Lecture Outline #13: Thyroid Hormones
I. INTRODUCTION
1. Thyroid hormones are the principal regulators of basal metabolic rate (energy production).
2. They are also important for growth and development and homeostasis.
II. ANATOMY OF THE THYROID GLAND (Fig.13.2)
1. The thyroid arises from an evagination of the mid-ventral pharynx.
2. The gland consists of masses of irregular follicles (Fig. 13.3).
a. follicles consist of a single-cell layer of cuboidal epithelial cells.
b. there are up to 3 million follicles in the gland, with some up to 1 cm in diameter.
c. follicles are imbedded in collagenous connective tissue (& "C" cells).
d. inside (antrum) a follicles is colloid-like material called thyroglobulin [thyroglobulin].
3. Thyroid gland and follicle cells are innervated by sympathetic postganglionic neurons.
III. THYROGLOBULIN BIOSYNTHESIS
1. Thyroglobulin (TG) is a large (670,000 M.W.) polypeptide (5,000 AAs; 3% tyrosine).
2. TG is synthesized on ribosomes of follicle cells in response to TSH/cAMP. (Fig. 13.4)
3. Monosaccharides are added to TG in Golgi apparatus (10% of TG weight).
4. This TG colloid is incorporated into exocytotic vesicles and extruded into the follicular antrum.
IV. BIOSYNTHESIS (anabolism) of THYROID HORMONES
A. IODIDE (I-) TRANSPORT (Fig. 13.4)
1. Dietary iodine is converted to iodide (I-) in intestines and absorbed into the blood.
2. Follicle cells actively transport iodide inside and across to the antrum in response to TSH action.
B. IODINATION
1. Thyroid peroxidase (TPO) is a hemoprotein that attaches I- to tyrosines on TG.
2. On the average, only about 10% of the tyrosine residues are iodinated.
3. Most of this iodination takes place at the antral surface of follicle cells.
4. The iodinated compounds are monoiodotyrosine (MIT) and DIT. (Fig. 13.1, and see Fig. 13.8)
C. COUPLING
1. MIT and DIT are joined by TPOs to form T3 and T4 (Fig. 13.5)
D. HYDROLYSIS
(NOTE: See items V.1 & V.2 in the next section, just below)
V. THYROID HORMONE SECRETION AND TRANSPORT (Fig. 13.4)
1. TSH binds to receptors on follicle cells and stimulates cAMP & phospholipase C.
2. cAMP-mediated actions include pseudopod formation on apical surface of cells, endocytosis of TG, phagolysosome formation, release of free T3 & T4, and exocytosis of remaining TG from basal side of follicle cell.
3. The
hormones are transported in plasma in conjugation with plasma proteins derived
from the liver: thyroxine-binding
globulin (70-75%), transthyretin (15-20%),
and albumin
(5-10%). (less than 0.5% is
transported in the
4. There is 50X more T4, than T3 in the blood.
VI. MECHANISM OF ACTION OF THYROID HORMONES
1. T3 and T4 both cross the plasma membrane of target cells. (see Fig. 13.10)
2. During entry, a deiodinase enzyme in the plasma membrane converts T4 to T3.
a. Type I (T4 5'-deiodinase) is found mainly in the liver, kidneys, & muscle. (converting 2/3's of T4)
b. Type II (T4 5’-deiodinase) is found mostly in the pituitary, brain, brown fat and gonads.
3. T3 diffuses into the nucleus and binds to receptors on the chromatin.
4. This activates transcription of specific mRNA, and protein synthesis.
VII. FUNCTIONS OF THE THYROID HORMONES
A. OVERALL FUNCTIONS
1. They are needed for normal growth and differentiation of vertebrates.
a. they are required for normal STH action.
b. they are essential for CNS and gonad development.
2. They promote thermogenesis (calorigenesis), i.e., O2 consumption and energy production.
3. Their principal action is on formation of enzymes in mitochondria (Krebs cycle).
B. CALORIGENESIS
1. They effect both carbohydrate and protein metabolism in a biphasic manner:
a. carbohydrate metabolism:
(i) moderate levels increase both glycolysis and glycogen synthesis.
(ii) higher levels increase glycolysis, but decrease glycogen formation.
b. protein metabolism:
(i) acute effect increases anabolism of structural and functional proteins.
(ii) chronic effect is catabolism of structural proteins for energy source.
2. They decrease tissue storage and plasma content of lipids (fats).
VIII. METABOLISM (i.e., catabolism) OF THYROID HORMONES
1. Deiodination occurs in target cells by thyronine deiodinase even before T3 used. (about 80% of I- is reused).
2. Deamination (and transamination to an a-keto group) of T3 (and T4) in the liver (and in kidney).
3. Conjugation (i.e., enzymatic coupling) in liver to glucuronides and sulfates for easier passage with bile to intestines (or out the kidneys).
IX. FEEDBACK INHIBITION OF TSH SECRETION (or, see Fig. 13.9)
1. T3 (and T4) appear to hyperpolarize thyrotropes (reducing Ca++ flux).
2. T3 (and T4) also act directly on hypothalamus to reduce TRH secretion.
3. High levels of hCG stimulate the thyroid.
4. Dopamine, somatostatin, and glucocorticoids inhibit thyrotropes.
5. Starvation, injury, and infection (stress) inhibit thyrotropes.