Regulation of Thyroid Hormone Synthesis Flashcards

1
Q

Anatomy summary of the Thyroid Gland

A

a. The thyroid gland is located below the larynx, and there are two lobes on each side of the trachea.
i. A narrow band of the gland known as the isthmus connects the two lobes.

b. The blood supply to the gland is provided by the superior thyroid artery (from the external carotid) and the inferior thyroid artery (from the thyrocervical trunk of the subclavian artery).
i. Of all the endocrine organs, the thyroid receives the highest blood flow.

c. The functional unit of the gland is the follicle, consisting of a layer of cells surrounding a lumen filled with a substance known as colloid.
i. Thyroglobulin (TG) is the primary constituent of colloid. Blood vessels flow between the follicles.
ii. The parafollicular cells (C cells) are also found in between the follicles; these secrete calcitonin and will be discussed more in the lecture about control of calcium and phosphate.
iii. Nerves terminate on the blood vessels as well as the follicular cells raising the possibility of direct neural control of the gland.

d. Iodide and the amino acid tyrosine are the ingredients for thyroid hormone (TH) synthesis. The TH nomenclature is summarized here:
i. Thyronine, shown below, is the backbone of the THs. The 3, 5, 3’ and 5’ positions can be iodinated.
ii. 3, 5, 3’, 5’ tetraiodothyronine is the hormone T4, also known as thyroxine. 3, 5, 3’ triiodothyronine is the hormone T3. TH synthesis involves iodination of tyrosine residues, followed by the coupling of iodotyrosines to form the iodothyronines.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Anatomy and Blood Flow of Thyroid Gland

A

a. The thyroid gland is located below the larynx, and there are two lobes on each side of the trachea.
i. A narrow band of the gland known as the isthmus connects the two lobes.

b. The blood supply to the gland is provided by the superior thyroid artery (from the external carotid) and the inferior thyroid artery (from the thyrocervical trunk of the subclavian artery).
i. Of all the endocrine organs, the thyroid receives the highest blood flow.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Functional anatomy of the Thyroid

A

a. The functional unit of the gland is the follicle, consisting of a layer of cells surrounding a lumen filled with a substance known as colloid.
b. Thyroglobulin (TG) is the primary constituent of colloid. Blood vessels flow between the follicles.
c. The parafollicular cells (C cells) are also found in between the follicles; these secrete calcitonin and will be discussed more in the lecture about control of calcium and phosphate.
d. Nerves terminate on the blood vessels as well as the follicular cells raising the possibility of direct neural control of the gland.
e. Iodide and the amino acid tyrosine are the ingredients for thyroid hormone (TH) synthesis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

The Thyroid Hormone nomenclature is summarized here:

A

a. Thyronine, shown below, is the backbone of the THs.
i. The 3, 5, 3’ and 5’ positions can be iodinated.

b. 3, 5, 3’, 5’ tetraiodothyronine is the hormone T4, also known as thyroxine.
c. 3, 5, 3’ triiodothyronine is the hormone T3.
d. TH synthesis involves iodination of tyrosine residues, followed by the coupling of iodotyrosines to form the iodothyronines.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

T4 and T3

A

a. 3, 5, 3’, 5’ tetraiodothyronine is the hormone T4, also known as thyroxine.
b. 3, 5, 3’ triiodothyronine is the hormone T3.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Iodine uptake

A

a. Iodide is acquired from the dietary intake of iodine.

b. Ingested iodine is mostly absorbed from the gut in the form of iodide to enter an extracellular iodide pool.
i. Iodide exits this pool from the blood into the follicular cells of the thyroid gland.

c. The mechanism for iodide transport into the gland is also called the “iodide trap” mechanism.
i. The term “trap” refers to the fact that a membrane pump on the basal side of the follicular cell promotes accumulation of a concentration of iodide in the thyroid typically 30-40 times that in the serum.

d. Iodide is concentrated in the gland against an electrical as well as this chemical gradient.
i. Certain anions, notably perchlorate (ClO4), are transported by the same mechanism and thus act as competitive inhibitors of iodide uptake.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Iodine absorbed into the Follicular Cell

A

a. Once inside the follicular cell, iodide diffuses from the basolateral (closest to the blood) to the apical (closest to follicular lumen) side.
b. Iodide is moving with its electrical and chemical gradients when it exits the follicular cell at its apical side.
c. Colloid is found outside the follicular cell near the apical membrane.
d. Organification of iodide (incorporation of iodide into tyrosyl residues on thyroglobulin) occurs at the follicular cell-colloid interface.

