Cholesterol Metabolism

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1 Cholesterol Metabolism Lippincott s Illustrated Review Chapter 18 Steroid Nucleus 1

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3 Cholesterol was isolated from gall bladder stones in

4 Sources and Elimination of Cholesterol Synthesis: 1000 mg Liver, Small Intestine, Adrenal Cortex Dietary: 300 mg ( Low Cholesterol Diet) Elimination: Via the Bile Cholesterol, Bile Salts 4

5 Ergosterol Plant Sterols are Poorly Absorbed by Human 5

6 Cholesterol Synthesis Requires Carbon Source: Acetyl CoA Energy: ATP Reducing Power: NADPH O 2 Stages in Cholesterol Synthesis Acetyl CoA (C2) Mevalonate (C6) Isoprene Units (C5) Squalene (C30) Lanosterol (C30) Cholesterol (C27) 6

7 ? HMG CoA Reductase 7

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10 Acetyl CoA HMG CoA Mevalonate (C6) Dimethylallyl Pyrophosphate isopentenyl Pyrophosphate (C5) Geranyl Pyrophosphate (C10) FarnesylPyrophosphate (C15) Squalene (C30) Lanosterol (C30) 7 Dehydrocholesterol Cholesterol (C27) 10

11 Synthesis of Bile Acids Hydroxylation at Carbon 7 is the Rate-limiting Step 11

12 Lowering Cholesterol Level Dietary - Cholesterol intake - PUSFA / SFA - Fiber - Daily Ingestion of Plant Steroid Esters Inhibition of Synthesis Enterohepatic Circulation of Bile Acids 12

13 Inhibitors of HMG CoA reductase 13

14 Lowering Cholesterol Bile sequestering agents liver NH 3 + NH 3 + Bile acids Bile acids 90% 95 % reabsorbed 1. Bind bile acid 2. Utilize more cholesterol to make bile acids >10% 5% in in feces feces Esterification of Cholesterol in the Cells 14

15 Esterification of Cholesterol in the Plasma Lecithin: Cholesterol Acyl Transferase (LCAT) Lecithin (PC) Lysolecithin Regulation of Cholesterol Synthesis Regulation of Gene Expression Covalent Modification Hormonal Regulation Proteolytic Regulation 15

16 Regulation of Cholesterol Synthesis Regulation of Cholesterol Synthesis Regulation of Gene Expression Expression of the HMG CoA Reductase Gene Requires a Transcriptional Factor (Protein): Cholestrol SRE DNA SREBP mrna 16

17 Regulation of Cholesterol Synthesis Regulation of Gene Expression Covalent Modification AMP Protein Kinase HMG CoA Reductase HMG CoA Reductase P Phosphatase Regulation of Cholesterol Synthesis Regulation of Gene Expression Covalent Modification Hormonal Regulation Glucagon: Phosphorylated Form Insulin: Dephosphorylated Form ( Phosphatase) 17

18 Regulation of Cholesterol Synthesis Regulation of Gene Expression Covalent Modification Hormonal Regulation Proteolytic Regulation Cholesterol HMG CoA Reductase Proteolysis HMG CoA Reductase 18

19 Transport of Cholesterol in the Blood Chylomicrons remenats Liver VLDL IDL LDL HDL Liver Liver extrahepatic tissues Risk factor for coronary heart disease. 19

20 ph 20

21 Macrophage Scavenger Receptor Non specific modified (damaged) LDL No down regulation Macrophage LDL foam cells Accumulation of foam cells in the subendothelial space Early evidence of atherosclerotic plaque Familial Hypercholesterolemia Homozygotes 680 mg/dl Heterozygotes 300 mg/dl Absence of LDL receptor / Abnormal Receptor Homozygotes No Receptors Hetero ½ Normal Number Accumulation of ldl more IDL LDL Cholesterol deposition in tissues Atherosclerosis Death in childhood 21

22 Origin HDL Liver and Intestine: Nascent Discoid Shape ApoA1 ApoA1 Maturation of HDL Cholesterol Cholesterol Esterification 22

Transport Bile F C Liver CE SR-BI A-I CE Mature HDL LCAT A-I CE F FC C ABC1 Nascent HDL Macrophage ABC1 = ATP-binding cassette protein 1;

23 Reverse Transport of Cholesterol From Cells to Liver Foam Cells in Vascular Tissues 1)Directional Movment; Role of ABC1 Memberane 2)Esterification of Cholesterol LCAT Ch Ch-FA cholesterol is trapped within the core of HDL HDL Metabolism and Reverse Cholesterol Transport Bile F C Liver CE SR-BI A-I CE Mature HDL LCAT A-I CE F FC C ABC1 Nascent HDL Macrophage ABC1 = ATP-binding cassette protein 1; A-I = apolipoprotein A-I; CE = cholesteryl ester; FC = free cholesterol; LCAT = lecithin:cholesterol acyltransferase; SR-BI = scavenger receptor class BI 23

24 Fate of HDL cholesterol * Uptake by liver Binding to Specific Receptor on Hepatocytes * Transfer of cholesterol into cells scavenger receptor SR_B1 - On many cell types - Can be upergulated if ch. Is needed - Not down regulated * HDL interaction with other particles exchange of components. 24

number Done by Corrected by Doctor

number Done by Corrected by Doctor number 29 Done by Ali Yaghi Corrected by Shahd Alqudah Doctor Faisal Al-Khatibe In this lecture we will continue the steps of synthesizing cholesterol. in the previous sheet we reached the step of forming