Regulation of Thyroid Hormone Synthesis Flashcards
Anatomy summary of the Thyroid Gland
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.
Anatomy and Blood Flow of Thyroid Gland
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.
Functional anatomy of the Thyroid
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.
The Thyroid Hormone nomenclature is summarized here:
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.
T4 and T3
a. 3, 5, 3’, 5’ tetraiodothyronine is the hormone T4, also known as thyroxine.
b. 3, 5, 3’ triiodothyronine is the hormone T3.
Iodine uptake
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.
Iodine absorbed into the Follicular Cell
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
Thyroglobulin
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.
Synthesis of Thyroid hormone
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.
Secretion of Thyroid hormone
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.
Transport of Thyroid Hormone
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.
In sum, TG in the colloid serves as an extracellular reservoir of TH.
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.
Half Life of T3 and T4
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.
T3 and T4 with their Receptors
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.
ACTIONS OF THYROID HORMONE
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.
