Flashcards in L3 Thyroid Hormone Deck (10):
1
Synthesis of T3 and T4 (basics)
Synthesized from tyrosine residues on thyroglobulin (TG)
- Requires dietary iodide
- Synthesis controlled by TSH
T3 = triiodothyronine (biologically active)
T4 = thyroxine (preferential synthesis, prohormone)
Reverse T3 also produced, biologically inactive
2
Iodide transport and storage
- Most is stored in the thyroid gland
- Concentrated in gland by a 2Na+/I- symporter (no ATP)
- Gland can autoregulate iodide transport according to needs
- Chronic iodide deficiency can lead to hypothyroidism (problem in landlocked areas) - can be corrected with dietary supplements
- Most is associated with colloidal TG
- Ultimately TH is metabolized and iodide is excreted
3
Steps of TH synthesis and storage
1. Thyroglobulin (TG) are produced in ER, packaged into vesicles, exocytosed into follicle
2. I- enters thyrocyte and rapidly associates with apical membrane
3. In follicular lumen, I- is oxidized to iodine by thyroid peroxidase and is put on tyrosine residue on TG (replaces H+)
4. MIT: binding of one Iodine, DIT: binding of two iodine (called organification). Tyrosine perioxidase also combines DIT+DIT to make T4. Also some T3 is made (DIT+MIT)
5. Endocytosed back into cell and stored as colloid
6. Colloid proteolysis is stimulated by TSH. DIT and MIT reenter pool for more synthesis, T3 and T4 released into blood
4
Thyrocyte response to TSH
- Secretes T4 (93%) and T3 (7%)
- Most circulating TH is bound to TBG (70%), other binding proteins are transthyretin and albumin
- Free TH is what circulates (~0.03 T4 and 0.3% T3) and enters tissues --> binds to receptor on the thyroid response element (TRE) of gene --> T3/T4 binding regulates transcription of these genes
5
How is T3 generated from T4?
- T4 is metabolized by peripheral deiodinases
- Antithyroid agents (used to tx hyperthyroidism) inhibit the conversion of T4 to T3
- T4 is used to treat hypothyroidism because of its longer half-life and greater stability
- THs have slow onsets and long duration of action
6
Effects of thyroid hormone
- Increase metabolic rate of O2 consumption
- Important for BMR (increases in hyper and decreases in hypothyroidism)
- Acts with GH and somatomedins to promote bone formation
- Promote ossification and fusion of bone plates/maturation
- Essential for CNS development in perinatal period - TH deficiency in infants results in mental and growth retardation
- Treat with thyroxine/T4
7
Physiological effects of low levels of thyroid hormone
- Decreased BMR
- Carbohydrate metabolism: decreased gluconeogenesis and glycogenolysis, normal serum [glucose]
- Protein metabolism: decreased synthesis and proteolysis
- Lipid metabolism: decreased lipogenesis, lipolysis, increased serum [cholesterol] - increased risk for arteriosclerosis
- Decreased thermogenesis
- Normal levels of serum catecholamines
8
Physiological effects of high levels of thyroid hormone
- Increased BMR
- Carbohydrate metabolism: increased gluconeogenesis and glycogenolysis, normal serum [glucose]
- Protein metabolism: increased synthesis and proteolysis, muscle wasting (proteolysis outweighs synthesis)
- Lipid metabolism: increased lipogenesis, lipolysis, decreased serum [cholesterol]
- Increased thermogenesis
- Increased expression of beta adrenoreceptors (increased sensitivity to catecholamines, which remain at normal levels). Beta adrenergic antagonists can treat hyperthyroidism symptoms
9
What is thyroid function regulated by?
- Hypothalamic TRH (+): stim TSH release through GPCR linked to PLC/IP3/intracellular Ca
- Anterior pituitary TSH (+): stim TH release through GPCR linked to adenylate cyclase and cAMP
- Circulating T3 and T4 (-): negative feedback
- Dopamine and somatostatin inhibit TSH release
10