4-Mammalian%20thyroid%20axis[1] - The -Thyroid Axis of...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

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 ...
View Full Document

{[ snackBarMessage ]}

Ask a homework question - tutors are online