Cholesterol metabolism ط      Sources , distribution and balance in tissues

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 CH3 groups at C10 (forms C19) & 1 methyl groups CH3 at C13 (forms C18) 3.        Hexose => dehydrogenation => pentose (+NADPH/CO2) => 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 CO2 and H2O 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/+CO2)  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/O2/+H+)  Lanosterol (30C, rings) Lanosterol  –1NADH/4NADPH/3O2 +2NADH/HCOOH/2CO2 Zymosterol (27C, rings) Zymosterol  –NADPH/O2 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 CO2 + H2O - 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