Endocrinology/Objectives/Lecture 18
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Objectives: 13 - 14 - 15 - 16 - 17 - 18 - 19 - 20 - 21 - 22 - 23 - 24 - 25
Thyroid hormone synthesis
Recognize the structure of thyroid hormones and their precursors.
Thyroid hormones (T3 and T4) are synthesized from tyrosine. Iodide is successively added (by thyroperoxidase, TPO) to tyrosine residues present on colloidal thyroglobulin, beginning at the 3-position of tyrosine and forming 3-monoiodotyrosine (MIT). Another iodide may be added to the 5-position, forming 3,5-diiodotyrosine (DIT). MIT and DIT may couple to form 3,5,3'-triiodothyronine (T3), and two DITs may couple to form 3,5,3',5'-tetraiodothyronine (T4). The common structure of T3 and T4 resembles two tyrosine residues joined together. The phenyl ring carbons on the "complete" tyrosine are numbered 1-6, while the incomplete tyrosine phenyl ring has its carbons numbered 1'-6'.
State the human nutritional requirement for iodide.
The body needs 50 µg iodide per day, and since intestinal absorption of iodide has an efficiency of 30%, the dietary requirement of iodide is 150 µg/day.
State which tissues can take up iodine.
- Thyroid gland
- Salivary glands
- Mammary glands
- Chorion
- Stomach
Note that only the thyroid gland can oxidize iodide.
State the cell types and their functions in the thyroid.
- Follicular cells
- Take up iodide for the production of thyroid hormones in the colloid lumen. When less active, follicular cells assume a cuboidal shape; activated, they assume the cytoarchitecture of a secretory cell (i.e. columnar, increased apical invaginations).
- Parafollicular (C or "clear") cells
- Scattered at the basement membrane of follicular cells. Synthesize and secrete calcitonin, a hormone whose effect lowers blood calcium levels, but whose physiological effect is negligible compared to parathyroid hormone (PTH).
Describe the mechanism by which iodide is concentrated in the thyroid.
Driven by the Na+ concentration gradient across the basolateral membrane, iodide is concentrated within the follicular cell. The sodium gradient is established by primary active transport involving a Na+,K+-ATPase.
Give examples of inhibitors of the iodide pump and their mechanisms of action.
- The iodide pump (though it shouldn't be called a pump because it is secondary—not primary—active transport involving a Na+ concentration gradient) can be inhibited competitively. Inhibitors may both compete with iodide for transport into the cell and be concentrated within the cell (e.g. perchlorate, perrhenate, and pertechnetate) or may compete for transport but not be concentrated (e.g. thiocyanate). Pertechnetate is especially useful for radiographic imaging of the thyroid, while perchlorate is used to treat hyperthyroidism.
- Because pump activity relies on the Na+,K+-ATPase, its activity may be inhibited by ouabain.
- Drugs that impair cAMP signaling may also inhibit pump activity, since TSH increases cAMP to enhance pump activity.
- Propylthiouracil (PTU) does not inhibit the pump.
Describe the enzymes involved in iodide oxidation and organification.
Oxidation of iodide converts I- to I+. This reaction is catalyzed by luminal thyroperoxidase, a heme-containing enzyme that requires H2O2 for activity. The hydrogen peroxide is in turn produced by an NADPH-dependent enzyme resembling cytochrome C reductase.
Also within the lumen, thyroperoxidase catalyzes the organification of oxidized iodide, a process consisting of the addition of oxidized iodide to tyrosine residues on colloidal thyroglobulin. This reaction is carried out by the same heme- and H2O2-dependent thyroperoxidase that catalyzed the oxidation of iodide. Organification produces MIT (by adding a 3-position iodide) and DIT (by adding a 3- followed by a 5-position iodide). In this process, thyroperoxidase may combine a DIT with an MIT or a DIT to form T3 or T4. This process leaves behind dehydroalanine, a remnant of the MIT or DIT that was added to the DIT to form T3 or T4.
Thyroperoxidase activity is enhanced by TSH and depressed by PTU.
Discuss the structure and role of thyroglobulin in thyroid hormone synthesis.
Thyroglobulin is a 660 kDa homodimer with 8-10% carbohydrate, 0.2-1% iodide, approximately 134 tyrosine residues, 5 MIT, 4.5 DIT, 2.5 T4, and 0.5 T3. At least 3,435 molecules of ATP are required per T3 or T4 molecule (two ATPs for each peptide bond), not including other energy costs.
The tyrosine residues on thyroglobulin are the ones that will go on to form MIT, DIT, T3, and T4. Because iodotyrosine residues cannot be incorporated into proteins (there is no tRNA for iodotyrosine), MIT and DIT must be deiodinated before being reclaimed by thyroglobulin.
Thyroglobulin allows thyroid hormones to be stored in the colloid for many weeks.
Contrast thyroid hormone storage with storage of other hormones.
