1 / 28

Chapt. 34/5

Chapt. 34/5. Ch. 34/5 Student Learning Outcomes : Describe how steroid hormones are from cholesterol: Adrenal corticol hormones include: Cortisol, aldosterone, adrenal sex steroids Gonadal hormones include: Sex steroids testosterone, estrogen

kirk-padilla
Download Presentation

Chapt. 34/5

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Chapt. 34/5 • Ch. 34/5 • Student Learning Outcomes: • Describe how steroid hormones are from cholesterol: • Adrenal corticol hormones include: • Cortisol, aldosterone, adrenal sex steroids • Gonadal hormones include: • Sex steroids testosterone, estrogen • Briefly describe structure/ function of Eicosanoids: • Prostaglandins, thromboxanes, leukotrienes

  2. Cholesterol is precursor of steroid hormones • Cholesterol is precursor of steroid hormones: • From diet, synthesized in tissues, intracellular pools, LDL • Glucocorticoids – cortisol from adremal gland, • synthesis stimulated by ACTH (adrenocorticotropic hormone) • Mineralocorticoids – aldosterone from adrenal cortex, secreted in response to antiotension II, III, ↑K+ levels, low Na+ • Androgens – testosterone from Leydig cells of testes; secreted in response to LH (luteinizing hormone) • Estrogens – from ovarian follicle, corpus luteum; secretion stimulated by FSH (follicle stimulating hormone) • Progestins – progesterone from corpus luteum, secretion stimulated by LH

  3. Steroid hormones • Steroid hormones bind intracellular receptors: • Travel through blood bound to albumin or other proteins • Hydrophobic hormones diffuse across cell membrane • Bind cytoplasmic or • nuclear receptors • to alter transcription Fig. 16.12 steroid hormones bind intracellular receptors, activate transcription

  4. Overview Steroid hormones • Steroid hormone synthesis: • Adrenal cortex, gonads • From cholesterol (diet or synthesis) • 4 cytochrome P450 enzymes • Mono-oxygenases transfer e- • from NADPH to O2; oxidize ring • Some enzymes work in • more than one path • 3-b-HSD not a P450 enzyme Fig. 34.23

  5. P450 enzymes • Cytochrome P450 enzymes • 10 gene families, 100 isozymes (CYP) • Induced by substrates (alcohol, drugs, toxicants) • Mono-oxygenases • Donate single e- to O2 Figs.19.12, 13

  6. Steroid hormones I • I. Cholesterol to progesterone: • Mitochondrial inner membrane • Rate-limiting step P450SCC (CYPIIA) • Cleavage of side chain • Forms pregnenolone • Then Smooth ER for other steps • 3-b-HSD is not a P450 enzyme Fig. 34.23 top

  7. Steroid hormones • A. Cortisol synthesized in Adrenal cortex: • ACTH stimulates synthesis and secretion, • G-protein coupled receptor, cAMP, PKA • Middle layer of adrenal cortex – Zona fasciculata • Dietary cholesterol or synthesized; stored as ester • Mitochondrion and ER involved Fig. 34.24

  8. Steroid hormones • B. Aldosterone is synthesized in Adrenal cortex: • Zona glomerulosa layer of adrenal cortex • Cholesterol to pregesterone, then differ → DOC • Some enzymes same as for cortisol • Octapeptide angiotensin II stimulate synthesis • Also hyperkalemia, low Na+ • Stimulates Na+ uptake by kidney, ↑ extracellular fluid Fig. 34.23 part

  9. Sex hormones • C. Adrenal androgens are weak androgens: • Converted to testosterone or estrogens in other tissues • Made in zona reticulosum • DHEA, androstenedione • Most of androgens made by adrenal gland Figs. 34.23,25

  10. Testosterone • D. Testosterone, Dihydroxytesterone from testes • LH from anterior pituitary stimulates • synthesis (controls CYPIIA) • Testosterone made in Leydig cells, • path like adrenal • 5-a-reductase forms DHT • DHT stimulate production sperm proteins • in Sertoli cells, secondary sex characters

  11. Estrogens • E. Estrogens, progestins from ovaries • CytP450 enzymes in all cells; FSH signals • Granulosa cells mostly secrete estrogen • Thecal, stromal cells mostly secrete androgens • Corpus luteum mostly progestins • Estrones more in muscle, adipose

  12. Vitamin D • XI. Vitamin D: • Family of calciferols • Involved with Ca2+ homeostasis • From diet or synthesized in body • Skin needs UV to synthesize cholecalciferol • Liver and kidney finish • Binds nuclear hormone receptor VDR • Activates transcription of genes Fig. 34.26 Vitamin D calcitrol

  13. Table 34.5 Lipid-lowering agents • Agent mechanism ↓total cholesterol • Statins inhibit HMG-CoA reductase 15-60% • Bile acid resins ↑fecal excretion bile salts 15-20% • Niacin activates LPL; reduces 22-25% • hepatic production of VLDL; • reduces catabolism of HDL • Fibrates antagonizes PPAR-a, 12-15% • causes ↑ in LPL activity, • ↓in apo CIII, ↑ in apoA1 • Ezetimibe reduces intestinal absorption of 10-15% • free cholesterol from gut lumen

  14. Sex hormones • Treatment of Diabetes II with Metformin: • Impairs gluconeogenesis (liver is resistant to insulin effects) • Metformin activates LKB1 kinase, activates AMPK → PO4, sequester TORC2 (cofactor of CREB) in cytoplasm so NOT increase gluconeogenic gene expression • AMPK also inhibits liver lipogenesis, • AMPK increases muscle uptake of glucose Fig. 34.27

