1. Cholesterol metabolism ط Sources, distribution and balance in tissues ط Overview of steps involved in synthesis of cholesterol ط Key enzyme, HMG CoA reductase and regulation D4 409-15

2. Introduction 1. Chol is distributed in free (25-30%) & esterified (70-75%) form 2. fig10.28, Chol consists of 27 C: 4 fused 17 C rings (C1-17) & 8 hydrocarbon chain on fourth-ring (C20-27) 1 OH group at C3 in first-ring, where LC-FA attach for esterifcation 1 unsaturated centre between C5 & C6 in second-ring 1 methyl CH 3 groups at C10 (forms C19) & 1 methyl groups CH3 at C13 (forms C18) 3. Hexose => dehydrogenation => pentose (+NADPH/CO 2 ) => transformation => other pentoses => rearrangement => Hexoses 4. ketose as donor & aldolase as acceptor

3. Role of Cholesterol in Cells (most are free) 1. Major sterol component of plasma & intracellular membrane · Abundant in myelinated structures of brain & CNS · Small amount in mitoch inner memb 2. Precursor of Bile Salts synth in liver · To absorb dietry TG & fat soluble vit · Excreted in the form of Bile acids through intestine · Not hydrolized to CO 2 and H 2 O 3. Precursor of various hormones: · steroid hormones (progesterone, estrogen, testisteron) · corticosteroids (cortisol) · minerocorticoids (aldosterone) 4. Chol biosynthesis provides substrates for KB formation & Vit D

4. Synthesis of Cholesterol 1. Formation of Mevalonic Acid (MA): FA / keto-AA / Pyr / acetate ==> ACoA (thioester bond) fig10.31, ACoA (2C) + ACoA (2C)  AACoA Thiolase (+CoA)  AACoA (4C) ACoA + AACoA  HMGCoA Synthase (+CoA)  HMGCoA (6C) fig10.32, HMACoA  HMGCoA Reductase “rate-limiting enzyme” (–2NADPH)  MA (6C)

5. Synthesis of Cholesterol 2. fig10.33, Formation of Farnesyl Pyrophospahte (FPP): MA  MK (–ATP)  5PM (6C)  PMK (–ATP)  5PPM (6C) 5PPM (6C)  PPMDC (–ATP/+CO 2 )  IPPP (5C) IPPP (5C)  Isomerase (+H + )  33DMPP (5C) IPPP (5C) + 3,3DMPP (5C)  PT-ase (+PPi)  GPP (5C) IPPP (5C) + GPPP (5C)  GT-ase (+PPi)  FPP (15C)

6. Synthesis of Cholesterol 3. fig10.34, 10.36, 10.37, Formation via Squalene: FPP (15C) + FPP (15)  Squalene Synthase (–NADPH)  Squalene (30C) Squalene (30C)  Squalene Oxidase “cyclase” (–NADPH/O 2 /+H + )  Lanosterol (30C, rings) Lanosterol  –1NADH/4NADPH/3O 2 +2NADH/HCOOH/2CO 2  Zymosterol (27C, rings) Zymosterol  –NADPH/O 2  7Dehydrocholesterol (27C, rings) 7Dehydrocholesterol  (–NADPH)  Cholesterol (27C, rings)

7. Control of Cholesterol metabolism & Balance ط Cholesterol Balance, Factors regulating cholesterol synthesis and degradation ط Clinical Aspects: Hypercholesterolemia causes and treatment Atherosclerosis, coronary heart diseases ط Cholesterol as precursor of bile salts, Steroid hormones and vitamin D ط Bile acids and bile salts D4 415-20 Excretion of Cholesterol ط Cholesterol as precursor of bile salts, Steroid hormones and vitamin D ط Bile acids and bile salts D4 415-20

8. Regulation of Cholesterol Biosynthesis 1. Incorporation into plasma LP: Chylom, HDL, VLDL 2. Uptake of chol ester by cells (endocytosis): Cell surface: Clathrin-coated LDL Receptor (Apo-B100) Formation of clathrin-coated vesicle => endocytosis => vesicle (endosome) + clathrin (return to surface) Endosome fuse to lysosome => chol ester hydrolyzed to chol + LC-FA a) Return to cell surface: inhibits nourishment of LDL Receptor (down regulation) b) Defuse into the cytoplasm: Inhibits HMGCoA Reductase (maybe at DNA level, synth) c) Enters End Retic: activates ACAT for esterification of Chol (Chol + PTA => Chol Oleate + LPTA) fig10.39

9. Regulation of Cholesterol Biosynthesis 3. Intestinal excretion as BA (cholic, chenodeoxycholic): fig10.41, Reactions (Chol => BA): - Epimerization of OH group at C3 - Reduction of == double bond between C5 & C6 - Introduction of OH group at C7 (CDC) or at C7 & C12 (Cholic) - Elimination of 3Cs (from 27C to 24C) Conjugation of AA to form BS: - Glycocholic, taurocholic Enterohepatic Circulation: Chol => LIVER => BA/BS => canaliculi => Duct => GB => Duedenum * Stool (out) * i. Ileum => primary BA (active transport)=> portal vein => LIVER ii. Colon => convert primary BA by Bacteria to secondary BA (passive transport) => LIVER Importance of BA/BS: - Solubulization of Chol; lead to excretion & prevent precipitation - Chol is not oxid to CO 2 + H 2 O - Activates pancreatic Lipase (indirectly); acts as emulsifying agent for absorption of other fats - Facilitates absorption of fat soluble vitamins

10. Vitamin D Synthesis (fig10.43) · Under SKIN: Sun UV ray + 7 Dehydrocholesterol  fusion of C9 & C10 in second-ring  Provitamin D3 Pro  thermal non-enzymatic (slow ~36h)  Vitamin D3 (cholecalciferol) · Reach LIVER: Vitamin D3 (25 Hydroxy Cholecalciferol) · Reach KIDNEY: inhibits Ca ++ excretion => · Reach INTESTINE: Enhances Ca ++ absorption by inducing synthesis of prt required for trasport => · Reach BONE: Stimulates Osteoblast formation and enhance bone resorption