e. Iodide has to be oxidized before it can participate in tyrosyl iodination; the nature of the iodide intermediate is not understood.
i. The enzyme that catalyzes iodination of thyroglobulin, thyroperoxidase, is a membrane bound glycoprotein, and immunohistochemical studies suggest it is present in the microvilli of the apical membrane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Thyroglobulin

A

a. Thyroglobulin (TG) is a glycoprotein of 660 kD composed of two identical polypeptides.
b. TG is synthesized on the rough endoplasmic reticulum within the follicular cell and transported to the Golgi apparatus, where it is glycosylated and packaged into secretory vesicles.
c. The secretory vesicles are released from the apical side of the follicular cell into the lumen and thus TG enters the colloid. All the iodination and coupling reactions of TH synthesis occur on tyrosyl residues of TG.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Synthesis of Thyroid hormone

A

a.Synthesis: In the first step, thyroperoxidase catalyzes the iodination of tyrosyl moieties on TG. In this way mono- (MIT) and diiodotyrosine (DIT) are formed on TG.

b. Certain compounds act as inhibitors of iodination.
i. These decrease TH synthesis and secretion, ultimately leading to elevated levels of TSH and hypertrophy of the gland, a condition known as a goiter.
ii. These inhibitory compounds are thiourea drugs (e.g., propylthiouracil-PTU, and methimazole) and since they lead to enlarged thyroid glands (goiters), they are also termed goitrogens.

c. Next, 2 DITs or 1 DIT and 1 MIT couple to form iodothyronines. The coupling reaction is thought to be catalyzed by thyroperoxidase as well, and thus probably occurs near the apical membrane.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Secretion of Thyroid hormone

A

a. The prequel to secretion is the endocytosis of TG from the lumen (colloid) into the follicular cells.
b. Drops of colloid move into the follicular cell and coalesce with lysosomes; the lysosomal enzymes act on TG to cleave T4 and T3 from it. Under normal conditions, the amount of T4 removed is in excess (~20X) of the amount of T3 removed and thus released.
c. It is not clear how release of the hormone occurs. It may be facilitated by specific carrier proteins.
* Note that the proteolytic action of the lysosomal enzymes will cleave iodotyrosines (MIT and DIT) from TG as well. These are de-iodinated, and the tyrosine and iodide are both reincorporated into TG.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

Transport of Thyroid Hormone

A

a. Once in the blood, the majority of THs exist either in a protein bound form (up to 99.97% under normal conditions) or in free form (a minor part, ~0.03% T4 and 0.4% T3).
b. The free from is the active form.

c. TH binding proteins include thyroid binding globulin (TBG), thyroid binding pre-albumin (TBPA) and albumin.
i. Under normal conditions, only about 30% of the binding sites on these proteins are occupied by TH; the majority is available.

d. Measurements of TH levels are complicated by the fact that the majority is not free but bound to proteins.
i. However, it is the free form that is important for evaluation of thyroid function.

e. Thus, measurements of plasma TH levels must include values for the bound or free form in addition to the total TH in the blood.
i. This is particularly important, because certain physiological states, such as pregnancy, increase TBG and TBPA.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

In sum, TG in the colloid serves as an extracellular reservoir of TH.

A

a. Further, in the blood, the protein bound TH acts to delay, buffer and prolong the effects of TH action
b. . This latter mechanism is more pronounced for T4 than for T3, in part because proportionally more (~10X) T4 is protein bound due to the higher affinity of TBG for T4.
c. The half-lives of T4 and T3 are 7 days and 1 day, respectively. The lower affinity for T3 can in part explain the more rapid onset of action of T3 and its shorter half life in the serum.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Half Life of T3 and T4

A

The half-lives of T4 and T3 are 7 days and 1 day, respectively. The lower affinity for T3 can in part explain the more rapid onset of action of T3 and its shorter half life in the serum.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

T3 and T4 with their Receptors

A

a. T3 is considered to be the active form of TH, because the affinity of the TH receptor is 10 fold greater for T3 than for T4.

b, T3 and T4 both enter cells by active transport.

c. T4 is converted to T3 by 5’-deiodinase (T4 is often considered to be a prohormone).

d. T3 enters the nucleus where it interacts with nuclear receptors (TRs); there are several isoforms of thyroid hormone receptors
i. The T3-receptor complexes then act on DNA to direct transcription of specific mRNAs.

e. One species of mRNA that has received particular attention is the Na-K ATPase, also known as the Na-K pump; the transcription of respiratory enzymes of the mitochondria is also stimulated.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

