lecture 8- thyroid hormones: transport, metabolism and actions

thyroid hormones

• derived from tyrosine

• reverse t3 is inactive form of thyroxine

• less than 1% of rt3 is secreted

thyroxine(t4)

• insoluble in serum

• transported in serum with specific binding proteins

• binding proteins synthesised in liver

• liver disease can lead to loss of effective t4 transport to peripheral tissues

• liver disease may be a reason for thyroid disease

thyroid hormone binding proteins

• reservoir of thyroid hormones in blood

• albumin is ubiquitous(very common)

• albumin binds 5-10% of plasma t4

• transthyretin(TTR) binds 20% of plasma t4, important for delivery to CNS

• thyroxine-binding globulin(TBG) binds 70-75% of plasma t4, large circulating reservoir of t4, prevents loss in urine

thyroid hormone transport

• bound t4 circulated around the body

• needs to be free to interact with receptors

• different degree of looseness to binding proteins

• t4 needs to be converted to t3(active form)

• thyroid hormone produced daily from thyroid gland

affinity and capacity of t4 binding proteins

• albumin has loose bond with thyroid so it is released easily

• when there is a lot of albumin, large capacity for binding protein to bind to hormone

• TBG has high affinity and low capacity for t4

• transthyretin has low affinity has a low affinity and high capacity for t4

• albumin has a very low affinity and high capacity for t4

specificity of thyroid hormone binding proteins- t3

• TBG binds to t4 and t3, half life 5 days

• transthyretin binds t4 only, half life 2-3 days

• albumin binds to t3 and t4, half life of 15 days

• protein bound t4: protein bound t3 is 20:1

thyroxine binding globulin(TBG)

• single polypeptide chain

• 20 CHO by weight

• increased by t4 and oestrogens/androgens

• stability and half-life extended after t4 binding

• doubles in concentration during pregnancy

• levels lowered by corticosteroids, illness, stress, cirrhosis, nephrotic disorders

• leaky nephrons- excrete it, lose from circulation

t4 location

• small percentage will never be bound

• t4 needs to be converted to t3 first

TBG and TTR functions

• prolong t4 availabilityy to target tissues

• buffer effects of altered t4 secretion rate from thyroid gland

• reservoir for t4 storage

• determine and control rate and direction of delivery of t4 to specific tissues

transport of t3 and t4 into cells

• bound t3 and t4 can’t enter cells

• free t3 and t4 enter cells via specific transporters(MCT8, MCT10, OATP1c1)

• t4 is inactive and must be converted to t3 by intracellular iodothyronine deiodinases

iodothyronine deiodinases

• seleno-cysteine containing enzymes

• selenium accepts iodide

• inactive t3 is there to make sure correct amount of thyroid hormone is present to allow correct brain development in the foetus

• DIO3 fine tunes concentration of thyroid during development

iodothyronine deiodinaase 1 -DIO1

• predominates in liver, kidney and muscle

• also found in thyroid

• produces most of circulating t3

iodothyronine deiodinase 2- DIO2

• predominates in areas of CNS, pituitary thyrotropes

• controls intracellular t3 concentration

• important for feedback regulation

• found in skeletal muscle in some species

iodothyronine deiodinase 3-DIO3

• produces inactive rt3

• prevents thyroid hormone access to specific tissues

thyroid hormone action

• thyroid hormone receptor(TR)

• TR alpha and beta

• found in nucleus

• heterodimer with retinoid X receptor

• works as a transcription factor

• binds to thyroid responsive elemen(TRE)

• increased 15 fold affinity for t3 than t4, so t3 more active

• increased gene transcription

• can also inhibit gene transcription

in the anterior pituitary gland

• t3 responsive genes include those encoding increased growth hormone, decreased prolactin, decreased alpha and beta subunits of TSH

• when t3 bound it triggers transcription

biological actions of thyroid hormones

• control of basal metabolic rate

• growth regulating roles of thyroid hormones

• role of thyroid hormones in foetal development

• cardiovascular effects

• musculoskeletal effects

control of basal metabolic rate

• influence expression of particular proteins

• increase oxygen demand

• increased cardiac output and ventilation rate

• increased waste products

• insensible water loss- breathe out more deeper, lose water from lungs

• hyperthyroidism leads to high metabolic rate, tremor, muscle wastage

• most common endocrine disorder in cats, weight loss despite normal or increased appetite

growth regulating roles of thyroid hormone

• most bodily functions affected

• often synergise with other hormones

• deficiencies lead to abnormal growth, development, reproduction, behaviour, metabolism

• exert effects on all organs and tissues throughout life

• absence of thyroid hormone in children leads to growth problems

• leads to arrest of bone elongation, delayed bone maturation, reduction in growth hormone secretion

thyroid hormone in foetal development

• key role in developing neural and skeletal systems

• loss of t4 supply to foetus leads to irreversible intellectual disability and dwarfism

• cretinism- iodine deficiency syndrome

• metamorphosis requires thyroid hormones

cardiovascular effects

• t3 increases cardiac contraction and output, heart rate, oxygen supply to tissues, CO₂ removal from tissues

• direct effects- increased myocardial Ca uptake, increased expression of alpha myosin heavy chain decreased beta, increased expression of ryanodine receptor(RYR) in SR

• indirect effects- increased metabolism, thermogenesis, vasodilation, increased sensitivity to catecholamines

musculoskeletal effects

• t3 has potent stimulatory effect on bone turnover, increasing formation and resorption

• t3 increases linear bone growth after birth

• t3 increases rate of muscle relaxation

• normal skeletal muscle function needs t3

• smaller skull for hypothyroid individuals