administration induced ALAS activity to identical levels in both hypothyroid and T3-replaced animals when administered at a dose of 200 mg/kg body wt. A dose of 400 mg/kg body wt allylisopropylacetamide, one associated with maximal induction of ALAS, resulted in an 80% higher enzyme activity in T3-treated animals compared with controls. Exogenous T3 had no effect on ALAS activity in sham-operated animals. These findings indicate that thyroid status can influence the activity of ALAS, the rate-limiting enzyme in the synthesis of heme in rat liver, as well as heme degradation and the content of cytochrome P450 in this organ.     

Thyroid hormone regulation of the NADH shuttles in liver and cardiac mitochondria

Thyroid hormone can potentially regulate the malate/aspartate and alpha-glycerophosphate shuttle pathways in cardiac mitochondria either directly, by altering gene expression, or indirectly, by increasing myocardial workload. The goal of the current study was to determine the influence of thyroid hormone on the NADH shuttles in cardiac and liver mitochondria. Malate/aspartate and alpha-glycerophosphate shuttle capacities were significantly increased in cardiac mitochondria from adult rats treated for 9 days with T3 compared to saline-treated controls. Liver mitochondria demonstrated a significant increase in alpha-glycerophosphate and no change in malate/aspartate shuttle capacity. T3 increased steady-state mRNA levels and activity of mitochondrial alpha-glycerophosphate dehydrogenase in both myocardium and liver. Quantitative immunoblot studies demonstrated a significant increase in aspartate-glutamate carrier levels in T3-treated myocardium suggesting a regulatory role of the aspartate/glutamate carrier in T3-treated hearts. Thyroid hormone effects on the NADH shuttles are tissue-specific. Changes in the NADH shuttles in the presence of thyroid hormone excess occur both directly at the gene level and indirectly as an adaptive response.     

Thyroid hormone regulation of extrathyroidal iodoproteins.

The effect of thyroid status on plasma and tissue levels of labeled nonextractable iodine (NEI) derived from the metabolism of radioiodothyronines was examined in the rat. Concentrations of radioiodoprotein were substantially elevated in plasma, kidney, and liver in thyroidectomized animals 72 h postinjection of [125I]triiodothytonine ([125I]T3). Similarly, total rat concentrations of radioactive NEI were increased (52%) 72 h after injection of [125I]T3. NE125I concentrations from [125I]T3 in plasma, kidney, and liver were diminished progressively in thyroidectomized animals maintained on increasing doses of thyroxine replacement, demonstrating that iodoprotein levels were inversely related to thyroid state. The plasma disappearance rate of radioiodoprotein from [125I]T3 was markedly slowed in hypothyroid animals and accelerated in intact controls rendered hyperthyroid with daily injections of T4, 8 mug/100 g BW. Propylthiouracil (PTU) treatment of thyroidectomized rats maintained on T4, 2 mug/100 g BW per day resulted in increased NE125I from [125E]T3 in plasma, kidney, and liver. The results of the foregoing investigations suggest that thyroid hormone regulates levels of iodothyronine-derived iodoproteins by influencing the rate of degradation of iodoproteins. Moreover, the observed elevation of iodoprotein levels in T4-maintained thyroidectomized animals after PTU administration appears consistent with the modification of thyroid status due to the peripheral antithyroxine effect of PTU.     

Thyroid hormone regulation of calcium cycling proteins.

Alterations in thyroid hormone levels have a profound impact on myocardial contractility, speed of relaxation, cardiac output, and heart rate. The mechanisms for these changes include altered expression of several key proteins, involved in the regulation of intracellular calcium homeostasis. Most notably, increases in thyroid hormone and the coordinated increases in cardiac contractile parameters are marked by increases in the levels of the sarcoplasmic reticulum (SR) Ca2+-adenosine triphosphatase (ATPase) and decreases in its inhibitor, phospholamban. These changes at the protein level result in enhanced SR calcium transport and myocyte calcium cycling, leading to increases in the force and rates of contraction as well as relaxation rates at the organ level. However, decreases in thyroid hormone levels are associated with opposite alterations in these two proteins, leading to reduced myocyte calcium handling capacity and lower cardiac contractility. Furthermore, changes in the relative ratio of phospholamban/Ca2+-ATPase correlate with changes in the affinity of the SR Ca2+-transport system and relaxation rates in beating hearts. These findings suggest that thyroid hormone directly regulates SR protein levels and thus, cardiac function.     

Thyroid hormone regulation of the pulsatile discharges of luteinizing hormone in ovariectomized rats.

