Steroid hormones and nuclear receptors

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Steroid hormones and nuclear receptors
2011-02-02 23:10:05

block 3 wk5
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  1. 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.
  2. 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
  3. 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
  4. 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
  5. cortisol levels change due to...
    • highest in the morning (circadian rhythm)
    • pregnancy - high ACTH and cortisol as pregnancy progresses
  6. 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
  7. Addison's disease
    • destruction of adrenal cells
    • tuberculosis or autoimmune
    • treatment: lifelong replacement therapy of cortisol and aldosterone
  8. 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
  9. thyroid gland embryology
    • invagination of foramen cecum through thyroglossal duct
    • ectopic tissue may be anywhere along the duct, doesn't function properly
  10. 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
  11. 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-
  12. 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