1 / 10

Cholesterol  metabolism ط       Sources , distribution and balance in tissues

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. Introduction

tariq
Télécharger la présentation

Cholesterol  metabolism ط       Sources , distribution and balance in tissues

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  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

More Related