  15. Key concepts of chapt. 34 • Cholesterol is precursor of steroid hormones • Cholesterol obtained from diet or synthesized • HMG-CoA reductase is rate-limiting • Defects in LDL receptor increase blood cholesterol • Adrenal gland, gonads synthesize steroid hormones • Lipid-lowering agents include statins, bile acid resins, niacin, fibrates, and ezetimibe

  16. Chapter 35 • Eicosanoids: • Prostaglandins (PG) • Thrombaxanes (TX) • Leukotrienes (LT) • Every cell, signal activates phospholipase • Potent ‘local hormones’ act nearby • Produced from fatty acids, from • membrane phospholipids • Arachidonic acid is • major precursor, 3 paths • Short half-lives Fig. 35.1 overview of eicosanoid metabolism

  17. Roles of Eicosanoids • Inflammatory response after infection, injury: • Vasodilation increases blood flow in damage area • Control bleeding through clots, activate complement • White blood cells move to injury, make cytokines • Can give symptoms pain, swelling, fever • Inappropriate response is allergy, hypersensitivity • Smooth muscle contraction • Increase water, sodium excretion by kidney • Some constrictors of blood vessels, • Some dilators • Regulate blood pressure • Aspirin inhibits COX enzyme

  18. Arachidonic acid precursor • Arachidonic acid is precursor • Polynsaturated C20 fatty acid, from diet or made from essential Linoleate fatty acid • Phospholipases cleave from phospholipid in plasma membrane (C2 position) • Stimuli include histamines, cytokines Fig. 35.2 Fig. 33.30

  19. II. Pathways of eicosanoids • II. Pathways for eicosanoid synthesis: • A. Cyclo-oxygenase (COX) → PG, TX • B. Lipoxygenase → Leukotrienes • C. Cytochrome P450 → epoxides • Different enzymes in different tissues gives specialization Fig. 35.3

  20. Cyclo-oxygenase pathway • Cyclo-oxygenase Pathway: • Prostaglandins are large family: • Letter = ring substituents • Numeral subscript = double bonds • PGF also have subscript • Ex. PGA1, PGF2a Fig. 35.4-6 PG generic structure: C20 fatty acid; 5-membered ring Fig. 35.6 numeral is double bonds: 2 is most common Fig. 35.5 PG structures

  21. Cyclo-oxygenase pathway • Cyclo-oxygenase Pathway: • Thromboxanes • TXA2 from platelets is most common thromboxane: • stimulates platelet aggregation • causes vasoconstriction Fig. 35.7 TX generic structure: C20 fatty acid, 6-member ring with O TXA2 has extra O C9-11

  22. Formation of prostaglandins and thromboxane • Prostaglandins, thromboxane from Arachidonic: • Mostly the 2 series in normal diet • COX enzyme adds 2 O2 → PGG2 • Peroxidase forms PGH2 • Tissue-specific next steps • COX-1 constitutive, all tissues • only form in platelets • COX-2 inducible • (inflammation) • COX-2 inhibitors Provide pain relief Fig. 8

  23. COX inhibitors provide pain relief • COX inhibitors reduce prostaglandin production: • Reduce inflammatory response, provide pain relief • Nonsteroidal anti-inflammatory drugs (NSAIDs): • Aspirin irreversibly inactivates enzyme • acetaminophen, ibuprofen reversible inhibitors • Block both COX-1 and COX-2 Search for selective COX-2: Less side-effects (GI and anti-platelet) Ex. Celebrex, Vioxx Fig. 9

  24. Tables 35.1, 35.2 Functions of prostaglandins, thromboxanes • Functions of prostaglandins, thromboxanes: • PGI2, PGE2, PGD2 • ↑ vasodilation, cAMP • ↓ platelet aggregation, leukocyte aggregation, T-cell proliferation, IL-1 and IL-2, lymphocyte migration • PGF2a • ↑ vasoconstriction, bronchconstriction, smooth muscle contraction • TXA2 • ↑ vasoconstriction, platelet aggregation, lymphocyte proliferation, bronchoconstriction • Compounds are rapidly inactivated by oxidation

  25. Lipoxygenase pathway: leukotrienes • B. Lipoxygenase path brief: leukotrienes (LT) • Adds O2 to form –OOH hydroperoxy (at C 5, 12, 15): 5-HPETE • LT made in leukocytes (triene = 3 C=C) • LTB4 increases: • Vascular permeability • T-cell proliferation • Leukocyte aggretation • INF-g (interferon), • IL-1, IL-2 • LTC4, LTD4 increase: • Brochoconstriction • Vascular permeability • INF-g (interferon) Fig. 11*

  26. Table 35.4 • Prostaglandin and thromboxane receptors: • Specific receptors for different hormones • all are G-protein coupled • signal through increase Ca2+ in cytosol • (PGF2a, TXA2, leukotrienes) • signal through adenylate cyclase-cAMP-PKA • (PGE, PGD, PGI series)

  27. Key concepts • Key concepts: • Eicosanoids (postaglandins, thromboxanes, leukotrienes) are potent regulators of cellular function) • Eicosanoids are derived from polyunsaturated fatty acid (20C) • Eicosanoids are important for inflammatory response, smooth muscle contraction, blood pressure. • PG and T require cyclo-oxygenase (COX) • LT requires lipooxygenase • Eicosanoids bind membrane receptors, • alter PKA or Ca2+ levels

  28. Review question • Review question: • 5. Certain prostaglandins, when binding to their receptor, induce an increase in intracellular calcium levels. The signal that leads to the elevation of intracellular calcium is initiated by which of the following enzyme? • Protein kinase A • Phospholipase C. • Phospholipase A2 • Protein kinase C • Cyclo-oxygenase

More Related