ACTIONS OF THYROID HORMONE

A

1) THs are the major regulators of metabolic rate. A clinical measurement that has fallen into disuse, basal metabolic rate or BMR, was used to evaluate thyroid function. This measurement indicated the basal heat production of an individual in units of kcal/hr/M2 surface area. Typical values for females and males are 36 and 40 kcal/hr/M2, respectively. Although BMR is not in significant use now, it is important to note that in the absence of THs, the BMR decreases dramatically.
2) TH is necessary for normal fetal and neonatal brain development. They regulate proliferation, differentiation, myelinogenesis, neurite outgrowth, and synapse formation. Thus congenital hypothyroidism can lead to severe and irreversible mental retardation. Neonatal screening for TH levels is thus very important. Even in adults, TH levels can regulate behavioral functions as we shall see under dysregulation of thyroid function.
3) Both TH and growth hormone are essential for normal growth. Children with low TH levels can show severely stunted growth. This is due to the many developmental effects of TH. In addition when TH levels are low, growth hormone levels also decline.
4) Thyroid hormones enhance the response to catecholamines and thus mimic the effects of sympathetic nervous system activation. There is evidence suggesting that the number of -adrenergic receptors increases in response to a hyperthyroid status. In fact, hyperthyroidism is often treated with -blockers.
5) Thyroid hormones have effects on metabolism, some of which are consequences of the calorigenic actions, while others are independent effects. These actions are time and dose dependent. In general, low to moderate doses of TH tend to be anabolic, while high doses are catabolic. High doses of TH lead to increased fuel consumption, protein breakdown and muscle wasting. Lipolysis is the net result of the actions of TH on lipid metabolism. Low to moderate doses of TH promote the conversion of glucose to glycogen, while high doses enhance glycogenolysis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

TSH and Regulation

A

a. In response to stimulation by TRH, TSH is released from thyrotrophs in the anterior pituitary.
i. TRH interacts with a membrane receptor, and thereby leads to increases in cAMP and hydrolysis of membrane phosphatidyl inositol.
ii. Free T3 and T4 can influence the response of the anterior pituitary to TRH; high free T3 and T4 levels reduce the response, whereas low free T3 and T4 levels sensitize the response.

b. TSH is carried by the blood to the thyroid gland.
i. At a cellular level, TSH interacts with a membrane receptor. Eventually, the steps of thyroid hormone synthesis are stimulated.
ii. For example, TSH stimulates the iodide pump, thyroperoxidase and endocytosis of colloid. (Asterisks in Figure 1 designate steps that are stimulated by TSH.)

c. TSH increases iodide transport with a latency (TSH also increases I- efflux, but its net effect is to increase transport into the follicular cells). This effect is seen with a latency. What else might have to occur first?

d. TSH also increases iodide Organification, the coupling of iodotyrosines, TG synthesis and its proteolysis following endocytosis from the colloid.
i. All of these actions lead to an increase in TH secretion. These actions are thought to be mediated by cAMP; TSH activates adenylate cyclase by binding to its receptor on the follicular cell membrane.
ii. There is increasing evidence that other second messengers (e.g., diacylglycerol, Ca-calmodulin and IP3) may also participate in mediating TSH stimulation.

e. TSH also affects the morphology of the gland. The follicular cells proliferate as well as enlarge and elongate; there are compensatory changes in the amount of colloid.

17
Q

Iodide and Regulation

A

a, Iodine deficient diets will eventually lead to decreased TH synthesis and secretion.

b. There is also an unexpected effect of high doses of iodine; in the short term, elevated iodide will also lead to a decrease in TH release, known as the Wolff-Chaikoff effect.
c. The underlying mechanism involves decreases in incorporation of iodide into TG and consequent TH synthesis. In addition, high iodide will diminish the response to TSH.
d. High iodine intake is sometimes used to prepare patients for thyroid surgery. However, high iodine intake is not used for chronic management of hyperthyroidism, because its effects are transient.

18
Q

CONTROL OF TSH SECRETION: NEGATIVE FEEDBACK

A

a. TSH is secreted by the anterior pituitary in response to stimulation by the hypothalamic hormone TRH.

b. Stimuli such as cold, fasting and stress alter hypothalamic release of TRH.
i. TH’s enter into a negative feedback in this system by inhibiting the secretion of TSH by the anterior pituitary; it is not clear if they also inhibit secretion of TRH by the hypothalamus.

c. Due to the difficulties in accurately assessing free TH levels, it is common to use TSH levels as an index of thyroid function.