Most other stored hormones are held within cytoplasmic granules that are exocytosed on demand. While thyroid hormones are secreted on demand, they are not stored intracellularly. Instead, they are bound to proteins (thyroglobulin) outside the cell in the follicular lumen. Thyroid hormones being protein bound is reminiscent of posterior pituitary hormones being bound to neurophysin prior to release, though the similarity between thyroid and neurohypophyseal hormone storage appears to end here.
Detail mechanisms of thyroglobulin degradation, iodide recycling, and hormone release.
Once thyroglobulin is endocytosed (under the influence of TSH and a cAMP cascade), endocytic vesicles fuse with lysosomes to form secondary lysosomes (phagolysosomes). Lysosomal proteases hydrolyze thyroglobulin's peptide bonds, releasing MIT, DIT, T3, and T4. T3 and T4 are secreted, while MIT and DIT are deiodinated (by an NADPH-dependent thyroid deiodinase), making tyrosine residues available for incorporation into nascent thyroglobulin.
Discuss thyroid hormone transport and activation.
Thyroid hormones are transported bound to proteins: thyroxine-binding protein (70%), thyroxine-binding prealbumin (10-15%), and albumin (15-20%). 99.97% of T4 and 99.7% of T3 is protein-bound, thus T4 has a longer half-life than T3 (6.5 compared to 1.5 days).
Peripheral deiodinase (also inhibited by PTU) can convert some T4 to either T3 (more potent) or reverse T3 (rT3; has no known physiologic activity, although high levels are found in chronic disease, carbohydrate starvation, and in the fetus). T3 binds the thyroxine receptor (TR) with ten times the affinity of T4.
State the forms of thyroid hormone receptor and their location within cells.
TR is encoded by two genes, TRα (with two nonfunctional splice variants) and TRβ (with two active splice variants), which are expressed differentially based on tissue type and stage of development. Each contains as a 10 kDa DNA-binding domain (containing two zinc-coordinated cysteine fingers) sandwiched between the N-terminus and a 27 kDa C-terminal hormone-binding domain.
Discuss how thyroid hormone receptors activate or inhibit transcription.
TR binds DNA in the presence and absence of thyroid hormones. In their absence, TR binds TREs and represses their transcription. Transcription may also be repressed in the presence of hormone. Genes that contain nTREs are suppressed by monomeric TR binding in the presence of hormone; one example of such an nTRE-containing gene is the TSH gene (i.e. TSHα and TSHβ).
In the presence of thyroid hormone, TR binds DNA either as a homodimer (TR:TR) or as an RXR-paired heterodimer (TR:RXR), the heterodimer usually being most active. In either case, TR binds the thyroid hormone response elements (TREs) of genes, which consist of inverted (palindromic) or direct repeats of AGGTCA. Direct repeats are usually separated by four base pairs. Binding of TR to TRE-containing genes enhances their expression.
Give examples of genes regulated by thyroid hormone.
| Gene | Product | Action |
|---|---|---|
| GH | Growth hormone | Enhanced growth |
| SERCA2 | Ca2+-ATPase | Increased heart rate |
| Specific myosin isoforms | Myosin | Muscle hypertrophy |
| TSHα and TSHβ | Thyrotropin | T3 and T4 cause ↓TSH |
Give examples of diseases involving hyper- and hypothyroid states.
- Endemic goiter (e.g. cassava goiter)
- Thyroid hypertrophy due to hypothyroidism secondary to insufficient dietary iodide intake and therefore elevated TSH production.
- Graves' disease
- Autoimmune hyperthyroidism in which receptor-activating antibodies are directed against the N-terminal (hormone-binding) side of the TSH receptor, causing effects that mimic the constitutive presence of TSH (e.g. goiter, chronically elevated thyroid hormone, heat intolerance, fibroblast proliferation). Enhanced glycoprotein and proteoglycan deposition contribute to exophthalmos. Treat by removing thyroid gland (though this won't relieve the exophthalmos because the antibody is still present and binds fibroblasts, causing their proliferation).
- Hashimoto's thyroiditis
- Autoimmune disease in which antibodies are directed against thyroglobulin, thyroperoxidase, or both. Initially results in hyperthyroidism, as colloid stores are broken down, resulting in massive outpouring of T3 and T4. Chronically results in hypothyroidism as thyroid gland degenerates.
- Viral thyroiditis
- Attack by a virus results in initial spike in thyroid hormone secretion (hyperthyroidism) followed by hypothyroidism.
- Congenital hypothyroidism
- Affected fetus has normal development in utero due to presence of maternal T3 and T4. At birth, maternal thyroid hormones are lost; child cannot produce his/her own thyroid hormones, resulting in impaired somatic growth and mental acuity.
List the actions of thyroid hormone.
- ↑Na+,K+-ATPase insertion in basolateral membrane → ↑oxygen consumption
- ↑Protein synthesis (in general) → ↑nitrogen balance
- ↑β-adrenergic receptor insertion (increased sensitivity to catecholamines)
- Amphibian metamorphosis
- Normal human growth and development (e.g. through expression of GH)