The pulsatile discharges of luteinizing hormone (LH) were characterized in ovariectomized rats in the presence or absence of thyroid hormone. LH secretion in ovariectomized rats with intact thyroid glands and thyroidectomized-ovariectomized rats receiving daily physiological doses of thyroxine (2 mug/100 g BW/day for 8 days) showed equivalent periodic discharges with frequencies between 15 and 45 min. Though the frequency of the plasma LH rhythm in untreated athyroid-ovariectomized rats was normal, the maximum and minimum concentrations were 2- to 3-fold higher than those of euthyroid-ovariectomized animals. On the other hand, treatment of athyroid-ovariectomized rats with a daily hyperthyroid dose of thyroxine (20 mug/100 g BW) for 8 days, attenuated pulsatile discharges of LH. The LH measured in the sera of these animals each gave dose-response curves by radioimmunoassay which were identical to the authentic rat LH reference preparation. Furthermore, neither the molecular profile nor the metabolic clearance rate of LH was affected by alterations in thyroid status. These results suggest that altered thyroid status does not influence the synthesis and metabolism of LH but does exert a profound effect on the secretion of this hormone by presumably acting directly on the hypothalamo-pituitary axis.     

Thyroid and steroid hormone regulation of proto-oncogene expression.

In contrast to the established effects of peptide growth factors on specific proto-oncogene expression, the actions of steroid and thyroid hormones are less clearly defined. However, there is increasing evidence that these hormones, acting through structurally related DNA-binding nuclear receptor proteins, influence proto-oncogene expression. This influence may determine the function of steroid and thyroid hormones in regulation of cell proliferation and maturation, and provide insight into the role of these hormones in oncogenesis.     

Thyroid hormone metabolism during liver regeneration in rats.

The metabolism of thyroid hormones was studied during the prereplicative period of liver regeneration. After partial hepatectomy, serum thyroxine (T4) and triiodothyronine (T3) levles progressively fell, and reached a nadir at 12 h proportional to the quantity of liver tissue exised. The diminution (60-80%) in serum iodothyronines was related specifically to partial hepatectomy because laparotomy, ether anesthesia, and other stressful surgical procedures did not induce similar changes. At least 3 phenomena appear to be involved: 1) increased utilization and turnover of thyroid hormone by the regenerating liver remmant. 2) diminished hormone secretion by the thyroid gland between 6-12 h after surgery, and 3) a slightly reduced concentration of serum iodothyronine carrier proteins. The results support the concept that the liver participates in the metabolic regulation of T2 and T4 which in turn, control hepatocellular growth. It is suggested, however, that additional unknown factors control increased hepatic thyroid hormone turnover after partial hepatectomy.     

Thyroid hormone and blood pressure regulation

Thyroid hormone has well-recognized effects on the cardiovascular system and blood pressure regulation. Blood pressure is altered across the entire spectrum of thyroid disease. The effects of hyperthyroidism include increased cardiac output, contractility, tachycardia, widened pulse pressure, decreased systemic vascular resistance, and increased basal metabolic rate. The manifestations of hypothyroidism are in marked contrast to those of hyperthyroidism and include decreased cardiac output, narrow pulse pressure, increased systemic vascular resistance, and decreased metabolic rate. Although thyroid hormone affects almost all tissues of the body and mediates changes in homeostasis, adaptations of the cardiovascular system can result in changes in blood pressure to accommodate the new demands on the system. In this paper, we review the direct and indirect thyroid hormone-mediated effects on blood pressure.     

Thyroid hormone feedback regulation of the secretion of bioactive thyrotropin in the frog.

Thyrotropin-releasing hormone (TRH), ovine corticotropin-releasing hormone (oCRH) (both 268 nM), and mammalian gonadotropin-releasing hormone (mGnRH) (268 and 2680 nM) stimulated the secretion of bioactive thyrotropin (TSH) by Rana esculenta pituitaries (pars distalis) in vitro. Preincubation of the pituitaries with 50 ng/ml (64 nM) thyroxine (T4) for 6 hr suppressed the TRH- and oCRH-induced (268 nM) secretion of bioactive TSH, but did not affect the response of the pituitaries to 268 nM mGnRH. Triiodothyronine (T3) (64 nM) reduced both the TRH- and mGnRH-stimulated release of bioactive TSH; the response of TSH to TRH even decreased toward basal levels while a significant TSH response to mGnRH remained. In a separate experiment, pituitaries were preincubated for 6 hr with different equimolar doses of T3 and T4 (6.4, 32, and 64 nM); neither treatment affected the mGnRH-stimulated secretion of bioactive TSH. On the other hand, T4 suppressed the TSH response to TRH in a dose-dependent manner. The inhibitory effects of thyroid hormones on the TRH-induced release of bioactive TSH was present for at least 4 hr after their removal from the incubation medium. These results suggest that thyroid hormones exert a negative feedback control on the secretion of bioactive TSH in adult frogs by a direct action on the pars distalis. There may also be differences in thyroid hormone sensitivities of the TSH responses to mGnRH and TRH.     

