Lecture 9. Dr. Sameh Sarray Hlaoui

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1 Lecture 9 Dr. Sameh Sarray Hlaoui

Steroid Hormoes aall steroid hormoes are derived from cholesterol but their structure differ from the cholesterol (rig structure ad side chais) anomeclature: Steroids with : 21-carbo: pregaes,

2 Steroid Hormoes aall steroid hormoes are derived from cholesterol but their structure differ from the cholesterol (rig structure ad side chais) anomeclature: Steroids with : 21-carbo: pregaes, 19-carbo: adrostaes 18-carbo: estraes. aare ot stored, but sythesized ad immediately released a Steroid hormoes are ot water soluble so they have to be carried i the blood complexed to specific bidig globulis. aall steroid hormoes are lipid soluble ad thus diffuse across lipid membraes of the target cell aezymes which produce steroid hormoes from cholesterol are located i mitochodria ad smooth ER

3 Types of steroid hormoes Steroid hormoes are classified accordig to their physiologic actio ad tissue of origi: Type of steroid hormoe Edocrie glad Name of steroid Fuctios Glucocorticoids Adreal cortex cortisol, corticosteroe - promote glucoeogeesis; favor breakdow of fat ad protei (fuel mobilizatio); - ati-iflammatory Mieralocorticoids Adreal cortex aldosteroe maitais blood volume ad blood pressure by icreasig sodium reabsorptio by kidey Adroges Testis testosteroe - developmet of male secodary sex characteristics; - prevets boe resorptio Estroges Ovary estradiol, estroe -developmet of female secodary sex characteristics; - -prevets boe resorptio Progestis Corpus luteum (ovary) progesteroe -prepares uterus liig for implatatio of ovum

4 Fuctios of Steroid Hormoes Steroid hormoes play importat roles i: - carbohydrate regulatio (glucocorticoids) - mieral balace (mieralocorticoids) - reproductive fuctios (goadal steroids) Steroids also play roles i iflammatory resposes, stress resposes, boe metabolism, behavior, mood

5 Sources of Cholesterol for Steroid Sythesis The cholesterol precursor comes from: -De Novo sythesis of cholesterol from acetyl CoA - released from cholesteryl esters by a esterase - uptake from lipoprotei (LDL)

6 Sythesis of Steroids athe first ezymatic step i steroid sythesis is the irreversible cleavage of 6 C from cholesterol (C27) yieldig pregeoloe (C21) a The ezyme that catalyzes this reactio is Cholesterol side-chai cleavage ezyme (cytochrome P450scc ezyme), located i the ier mitochodrial membrae +3NADPH+ 3O 2 P450scc + +3NADP + +3H 2 O Cholesterol (C27) pregeoloe (C21)

We have aqueous phase betwee the 2 membraes which ca ot be acrossed by the lipophilic cholesterol How does cholesterol get from the

7 Cholesterol is mostly located i the exteral mitochodrial membrae. The coversio of cholesterol to steroids occurs i the iteral mitochodrial membrae. We have aqueous phase betwee the 2 membraes which ca ot be acrossed by the lipophilic cholesterol How does cholesterol get from the exteral membrae to the iteral membrae? Aswer: Steroidogeic acute regulatory protei (StAR), which trasports cholesterol ito the mitochodria, movig it from the outer membrae to the ier membrae. It s the ratelimitig step i the sythesis of steroids.

8 Pregeoloe The precusor molecule for all C18, C19 ad C21 steroids. Produced directly from cholesterol,

glomerulosa, fasciculata, reticularis) ad secreted i blood i

9 Sythesis of corticosteroids ad adroges The corticotsteroids ad adroges are made i differet regios of the adreal cortex (zoa glomerulosa, fasciculata, reticularis) ad secreted i blood i respose to differet sigals P450scc P450scc P450scc Adreal cortex

glomerulosa) of adreal cortex asecretio of aldosteroe

10 Sythesis of Aldosteroe athe pricipal mieralocorticoid aproduced from progesteroe i the outer layer (zoa glomerulosa) of adreal cortex asecretio of aldosteroe is regulated by: - Na + cocetratios - Rei-agiotesi system (RAS)

