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RU BL 616 - Lecture Notes

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1Chapt. 34/5Ch. 34/5Student 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, leukotrienesCholesterol is precursor of steroid hormonesCholesterol 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 LHSteroid hormonesFig. 16.12 steroid hormones bind intracellular receptors, activate transcriptionSteroid 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 transcriptionOverview Steroid hormonesFig. 34.23Steroid 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-β-HSD not a P450 enzyme2P450 enzymesCytochrome P450 enzymes• 10 gene families, 100 isozymes (CYP)• Induced by substrates (alcohol, drugs, toxicants)• Mono-oxygenases• Donate single e- to O2 Figs.19.12, 13Steroid hormones II. Cholesterol to progesterone:• Mitochondrial inner membrane• Rate-limiting step P450SCC(CYPIIA)• Cleavage of side chain• Forms pregnenolone• Then Smooth ER for other steps• 3-β-HSD is not a P450 enzymeFig. 34.23 topSteroid hormonesFig. 34.24A. 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 involvedSteroid hormonesFig. 34.23 partB. 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 fluid3Sex hormonesC. 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 glandFigs. 34.23,25TestosteroneD. Testosterone, Dihydroxytesterone from testes• LH from anterior pituitary stimulatessynthesis (controls CYPIIA)• Testosterone made in Leydig cells,path like adrenal• 5-α−reductase forms DHT• DHT stimulate production sperm proteinsin Sertoli cells, secondary sex charactersEstrogensE. 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, adiposeVitamin DFig. 34.26Vitamin DcalcitrolXI. 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 genes4Table 34.5 Lipid-lowering agentsAgent mechanism ↓total cholesterolStatins 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 HDLFibrates antagonizes PPAR-α, 12-15%causes ↑ in LPL activity, ↓in apo CIII, ↑ in apoA1Ezetimibe reduces intestinal absorption of 10-15%free cholesterol from gut lumenSex hormonesFig. 34.27Treatment 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 glucoseKey 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 ezetimibeChapter 35Fig. 35.1 overview of eicosanoid metabolismEicosanoids: • Prostaglandins (PG)• Thrombaxanes (TX)• Leukotrienes (LT)• Every cell, signal activates phospholipase• Potent ‘local hormones’ act nearby• Produced from fatty acids, frommembrane phospholipids• Arachidonic acid ismajor precursor, 3 paths• Short half-lives5Roles 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 pressureAspirin inhibits COX enzymeArachidonic acid precursorFig. 35.2Arachidonic 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, cytokinesFig. 33.30II. Pathways of eicosanoidsII. Pathways for eicosanoid synthesis:A. Cyclo-oxygenase (COX) → PG, TXB. Lipoxygenase → LeukotrienesC. Cytochrome P450→ epoxides• Different enzymes in different tissues gives specializationFig. 35.3Cyclo-oxygenase pathwayFig. 35.4-6 PG generic structure: C20 fatty acid;5-membered ring Fig. 35.5 PG structuresFig. 35.6 numeral is double bonds: 2 is most commonA.


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