Thyroid hormone regulation of hypothalamic immunoreactive thyrotropin

Immunoreactive TSH (IR-TSH) has been identified in the hypothalamus and other brain areas in intact and hypophysectomized rats. To determine if thyroid hormones regulate IR-TSH in the rat brain, the effects of T3 and T4 on pituitary and hypothalamic IR-TSH content were studied in intact and hypophysectomized rats. Female rats received daily injections of T3 (0.1, 1.0, or 10 micrograms/100 g BW) or T4 (0.5, 2.5, or 5.0 micrograms/100 g BW) for 7 days. The chronic administration of T3 and T4 decreased the plasma concentration and pituitary content of IR-TSH in a dose-dependent manner. In intact rats, the administration of T3 did not affect the content of IR-TSH in the median eminence, ventral hypothalamus, or dorsal hypothalamus. In contrast, administration of T4 significantly increased the content of IR-TSH in the median eminence and ventral hypothalamus in a dose-dependent manner. Similarly, in hypophysectomized rats daily administration of T4 resulted in a dose-dependent increase in the concentration of IR-TSH in the median eminence and ventral hypothalamus. In hypophysectomized rats infusion of colchicine into the lateral ventricle, which blocks axonal transport, decreased the content of IR-TSH in the median eminence (631 +/- 59 vs. 439 +/- 36 microU/mg), increased the content of IR-TSH in the ventral hypothalamus (45 +/- 5 vs. 87 +/- 10 microU/mg), and blocked the T4-induced increase in IR-TSH in the median eminence. In intact rats, administration of iopanoic acid, which blocks the conversion of T4 to T3, decreased the content of IR-TSH in the median eminence (688 +/- 44 vs. 450 +/- 38 microU/mg) and ventral hypothalamus (103 +/- 16 vs. 70 +/- 5 microU/mg) and blocked the T4-induced increase in IR-TSH in the median eminence (1025 +/- 82 vs. 644 +/- 62 microU/mg) and ventral hypothalamus (229 +/- 23 vs. 117 +/- 11 microU/mg). These data indicate that TSH content in the median eminence and ventral hypothalamus is regulated by a thyroid hormone-sensitive mechanism which requires the local monodeiodination of T4 to T3. In addition, the effect of colchicine on the IR-TSH content in the median eminence and the T4-induced increase in brain IR-TSH are consistent with previous reports demonstrating that hypothalamic IR-TSH is regulated independently of pituitary and serum TSH.     

Thyroid hormone binding in rat liver cytosol

Binding of 3,5,3'-tri-iodothyronine (T3) and thyroxine (T4) to components of perfused rat liver supernatant fraction and isolated liver cell cytosol was studied. Of the four binding fractions in supernatant (X, A, Y and Z) separable by gel chromatography, both T3 and T4 bound preferentially to the A-fraction, which was shown to contain albumin as the major binding protein. When cytosol prepared from isolated cells was examined, T4 was again bound mainly in the A-fraction; however, T3 was observed to bind predominantly in the Y-region. Hormone binding to soluble protein in the latter system is thought to reflect the pattern in vivo, better than does binding in supernatant, although the possibility exists that the concentration of albumin observed in cytosol may be artificially high due to transfer of membrane-bound albumin during cell disruption. Nevertheless, albumin (possibly derived from more than one intracellular source) is capable of binding T4 in vivo. The presence of this protein within the hepatocyte may thus contribute to the high T4 binding capacity of the liver compared to other tissues.     

Thyroid hormone regulation of the catecholamine effects in human adipose tissue

The possibility of a relationship between the thyroid hormone level and the peripheral action of catecholamines was examined in 4 normal-weight and 19 obese euthyroid subjects as well as in 27 hyperthyroid subjects by comparing the serum thyroid hormone level and the in vitro effect of catecholamines on lipolysis and cyclic AMP accumulation in adipose tissue incubated with and without isopropyl noradrenaline (ISNA) or noradrenaline (NA). ISNA- and NA-induced rates of lipolysis and cyclic AMP production were significantly correlated with free thyroxine index (r = 0.63-0.74) and with the serum triiodothyronine level (r = 0.83-0.87). The thyroid hormone level was neither correlated with basal rate of lipolysis nor with basal cyclic AMP production (r < 0.2). These results suggest that the magnitude of catecholamine-induced cyclic AMP production by peripheral cells may be regulated by the level of circulating thyroid hormones. The effect of thyroid hormones on lipolysis appears to be specifically linked to the action of catecholamines.     

Thyroid hormone deiodination in birds.

Because the avian thyroid gland secretes almost exclusively thyroxine (T4), the availability of receptor-active 3,3',5-triiodothyronine (T3) has to be regulated in the extrathyroidal tissues, essentially by deiodination. Like mammals and most other vertebrates, birds possess three types of iodothyronine deiodinases (D1, D2, and D3) that closely resemble their mammalian counterparts, as shown by biochemical characterization studies in several avian species and by cDNA cloning of the three enzymes in chicken. The tissue distribution of these deiodinases has been studied in detail in chicken at the level of activity and mRNA expression. More recently specific antibodies were used to study cellular localization at the protein level. The abundance and distribution of the different deiodinases shows substantial variation during embryonic development and postnatal life. Deiodination in birds is subject to regulation by hormones from several endocrine axes, including thyroid hormones, growth hormone and glucocorticoids. In addition, deiodination is also influenced by external parameters, such as nutrition, temperature, light and also a number of environmental pollutants. The balance between the outer and inner ring deiodination resulting from the impact of all these factors ultimately controls T3 availability.