PGY452 552 Endocrine physiology 10 Thyroid hormone A B C D E Synthesis Buffering metabolism Effects HPA regulation feedback Pathophysiology The Thyroid First recognized gland hormone Amide hormone Many similarities to steroids Essential in childhood for normal growth development Adults normal metabolism Known for pathophysiology 2 Thyroid gland Follicles follicular cells follicular lumen Follicular cells Follicular lumen Capsule C cell calcitonin Capillary 3 Thyroid hormones are made from iodine and tyrosine Tyrosine Y or Tyr MIT monoiodothyronine DIT di iodothyronine T3 tri iodothyronine T3 T4 collectively known as thyroid hormone Unique biosynthetic pathway T4 thyroxine Depends on thyroid anatomy Only biological role for iodine Five Steps to synthesis 4 Step 1 thyroglobulin synthesis thyroglobulin has 140 tyrosines substrate for iodination Follicular cells synthesize thyroglobulin 5496 amino acid protein Pol II ECF Follicular cell OH Transported to lumen via exocytosis CH2 C R H N C O Follicular Lumen C H O N H C C R 5 Step 2 Active transport of iodine from the blood I Pendrin Na independent Cl I transporter Na I cotransporter follicular cell I 2 Na I ATP 3 Na 2 K ECF Na K ATPase provides energy ADP Iodine lumen down concentration gradient through Pendrin Iodine uptake 80 g day Capacity 8 mg Follicular cell Follicular Lumen 6 Step 3 Iodine conjugation to thyroglobulin Thyroid peroxidase complex H2O2 I I Follicular cell Follicular Lumen 0 90 DIT OH I Organification O N H C CH2 C C CH2 O C H I O C H O N H C C CH2 CH2 C Organification required for Iodine Trap High iodine leaving lumen OH Thyroglobulin I 7 OH OH Iodinated Thyroglobulin Colloid Step 4 Colloid formation Within OH I I OH I I CH2 C C H Spontaneous rearrangement N H O O I I Within OH I Between CH2 I C C H N H O CH2 C C H CH2 N H O Follicular Lumen C O C H N H Colloid is the major source of stored thyroid hormone Usually several weeks supply 8 Step 5 Colloid T4 T3 10 Colloid digested by proteases to give T3 T4 Iodine scavenged by thyroid deiodinase transported to lumen through Pendrin I DIT MIT 90 Endocytosis into follicular cells T3 T4 pass through a transporter to ECF ECF Follicular cell Follicular Lumen 9 T4 critical to thyroid buffering system Thyroid gland makes 90 T4 Half lives t1 2 I 24 hr for T3 8 days for T4 BUT T3 activity 15x T4 AND the available T3 concentration is much higher Free T3 of total free thyroid hormone How 1 Affinity for thyroxin binding globulin 2 Conversion of T4 T3 OH I O I I T4 OH I O I I T3 10 1 T4 T3 binding proteins buffer serum concentration TBG TBG Thyroxin binding globulin Major thyroxin binding protein Glycoprotein 54 kD Made in liver Binds one T4 or T3 25x higher affinity for T4 Increases T3 free T3 T4 10 Made 90 99 50 Bound 99 98 0 50 Free 0 02 1 Ratio free 0 36 11 2 Conversion of T4 T3 TH 5 3 deiodinase T4 T3 o o TBG TBG Liver kidney Circulates TBG Target cell T4 T3 Doesn t circulate Target OH I T4 Liver kidney I I I T3 I O O I OH I I O I OH OH I Receptor I O I T3 I I I I T4 12 Signaling T3 activates thyroid nuclear receptor Type II nuclear receptor Heterodimer H Thyroid H co transporter MCT8 H Thyroid receptor Two forms Tissue specific Gene expression Retinoid X receptor TRE Thyroid response element Regulates transcription Similar to steroids RXR TR TRE CCorepressor oac tiva to r Pol II 13 Thyroid hormone metabolism Type 1 iodothyronine deiodinase D1 T4 T3 rT3 T2 D1 D3 Type 2 iodothyronine deiodinase D2 T4 T3 rT3 T2 D2 D1 Type 3 iodothyronine deiodinase D3 D3 D1 D1 D2 T4 rT3 T3 T2 TBG bound hormone is not metabolized Modified by glucuranation or sulfation Excreted 14 Thyroid hormone function T3 THR transcription factor is required for normal expression of genes required for metabolism stress response and development in many tissues especially in fetal neonatal development 15 Systemic effects of thyroid hormone Essential for growth development maturation during fetal development in children Musculoskeletal Central peripheral nervous system adrenergic response Receptor synthesis Epinephrine norepinephrine Endocrine system Sympathetic nervous system Important for normal cardiac output Thyroid hormone levels don t change much Except in pathophysiology 16 Metabolic effects are futile LPL Glycogen 3 2 Amino Acids 4 NEFA ATP 1 HSL p ox s ho Proteins Citric oxidation acid Muscle TA G cycle Adipose Liver Pyruvate 17 Metabolic effects are futile 1 Increases BOTH protein synthesis degradation but degradation more resulting in an increase in plasma amino acid concentrations 2 Stimulates synthesis of hormone sensitive lipase lipoprotien lipase and lipogenic enzymes resulting in an increase in plasma free fatty acids 3 The lipids amino acids are taken up by the liver 4 Where they are used for energy and substrates respectively for gluconeogenesis resulting in increased glycogen stores The protein metabolism issue in skeletal muscle is a bit complex Some sources claim that TH is more anabolic toward skeletal muscle protein in children and more catabolic in adults The anabolism catabolism effect is also dose dependent Higher TH concentrations seem to favor muscle protein anabolism This is obviously something I won t hold you to 18 General BMR increase ATP use from futile metabolism O2 consumption Oxidative phosphorylation Thermogenesis Thermogenesis Maintain membrane ADP potential 15 40 cell s energy use Proteins TAG 2 K ATP ATP NEFA Amino acids Glucose ATP Electrogenic ATPase synthesis O2 Heat ATP ATP 3 Na Oxidative phosphorylation O2 ATP 19 Hypothalamus Regulation through HPA Thyroid releasing hormone TRH Tripeptide from large precursor Pulsed release Weak regulation Tonic release TRH Energy IN Thermal Controls release of TSH Thyroid stimulating hormone TSH Thyrotrophs Glycoprotein MW 28 000 2 subunits common to other hormones Follicle stimulating hormone Luteinizing hormone Chorionic gonadotropin unique to TSH is glycosylated TSH Anterior Pituitary a b 20 TRH TSH increase thyroid hormone synthesis TSH TSH Stimulates growth Same Receptor division of follicular cells TRH TSH Same Receptor s AC cAMP cAMP q PLC q ATP PKAii cAMP PLC PLC PLC PKC PKA cAMP PKC PKAii cAMP P P TSH Expression and activity of all proteins involved in thyroid hormone synthesis Pol II Ca2 Pol II Ca2 Thyrotroph Follicular cell 21 HPA feedback control Long loop negative feedback Short loop negative feedback Environmental Energy IN T4 T3 in thyrotrophs hypothalamic PVN I I I 22 Pathophysiology hypothyroidism Metabolic symptoms