06. Thyroid Gland

• thyroid gland secretes two main hormones - T3 and T4 (thyroxine)

  • important for developmental growth and metabolism
• thyroid hormone is made and stored in the lumen of the thyroid gland as colloid
• the thyroid is a thin fibrous capsule containing follicles and connective tissue - in and around the follicles are C cells
• C cells are the minority of thyroid cells

  • secrete calcitonin in response to high calcium levels - this inhibits osteoclasts from reabsorbing bone
  • decreases calcium in blood
  • other tissues also produce calcitonin so replacement is not required in the absence of a thyroid gland
• follicular epithelial cells are the majority of thyroid cells - line the follicles

  • responsible for production of T3 aND T4
  • controlled by thyroid stimulating hormone (TSH)
• thyroid hormone is derived from tyrosine and bound to iodine
• iodine occurs naturally in seawater and soil -> supplemented in UK milk
• iodine is transported into the cell from the blood (rate limiting step) - occurs against concentration gradient, mediated by sodium/iodide symporter located on basolateral cell membrane

  • once inside, iodide moves across the cell to the apical membrane and is transported out into the lumen
  • passive transporter - mediated by anion transporter pendrin
• thyroglobulin = most highly expressed protein in thyroid, serves as a scaffold for hormone synthesis and storage

  • very large, secreted into lumen
  • provides the tyrosine residues on which thyroid hormones are made
  • once thyroid hormones are made, its stored still attached to the thyroglobulin
• thyroid peroxidase (TPO) is a protein located on the apical membrane - catalyses oxidation of iodide to facilitate iodination of thyroglobulin tyrosine residues and also coupling of the iodotyrosines to form thyroid hormone

  • requires hydrogen peroxide
• iodinated thyroglobulin is stored in the lumen as colloid - when required its endocytosed into vesicles

  • fuse with lysosomes - thyroglobulin is digested by proteolytic enzymes to release T3 and T4
  • T3 and T4 secreted into bloodstream via thyroid hormone transporters like MCT8
• calcitonin inhibits osteoclast activity and bone resorption
• TSH is secreted by the anterior pituitary in response to TRH which is released by the hypothalamus when thyroid hormones are low

  • T3 and T4 have negative feedback
• TSH receptor is a GPCR located on basolateral membrane

  • TSH binding -> adenylyl cyclase -> cAMP -> binds PKA, activating it -> phosphorylates and activates a number of protein substrates like TFs
  • phosphorylation of CREB increases its transcriptional activity -> higher expression of thyroid specific genes like thyroglobulin
• TSH stimulates the expression of NIS (sodium/iodide symporter)

  • may also be important for localisation of pendrin at apical membrane
  • induces thyroglobulin expression
  • involved in iodination and conjugation steps through increased TPO expression
  • stimulates endocytosis of colloid
• thyroid hormones are hydrophobic - 70% bound to TBG in blood, rest bound to TTR and albumin
• there is far more T4 than T3 in circulation - mostly T4 secreted by thyroid

  • T4 = prohormone while T3 is the biologically active form
  • T4 is more stable than T3 - acts as a reservoir of inactive thyroid hormone
• T4 is converted into active T3 by deiodinases

  • three types - D1, D2 and D3
  • predominantly D2
  • D3 makes inactive form called reverse T3
• BMR = minimum energy expenditure required for basic bodily functions while at rest

  • thyroid hormone increases BMR through O2 consumption and heat production
• thyroid hormone actions:

  • alters mitochondrial activity
  • stimulates carbohydrate and fat metabolism
  • decreases circulating cholesterol
  • regulates contractility and heart rate
• thyroid hormone receptors are nuclear receptors - activate transcription factors and bind to thyroid hormones response elements

  • thyroid receptors can still bind to TREs in absence of ligand - co-repressor proteins bid and suppress gene expression