11 Rei-Agiotesi-Aldosteroe System (RAS) Reduced blood flow to kidey ezyme rei breaks dow agiotesioge (secreted from liver) agiotesi I agiotesi II aldosteroe secretio (act o kidey by stimulatig sodium ad water retetio)

12 Cortisol/Hydrocortisoe Sythesized i the middle layer (zoa fasciculata) of the adreal cortex, i respose to ACTH (adreocorticotropic hormoe), secreted by aterior pituitary glad. ACTH secretio is cotrolled by feed back ihibitio by a high level of cortisol. Ivolved i: Stress adaptatio, Elevatio i blood pressure ad Na + uptake, Modulatio of immue respose Glucose metabolism: stimulates glycoge formatio ad decreases glucose utilizatio.

Adroges Secreted by the ier layer (zoa reticularis) of adreal

Productio is stimulated by ACTH Estroe Mai product: adrosteedioe

13 Adroges Secreted by the ier layer (zoa reticularis) of adreal cortex. Productio is stimulated by ACTH Estroe Mai product: adrosteedioe (a itermediate compoet) coverted i the peripheral tissues ito testosteroe, estroe ad estradiol. Testosteroe: male sex hormoe, resposible for secodary male sex characteristics. Estroe: female sex hormoe, resposible for secodary female sex characteristics Estradiol: primary female sex hormoe, essetial for the developmet ad maiteace of female reproductive tissues Testosteroe Estradiol

14 Mechaism of steroid hormoe actio aeach steroid diffuses across the plasma membrae of its target cell ad bid to a specific cytosolic receptor. formatio of active steroid-steroid receptor complex athese complex traslocate to ucleus where it bids to specific regulatory DNA sequeces: hormoe respose elemet (HRE) i associatio with coactivator proteis, thereby causig promoter activatio ad icreased trascriptio of targeted gees. ahormoe-receptor complexes ca also ihibit trascriptio i associatio with corepressor proteis.

Goadal Steroid Hormoes Testosteroe ad estradiol are two most importat steroids produced by the testes ad the ovaries a sigle hypothalamic releasig factor, Goadotropi Releasig Hormoe (GRH) stimulates

15 Goadal Steroid Hormoes Testosteroe ad estradiol are two most importat steroids produced by the testes ad the ovaries a sigle hypothalamic releasig factor, Goadotropi Releasig Hormoe (GRH) stimulates the aterior pituitary to release the Follicle Stimulatig Hormoe (FSH) ad Leutiizig Hormoe (LH) LH stimulates testes to produce testosteroe ad ovaries to produce estroges ad progesteroe. FSH regulates the growth of ovaria follicles ad stimulates testicular spermatogeesis.

16 Degradatio of Steroid Hormoes asteroids are coverted ito iactive metabolic molecules i the liver areactios iclude: Reductio of usaturated double bods Itroductio of additioal OH groups athe resultig structures are made more soluble (o eed for protei carriers) by cojugatio with glucouroic acid or sulfate These cojugate steroid metabolites: 20-30% of cojugated metabolites secreted i the bile ad the excreted i feces Remaider (70-80%) are released ito blood, filtered from the plasma i the kidey ad passig ito the urie.

17 THE END!

18 Steroidogeic Ezymes Commo ame "Old" ame Curret ame Side-chai cleavage ezyme; desmolase P450 SCC CYP11A1 3 beta-hydroxysteroid 3 beta-hsd 3 beta-hsd dehydrogease 17 alpha-hydroxylase/17,20 P450 C17 CYP17 lyase 21-hydroxylase P450 C21 CYP21A2 11 beta-hydroxylase P450 C11 CYP11B1 Aldosteroe sythase P450 C11AS CYP11B2 Aromatase P450 aro CYP19

19 Sythesis of cortisol: (1) P-450 scc (Mitochodria) (2) 3b-hydroxysteroid DH ad D 5,4 isomerase (ER) (3) 17a-hydroxylase (ER) (4) 21-hydroxylase (ER) (5) 11b-hydroxylase (Mitochodria)

Cholesterol metabolism

Chapter VII: Cholesterol metabolism Dr. Sameh Sarray Hlaoui Cholesterol - Atherosclerotic vascular disease: stroke, coroary artery disease - Structural compoet of cell membrae modulatig their fluidity.