4-Mammalian%20thyroid%20axis[1] - The

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Unformatted text preview: The HypothalamusHypothalamusPituitaryPituitary-Thyroid Axis of Mammals 1 • The thyroid gland is one of the oldest vertebrate thyroid gland is one of the oldest vertebrate endocrine glands phylogenetically • Thyroid hormones (THs) are stored extracellularly and the storage capacity of the gland is high • THs have direct as well as many permissive actions throughout the body ti th th • Thyroid disorders are the second most frequent endocrine diseases, they occur mainly in women II. Development and Organization of the Mammalian Thyroid Gland 2 Ontogeny of the thyroid gland colloid in lumen thyroid gland gland follicular cell capillary parafollicular cell blood vessel nerve 3 4 III Synthesis Secretion Action III. Synthesis, Secretion, Action and and Metabolism of Thyroid Hormones Dietary iodide and iodide uptake • Iodine is an essential constituent of THs is an essential constituent of THs • The main source of iodine is dietary iodide (I-) • In some regions environmental I- is in short supply, eventually leading to the formation of hypothyroid goiters 5 Worldwide location of iodide-poor regions Goiters due to iodine deficiency 6 Synthesis of THs Accumulation of iodide (I-) by follicular cells of iodide (I by follicular cells Synthesis of thyroglobulin Oxidation of iodide to iodine radicals Binding of iodine radicals to tyrosine residues in thyroglobulin • Coupling of iodinated tyrosines to form thyroxin • Storage of thyroglobulin containing thyroxin in the lumen of the follicle • • • • Na-I symporter (NIS) x pendrin 7 8 tyrosine monoiodotyrosine (MIT) diiodotyrosine (DIT) DIT + DIT tetraiodothyronine (T4) DIT + MIT (only if I- shortage) MIT (only if triiodothyronine (T3) 9 Secretion of THs • Engulfing of colloid by follicular cells of colloid by follicular cells (endocytosis) • Hydrolysis of thyroglobulin to release T4 • Conversion of some T4 to T3 • Entry of T3 and T4 into the general circulation 10 11 endolysosome 12 Peripheral metabolism of THs glucuronide conjugation deiodination inner ring outer ring I HO 5' 4' I 3' deamination I 6' 1' O 5 1 4 2' 6 3 NH CH 2 CH 2 COOH 2 I decarboxylation sulfate conjugation ether-link cleavage 13 TH deiodination by iodothyronine deiodinases: I I HO I CH2 I I CH2 COOH IRD T4 I NH2 O CH I ORD HO NH2 O CH COOH NH2 HO O I I CH2 CH COOH I T3 rT3 ORD IRD NH2 HO O I CH2 CH COOH I T2 14 Transport and uptake of THs • Most THs in circulation are bound reversibly THs in circulation are bound reversibly to serum proteins: - thyroid-binding globulin = thyroxin-binding globulin (TBG) - transthyretin (TTR) = prealbumin (TBPA) - albumin (TBA) • Cellular uptake of free TH is regulated by TH transporters: - organic anion transporting peptides (OATP) - monocarboxylate transporters (MCT) Mechanism of action of THs • THs bind to nuclear thyroid hormone bind to nuclear thyroid hormone receptors (TRs), two genes TR and TR • Affinity of TRs for T3 >> T4 • TRs form heterodimers mostly with retinoid X receptors (RXRs) • Receptor complex interacts with a thyroid th response element (TRE) in the promoter region of thyroid responsive genes 15 CoR = corepressor, CoA = coactivator HMT = histone methyl transferase, HDAC = histone deacetylase HDM = histone demethylase, HAT = histone acetyl transferase CRC = chromatin remodeling complex • TR2 does not bind T3 dominant repressor activity 16 IV. Factors that Influence Thyroid Function in Mammals Endocrine factors • TRH stimulates synthesis and secretion of stimulates synthesis and secretion of TSH from the pars distalis • TSH stimulates synthesis and secretion of THs from the thyroid gland • THs exert a negative feedback on TRH and TSH synthesis and release TSH synthesis and release effect on TSH > on TRH • Melatonin inhibits hypothalamic TRH release 17 low activity animal mostly hypothyroid normal activity animal is euthyroid high activity animal can be hypo- or hyperthyroid 18 NonNon-endocrine factors • Amount of I- in the diet • Inhibitors of I- uptake: thiocyanate (SCN-), perchlorate (HClO3-), pertechnetate (TcO4-) • Inhibitors of iodination: propylthiouracil (PTU), methimazole (MMI), progoitrin goitrin of deiodination: PTU iopanoic acid • Inhibitors of deiodination: PTU, iopanoic acid (IOP) • Endocrine disrupters: dioxins, polychlorinated biphenyls (PCBs), polybrominated flame retardants, HClO3-, etc. Brain Eye Eye Control tadpoles Thyroid glands 500 µg perchlorate/L 19 Control 500 µg perchlorate/L V. Biological Actions of Thyroid Hormones in Mammals 20 Metabolic actions • Thermogenic action (cold adaptation): action (cold adaptation): - upregulation of basal metabolic rate (BMR) with increased oxygen consumption & glucose oxidation - uncoupling of oxidative phosphorylation via increase in uncoupling protein 1 (UCP-1) • Biphasic effect on carbohydrate, lipid & protein metabolism (together with other hormones) low levels = anabolic, high levels = catabolic permissive action direct control 21 22 Development: growth and differentiation • THs stimulate development and maturation of stimulate development and maturation of many organs, including brain, heart, lung & skeletal bones • Nervous tissue development is highly sensitive to abnormal TH levels • Severe maternal hypothyroidism during maternal hypothyroidism during pregnancy results in cretinism of the newborn 23 mutation in MCT8 cretinism postnatal hypothyroidism 24 Treatment of juvenile hypothyroidism Reproduction • Sexual maturation is generally delayed in maturation is generally delayed in hypothyroid mammals • May be linked to a decrease in gonadotropic hormone levels 25 EXAMPLES OF THYROID DISEASES 1° Hypothyroidism Hyperthyroidism 26 ...
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