Cholesterol metabolism

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1 Chapter VII: Cholesterol metabolism Dr. Sameh Sarray Hlaoui

2 Cholesterol - Atherosclerotic vascular disease: stroke, coroary artery disease - Structural compoet of cell membrae modulatig their fluidity. - Precursor of bile salts, steroid hormoes (sex hormoes, mieralocorticoides..) ad fat soluble vitamis (vit D). - Serve as compoet of lipoproteis.

3 Cholesterol A sterol, foud i all eukaryotic cells. 4 fused hydrocarbo rigs (A-D) called steroid ucleus. Rig A cotais a oxyge (as OH) o C3. Rig B has a double bod betwee C5 ad C6. Eight carbo brached hydrocarbo attached to C17 of D rig C 27 H 45 OH

4 Most plasma cholesterol is a esterified form with a fatty acid attached at C3: cholestryl esters Esterificatio occurs maily i liver Cholesterol is elimiated from the liver as umodified cholesterol i the bile or it ca be coverted to bile salts that are secreted ito the itestial lume.

5 Cholesterol Sythesis Primary site: liver (~1g/d) Sythesized from Acetyl CoA Cytoplasmic Tightly regulated process Over accumulatio ad depositio i coroary arteries atherosclerosis.

6 Step 1: Formatio of HMG-CoA Codesatio of 2 acetyl-coa acetoacetyl-coa by thiolase Acetoacetyl-CoA combies with third acetyl CoA Hydroxymethyl-glutaryl-coezyme A) HMG-CoA (6C) catalyzed by HMG-CoA Sythase.

7 Step 2: Sythesis of Mevaloic Acid Key step i sythesis of cholesterol HMG CoA is reduced by 2 molecules of NADPH i the presece of HMG-CoA Reductase: producig mevaloate or mevaloic acid

Step 3: Sythesis of isopetetyl Pyrophosphate (IPP) Steps: - Mevaloate is phosphorylated by 2 sequetial P i trasfers from ATP, yieldig the pyrophosphate derivative.

8 Step 3: Sythesis of isopetetyl Pyrophosphate (IPP) Steps: - Mevaloate is phosphorylated by 2 sequetial P i trasfers from ATP, yieldig the pyrophosphate derivative. - Decarboxylatio ATP-depedet with dehydratio yields isopeteyl pyrophosphate (IPP). - Isopeteyl Pyrophosphate Isomerase coverts IPP i 3,3-dimethylallyl pyrophosphate (DPP). isomerase Cosumptio of 3 ATP molecules

9 Step 4: sythesis of faresyl pyrophosphate (FPP) Preyl Trasferase catalyzes head-to-tail codesatios: + Dimethylallyl pyrophosphate (DPP) codeses with isopeteyl pyrophosphate (IPP) to form gerayl pyrophosphate (GPP) (10 C) (10 C) GPP codeses with aother IPP faresyl pyrophosphate (FPP) (15 C). Faresyl pyrophosphate (15 C)

Step 5: Sythesis of Squalee & Cholesterol

reducig aget) Catalyzed by Squalee Sythase

by a sequece of reactios that use molecular

reactios ad shorteig of the carbo chai by 3

10 Step 5: Sythesis of Squalee & Cholesterol Squalee: combie of 2 FPP; (NADPH is a reducig aget) Catalyzed by Squalee Sythase Cholesterol Sythesis: Formatio of laosterol by a sequece of reactios that use molecular oxyge ad NADPH Through a series of 19 reactios ad shorteig of the carbo chai by 3 (from 30 to 27), cholesterol is formed from laosterol.

11 Regulatio of cholesterol sythesis Differet types of cotrol: -HMG CoA reductase -Hormoal regulatio -Trascriptioal regulatio -Drugs

12 Cotrol of HMG-CoA Reductase -is a major cotrol poit. Short-term regulatio: -HMG-CoA Reductase is ihibited by phosphorylatio, catalyzed by AMP-Kiase (which also regulates fatty acid sythesis) Log-term regulatio Feed back ihibitio by cholesterol itself, oxidized derivatives of cholesterol (mevaloate ). Degradatio withi proteosome: HMG-CoA Reductase cotais a sterolsesig domai (SSD). Whe cholesterol level icrease i cells, ubiquiti protei will be attached to SSD by ubiquiti ligase allowig recogitio of HMG CoA reductase by proteosome.

