Student Learning Outcomes: 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

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

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

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

10 gene families, 100 isozymes (CYP) 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

I. Cholesterol to progesterone: 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

A. Cortisol synthesized in Adrenal cortex: 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

B. Aldosterone is synthesized in Adrenal cortex: 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

C. Adrenal androgens are weak androgens: 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

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

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

XI. Vitamin D: 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

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

Treatment of Diabetes II with Metformin: 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

Cholesterol is precursor of steroid hormones 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

Eicosanoids: Prostaglandins (PG) Thrombaxanes (TX) Leukotrienes (LT) 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

Inflammatory response after infection, injury: 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

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

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

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

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

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

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

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

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 INF-g (interferon) Fig. 11*

Prostaglandin and thromboxane receptors: 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)

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

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