56 - Iodine Metabolism and Thyroid Hormones Flashcards
Amount of iodine in a healthy adult
15-20 mg
Amount of iodine in the body that is stored in the thyroid
70-80%
Recommended daily intake of iodine
150 micrograms per day (1100 micrograms as the upper limit)
Health consequences of low iodine at all ages
1
2
3
1) Goitre
2) Hypothyroidism
3) Thyroid gland displays increased susceptibility to nuclear radiation
Foetal consequences of low iodine 1 2 3 4
1) Spontaneous abortion
2) Stillbirth
3) Congenital abnormalities
4) Perinatal mortality
Childhood, adolescent consequences of low iodine
Impaired mental function
Delayed physical development
Adult consequences of low iodine
1
2
3
- Impaired mental function
- Reduced work productivity
- Iodine-induced hyperthyroidism
Goitre
Physiological adaptation to chronic iodine deficiency.
Excessive TRH released, leading to excessive TSH stimulation (from anterior pituitary gland) of thyroid gland, leading to hypertrophy, hyperplasia.
Negative feedback regulation of thyroid gland
Hypothalamus releases thyroid stimulating hormone releasing hormone (TRH)
Anterior pituitary gland releases thyroid stimulating hormone
Thyroid gland releases T4/T3, which negatively feedback on pituitary gland and hypothalamus.
What do T3 and T4 refer to?
Number of iodine atoms joined to thyroid hormone (T3 has three, T4 has four)
Where do the cell bodies of neurons communicating with the posterior pituitary lie?
In the paraventricular nucleus of the hypothalamus
Protein transporters involved in moving TRH into pituitary gland cells
Monocarboxylate transporter 8 (MCT8) and organic anion transporter of polypeptides (OATP)
Nucleus involved in negative regulation of TRH release
Paraventricular nucleus
Structure of thyroid gland
Follicular glands, which is where most thyroid hormone is synthesised.
Follicles have lumens, into which hormone is secreted.
How does iodine enter thyroid follicular cells?
Through Na+/I- symporter
How does iodine travel into follicular lumen?
Through pendrin channel
What catalyses the iodination of thyroglobin?
Thyroperoxidase
Steps of biosynthesis of thyroid hormone 1 2 3 4 5 6
Involves iodination of tyrosine residues in thyroglobulin.
Iodination catalysed by thyroperoxidase.
If iodinated in one position, called monoiodotyrosine (MIT).
If iodinated in two positions, called diiodotyrosine (DIT)
- At the basolateral membrane of thyroid follicular cells, iodide is taken up by the sodium/iodide symporter (NIS). Sodium gradient of the cell is created by the Na+/K+-ATPase
- At the apical membrane, iodide enters the lumen of thyroid follicles via an anion exchanger termed pendrin.
- At the cell-lumen interface, iodide is oxidised by the thyroid peroxidase (TPO) and H2O2 to atomic iodine (I).
- Thyroglobulin (TG) is synthesised in the follicular cells and secreted into the lumen. TPO catalyses iodination of TG by the atomic iodine (I) to form mono- and di-iodotyrosines.
- TPO also catalyses coupling of the iodinated tyrosine residues to form the T3 and T4-moieties in TG which is then stored in as colloid in the lumen.
- Upon stimulation by TSH for secretion, the iodinated TG is internalised into the follicular cells where it is digested in lysosome to generate T3 and T4.
- T3 and T4 is released into the blood circulation by an unknown mechanism (possibly by monocarboxylate transporter).
How do T3 and T4 enter target cell?
Through thyroid hormone transporter.
How is T4 activated?
By conversion to T3 within target cell.
Cellular site of T3 action
Nucleus
What determines bioavailability of thyroid hormones?
Deiodination (of T4)
T4 structure
Two benzene rings.
Four iodines, two on each benzine ring.
Iodines that can be removed from thyroid hormones
5’ position iodines (2x 5’ position I and 2x 3’ position I)
Role of D1 and D2 deiodinases
Convert T4 to T3.
Convert rT3 to T2.
Role of D1 and D3 deiodinases
Reverse T3.
Function of rT3 not well understood. Might initiate actin polymerisation in astrocytes.
Role of D3 deiodinase by itself
Converts T3 to T2
T2
Inactive, rapidly degraded form of thyroid hormones
Product of decarboxulation of products of thyroid hormone
3-iodothyronamine
3-iodothyroamine role
1
2
3
- Reduce body temperature and cardiac output
- Signal through membrane-bound G protein coupled receptor (unknown receptor)
- Exact mechanism: unclear
Major physiological actions of thyroid hormone 1 2 3 4 5
1) Increases O2 consumption of almost all metabolically active tissues
2) Increases energy substrate uptake and utilisation
3) Increases energy consumption
4) Increases cellular respiration rates
5) Increases pulse rate and heart rate
Mechanism by which thyroid hormones create effects
Increased expression of genes of structural and functional proteins.
Increased expression of proteins involved in thermogenesis and mitochondrial function
Examples of genes stimulated by thyroid hormones
Myosin heavy chain
SERCA (Ca2+ pump in skeletal muscles, moves Ca2+ from cytoplasm into sarcoplasmic reticulum)
Beta-adrenoceptors
N+/K+ ATPase
How does thyroid hormone affect transcription?
- THR (thyroid hormone receptor) forms dimer with RXR (retinoid X receptor) and bind to the thyroid responsive element (TRE) upstream of the transcriptional start site.
- THR/RXR dimer bind to the co-repressor complex (CoR) which prevents transcription of the target gene
- Binding of T3 to THR replaces CoR with co-activator complex (CoA) to initiate transcription of the target gene
How does T3/thyroid hormone receptor/co-activator complex initiate gene transcription?
Bind to thyroid response element.
Replacement of the co-repressor complex with co-activator complex leads to removal of histone acetylation nucleosome removal, de-repressing gene
Isoforms of thyroid hormone receptor
Alpha and beta isoforms
How does TH affect mitochondria?
Leads to transcription of mRNAs, which lead to translation of transcription factors or co-activators.
These form mitochondrial proteins.
TH can also enter mitochondria, and binds to TH response elements on miDNA.
Mitochondrial protein particularly stimulated by TH
PGC-1alpha.
Transcription factor, particularly involved in thermogenesis, mitochondrial biogenesis.
Form of TH which has more genomic effects
T3
Form of TH which has more non-genomic effects
T4 (can bind to cell surface receptors)
Non-genomic effects of TH (T4 is predominant)
Alterations in ion flux across membrane.
Monocarboxylate transporter modulation (this transporter transports TH across membrane). Aspect of negative regulation.
TH cell surface receptor
Integrin alphaV beta3.