13 2- Hormoal Regulatio Isuli: Bids receptors o the membrae of liver cells. Isuli bidig activatio of HMG-CoA icreased cholesterol sythesis Glucago: Bids specific receptors o the membrae of liver cells. Glucago bidig iactivatio of HMG-CoA decreased cholesterol sythesis.

14 3- Trascriptioal Regulatio: The expressio of the gee for HMG CoA is cotrolled by the trascriptio factor SREBP-2 (Sterol regulatory elemet bidig protei-2). SREPB-2 is a protei of ER membrae, associate with aother ER membrae protei SCAP (SREBP cleavage activatig protei) ad form a complex. - Whe cholesterol level is low: the complex moves from ER to Golgi, where SREBP-2 is acted upo by 2 proteases which release domai of SREBP, that eters the ucleus, bids the SRE (sterol regulatory elemet) (i upstream of reductase gee), acts as trascriptio factor sythesis of HMG CoA cholesterol. - Whe cholesterol is abudat, it bids SCAP at its sterol sesig domai (SSD) ad iduce the bidig of SCAP to other membrae protei. Thus the SREBP-2 is retaied i the ER membrae o activatio of gee o cholesterol sythesis.

15 4- Drug Cotrol: Statis Statis: (or HMG-CoA reductase ihibitors) are a class of drugs used to lower cholesterol levels. They act as competitive ihibitors of HMG-CoA reductase: They get stuck i the active site with its substrate, HMG-CoA. This prevets the ezyme from bidig Nb of statis are o the market: Statis Atorvastati Fluvastati Lovastati Pravastati Rosuvastati Simvastati Trade ame Lipitor Lescol Mevacor, Altocor Pravachol, Selektie, Lipostat Crestor Zocor, Lipex

16 Degradatio of Cholesterol Humas caot degrade cholesterol to CO 2 ad H 2 O (we do t have these ezyme mechaisms) Rather, the sterol ucleus is elimiated from the body by: Coversio to bile acid ad bile salts Secretio of cholesterol ito bile

17 Bile Acid/Salt Metabolism Major excretory form of cholesterol Sythesized i liver, from cholesterol(27c) by loss of 3 carbos (24 C). Bile acid/salts ivolved i dietary lipid digestio as emulsifiers

18 The double bod i cholesterol B-rig is reduced. 2 or 3 hydroxyl groups are added i the steroid ucleus COOH at side chai (3OH) (2OH)

19 Types of Bile Acids/Salts Primary bile acids Good emulsifyig agets i. Cholic acid (3OH) ii. Cheodeoxycholic acid (2OH) Cojugated bile salts Amide bods with glycie or Taurie (orgaic acid) Very good emulsifier

20 BILE SALTS Cojugatio of bile acids i the liver with glycie or taurie produces bile salts: Cholic acid (3OH) Glycocholic Taurocholic BILE ACIDS BILE SALTS Cheodeoxycholic acid (2OH) Glycocheodeoxycholic Taurocheodeoxycholic The ratio of glycie to taurie forms i the bile is 3:1 Bacteria i the itestie ca decojugate bile salts

21 Fuctios of Bile Salts Ø Importat for cholesterol excretio: 1. As metabolic products of cholesterol 2. As solubilizer of cholesterol i bile Ø Emulsifyig factors for dietary lipids, a pre-requisite step for efficiet lipid digestio which facilitate itestial lipid absorptio. Hormoal Cotrol of Bile Secretio: Cholecystokii (CCK)

22 Eterohepatic Circulatio Most bile salts are reabsorbed by the liver: Eterohepatic circulatio. 5% will be lost i feces

23 Cholelithiasis Cholesterol Gallstoe Disease acauses: Bile salts i bile: adue to their deficiecy, cholesterols crystals precipitate i the gall bladder resultig i cholesterol gallstoe disease

24 THE END!

Fatty Acid Synthesis. Sources of Fatty Acids: Sites of Fatty Acid Synthesis:

Fatty Acid Synthesis. Sources of Fatty Acids: Sites of Fatty Acid Synthesis: Fatty Acid Sythesis Sources of Fatty Acids: Diet (pricipal source) Coversio of carbohydrates ad proteis to fatty acids. Sites of Fatty Acid Sythesis: Liver Lactatig mammary glads Adipose tissues. Fatty