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Nuclear receptors
- soluble ligand-activated transcription factors expressed in specific tissues/cells
- bind specific DNA sequences on “target genes” and activate transcription of these genes in a hormone-dependent manner.
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Name 5 nuclear receptors and drugs that target them
- PPAR-gamma: TZDs treat diabetes
- PPAR-alpha: fibrates treat hypertriglyceridemia (activation of genes involved in beta-oxidation)
- VDR: vitamin D, promotes Ca2+ absorption in intestine, treat dialysis pts and osteoporosis pts
- Thyroid hormone receptor: T4, treats hypothyroidism
- PXR: 50% of drugs activate this, alter metabolism
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steroid hormone synthesis (cortisol)
- HDL delivered to cell (some LDL)
- ACTH receptor activation by ACTH -> incr. PKA
- PKA activates lipase
- cholesterol ester -lipase-> cholesterol + FA
- -desmolase (in mitochondria)-> pregnenolone -> cortisol
- cortisol immediately released, neg feedback
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Cushing's Disease
- Pituitary tumor/taking glucocorticoids long-term/ectopic production of CRH
- causes high ACTH levels, darkening of the skin may occur b/c MSH is another product of POMC (big momma)
- High cortisol levels that result don't do negative feedback to pituitary
- Steroid diabetes - high blood sugar due to excess cortisol
- high BP, round face, upper body obesity, weak bones
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cortisol levels change due to...
- highest in the morning (circadian rhythm)
- pregnancy - high ACTH and cortisol as pregnancy progresses
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21-alpha-hydroxylase deficiency
- form of congenital adrenal hyperplasia (CAH) = also caused by 11-beta-hydroxylase deficiency
- pregnenolone -> progesterone
- progesterone normally converted to precusors for adrenal androgens and cortisol
- w/o 21-hydroxylase, all is converted to androgens
- no cortisol for neg feedback, so androgens get even higher
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Addison's disease
- destruction of adrenal cells
- tuberculosis or autoimmune
- treatment: lifelong replacement therapy of cortisol and aldosterone
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Describe RAAS
- Renin-angiotensinII-aldosterone system
- low BP, Na+, effective volume -> kidneys release renin
- renin converts angiotensinogen to angiotensin I
- ACE (angiotensin converting enzyme) in lungs/kidneys converts angiotensinI->angiotensin II
- Angiotensin II directly causes vasoconstriction by IP3/incr. Ca2+
- Angiotensin II -> aldosterone -> water and Na+, K+ retention
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thyroid gland embryology
- invagination of foramen cecum through thyroglossal duct
- ectopic tissue may be anywhere along the duct, doesn't function properly
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follicular cell
- thyroid cell; apical surface at colloid, basolateral at blood
- iodine concentrated 35-40x, bound by thyroglobulin in colloid
- iodine transport dependent on Na+/K+ ATPase to make gradient for Na+/I- symport
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Thyroid stimulating hormone receptor
- On follicular cells
- TSH binds, causes insertion of Na+/I- symporter
- Pendrin = I- transporter into colloid
- Follicular cells can use thyroid peroxidase for coupling rxns (MIT+DIT=T3, 2DIT=T4)
- Halogenase reclaims I-
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Deiodoinase
- Type II: T4->T3; in local tissues or in follicular cell
- upregulation when thyroid hormone drops
- overactive in Grave's Disease
- inhibited by caloric restriction, major illness, drugs, selenium deficiency, fetal life, severe hepatic disease
- Type I: inhibited at low thyroid hormone concentration
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