19
Q

Thyroid Hormone introduction

A

a. Thyroid hormone is a tyroisine derivative, BUT it acts differently than other tyrosine hormones
i. acts like a peptide and steroid hybrid

b. Unique component of thyroid hormone is Thyronine—> it is 2 tyrosine residues joined together
i. very hydrophobic, acts somewhat like a steroid

c. Thyronine, shown below, is the backbone of the THs.
i. The 3, 5, 3’ and 5’ positions can be iodinated.

ii. 3, 5, 3’, 5’ tetraiodothyronine is the hormone T4, also known as thyroxine.
iii. . 3, 5, 3’ triiodothyronine is the hormone T3.
* TH synthesis involves iodination of tyrosine residues, followed by the coupling of iodotyrosines to form the iodothyronines.

20
Q

Thyroid Hormone Synthesis

A

a. First thing we need is Iodide from the blood
i. picked up by thyroid gland–> the thyroid gland has to be very efficient to pick it up
ii. Thyroid gland needs high amount of blood

b. Need Follicle cells to take Iodide from blood
i. Will rely on Na/K ATPase to transport Na outside of the cell, will use the high Na+ in the blood
- active proces that requires ATP
ii. The high Na will use symport action to bring the iodide into the follicular cell
iii. Na/Iodide symport will bring both into the follicular cell

c. Once Iodide is in the follicular cell, will head towards the Thyroid lumen side of the cell, bind to the enzyme Thyroperoxidase
i. Thyroperoxidase will convert Iodide to active Iodide (ready to be transferred to Tyrosine residues)
ii. This enzyme is very active, keeps Iodide low inside the cell to keep efficient at picking up iodide
iii. “Iodide trap”–> keep iodide low in follicular cell for highly active transport

d. Will have Thyroglobulin on the lumen side of the thyroid gland. The thyroglobulin is made by the follicular cell
i. Thyroglobulin has tyrosine residues, it will be secreted into the lumen of the thyroid gland
ii. There is high amounts of thyroglobulin concentrated into the thyroid lumen, it is known as “Lumen Colloid” due to the high concentration of thyroglobulin

e. Thyroperoxidase will not only form active Iodide, it will also transfer active Iodide to thyroglobulin to the Tyrosine residues
i. Will form ether link between tyrosine residues, forming either T3 or T4

f. *Key to understand—> the T3 or T4 hormone made is still bound to the Thyroglobulin molecule
i. Thyroglobulin is endocytosed into follicular cell
ii. will be degraded into individual components by lysososme
iii. will allow T3, T4 and other stuff to be made

21
Q

Protein mechanism that brings iodide into the Thyroid Gland

A

a. Need Follicle cells to take Iodide from blood

b. Will rely on Na/K ATPase to transport Na outside of the cell, will use the high Na+ in the blood
i. active proces that requires ATP

c. The high Na will use symport action to bring the iodide into the follicular cell
i. Na/Iodide symport will bring both into the follicular cell

d. Once Iodide is in the follicular cell, will head towards the Thyroid lumen side of the cell, bind to the enzyme Thyroperoxidase
i. Thyroperoxidase will convert Iodide to active Iodide (ready to be transferred to Tyrosine residues)
ii. This enzyme is very active, keeps Iodide low inside the cell to keep efficient at picking up iodide
iii. “Iodide trap”–> keep iodide low in follicular cell for highly active transport

22
Q

Two functions of Thyroperoxidase

A
  1. Will turn Iodide into active form and move it into the lumen of the thyroid gland
    i. keeps iodide moving from follicular cell to the lumen, allowing the “Iodide trap” to continue
  2. Will put Iodide onto the tyrosine of thyroglobulin
    i. this happens in the lumen of the thyroid gland
23
Q

Thyroglobulin in creating

A

a. Will have Thyroglobulin on the lumen side of the thyroid gland. The thyroglobulin is made by the follicular cell
i. Thyroglobulin has tyrosine residues, it will be secreted into the lumen of the thyroid gland
ii. There is high amounts of thyroglobulin concentrated into the thyroid lumen, it is known as “Lumen Colloid” due to the high concentration of thyroglobulin

b Thyroperoxidase will not only form active Iodide, it will also transfer active Iodide to thyroglobulin to the Tyrosine residues
i. Will form ether link between tyrosine residues, forming either T3 or T4

c. *Key to understand—> the T3 or T4 hormone made is still bound to the Thyroglobulin molecule

d. Thyroglobulin is endocytosed into follicular cell
i. will be degraded into individual components by lysososme
ii. will allow T3, T4 and other stuff to be made—> will be secreted from cell

24
Q

Thyroid hormone creation according to Wiki

A

The steps in this process are as follows:[4]

  1. The Na+/I− symporter transports two sodium ions across the basement membrane of the follicular cells along with an iodide ion. This is a secondary active transporter that utilises the concentration gradient of Na+ to move I− against its concentration gradient.
  2. I− is moved across the apical membrane into the colloid of the follicle.
  3. Thyroperoxidase oxidises two I− to form I2. Iodide is non-reactive, and only the more reactive iodine is required for the next step.
  4. The thyroperoxidase iodinates the tyrosyl residues of the thyroglobulin within the colloid. The thyroglobulin was synthesised in the ER of the follicular cell and secreted into the colloid.
  5. Iodinated Thyroglobulin binds megalin for endocytosis back into cell.
  6. Thyroid-stimulating hormone (TSH) released from the adenohypophysis binds the TSH receptor (a Gs protein-coupled receptor) on the basolateral membrane of the cell and stimulates the endocytosis of the colloid.
  7. The endocytosed vesicles fuse with the lysosomes of the follicular cell. The lysosomal enzymes cleave the T4 from the iodinated thyroglobulin.
  8. The thyroid hormones cross the follicular cell membrane towards the blood vessels by an unknown mechanism.
25
Q

Thyroid Hormone in the blood

A

a. The thyroid hormone in the blood is 99% bound, very limited free amount
i. is predominantly abound to Thyroid Hormone Binding Globulin (THBG)

b. If you increase the amount of thyroid hormone being secreted, there will be more Free thyroid hormone (even if its a higher 1% free)
i. Free thyroid hormone will be controlled by increasing the amount of Thyroid hormone binding globulin

26
Q

Thyroid Hormone reaches cell

A

a. T3 and T4 will enter the target cell
i. T4 will get turned into T3 once it enters the target cell
ii. T3 is the active form

b. The T3 will bind to receptor protein in cyoplasm—> has transcription actions
i. acts upon Nuclear Receptors

27
Q

Mechanism of Thyroid Hormone in cell

A

a. The thyroid hormones function via a well-studied set of nuclear receptors; they also act in the nucleus of the cell, the thyroid hormone receptors.
b. These receptors, together with corepressor molecules, bind DNA regions called thyroid hormone response elements (TREs) near genes.
c. This receptor/corepressor/DNA complex can block gene transcription. When triiodothyronine (T3) binds a thyroid hormone receptor (TR), it induces a conformational change in the TR which displaces the corepressor from the receptor/DNA complex, resulting in recruitment of coactivator proteins and RNA polymerase, activating transcription of the gene.

28
Q

Actions of the Thyroid Hormone

A
  1. Basal Metabolic Rate is under tight regulation by thyroid hormone
    i. Low level of T3 hormone—> shift balance to anabolism (building-up)
    ii. High Levels of T3 hormone—> balance will shift to catabolism (break stuff down)
  2. Development–> need thyroid hormone for development
    i. needed for both brain and other body development
  3. Permissive for Beta Adrenergic receptors
    i. high thyroid hormone means more Beta receptors
    - Increases cardiac output
    • Increases heart rate
    • Increases ventilation rate
29
Q

Effects of triiodothyronine (T3) which is the metabolically active form:

A

Increased T3:

  • Increases cardiac output
  • Increases heart rate
  • Increases ventilation rate
  • Increases basal metabolic rate
  • Potentiates the effects of catecholamines (i.e. increases sympathetic activity)
  • Potentiates brain development
  • Thickens endometrium in females
  • Increases metabolism of proteins and carbohydrates (i.e. they have a catabolic action
30
Q

Regulation of Thyroid hormone

A

a. The hypothalamus will release TRH to the ant. Pituitary—-> the anterior pituitary will release TSH to the Thyroid gland
i. TSH will cause thyroid gland to increase T4 and T3

b. T3 will have negative feedback on the Hypothalamus
c. Will measure TSH for functioning of activity

d. TSH will lead to:
1) Higher growth of follicular cells
2) Higher transport of Iodide and higher Thyroperoxidase
i. higher amount of activating (organification) of Iodide
3) These all mean more Thyroid hormone being released

31
Q

Hyper and Hypo Throid hormone

A

Hypo Thyroid hormone:

  1. Hashimoto Thyroiditis = Low T3, high TSH
    i. Thyroid gland being destroyed by antibodies
  2. Pituitary= low T3 and low TSH
    i. secondary, low TSH production

Hyper Thyroid

  1. Grave’s Disease= High T3, low TSH
    i. T3 will inhibit hypothalamus TRH
  2. Pituitary = High T3 and High TSH
    i. secondary high release of TSH leads to high T3