Les deux sources du cholestérol

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1 Les deux sources du cholestérol
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2 Les deux sources du cholestérol
alimentaire ( mg/jour) Acides biliaires fécaux et stérols neutres Intestin Cholestérol biliaire (~1000 mg/jour) ~700 mg/jour Synthèse hépatique (~800 mg/jour) Tissus extra-hépatiques Slide 2 Cholesterol is obtained from two sources. First, cholesterol is synthesized primarily in the liver. Second, cholesterol is absorbed by the intestine from dietary and biliary sources, which is then transported to the liver.1,2 In individuals eating a relatively low-cholesterol diet, the liver produces about 800 mg of cholesterol per day to replace bile salts and cholesterol lost in the feces.2 Depending on diet, people typically consume 300 to 700 mg of cholesterol daily.3,4 Approximately 1000 mg of cholesterol is secreted by the liver into the bile. Thus, approximately 1300 to 1700 mg of cholesterol per day passes through the intestines,4 of which about 50% per day is absorbed.5 Because plasma cholesterol levels are maintained within a relatively narrow range in healthy individuals, a reduction in the amount of dietary cholesterol leads to increased synthesis in the liver and intestine.2 D’après Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Glew RH. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002: ; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998: ; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2-E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:

3 Synthèse du cholestérol
Acétyl-CoA Acétoacétyl-CoA HMG-CoA HMG-CoA réductase Hépatocyte Acide mévalonique Slide 3 The biosynthesis of cholesterol begins with acetyl-coenzyme A (acetyl-CoA)2 whose conversion to cholesterol occurs in a complex pathway involving numerous separate reactions.1 Initially, acetyl-CoA is converted to 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA). The next step, the conversion of HMG-CoA to mevalonic acid (MVA), or mevalonate, is catalyzed by HMG-CoA reductase, an intrinsic membrane-bound protein of the endoplasmic reticulum. The conversion of HMG-CoA, the substrate of HMG-CoA reductase, is the rate-limiting step in cholesterol biosynthesis.1,2 Increased intracellular cholesterol stimulates the phosphorylation of HMG-CoA reductase, which reduces its activity and speeds its rate of degradation.2 Cholestérol D’après Dietschy JM Am J Clin Nutr 1997;65:1581S-1589S.

4 Absorption du cholestérol
Slide 4 Entering the intestine from either dietary or biliary sources,4 cholesterol is emulsified in the lumen by bile acids to form mixed lipid micelles (micellar cholesterol). Micelles move lipids from the intestinal lumen to the mucosal surface where they are absorbed by enterocytes, perhaps through passive diffusion.4,5 Once inside epithelial cells, free cholesterol is esterified by acyl-coenzyme A:cholesterol acyltransferase (ACAT) and assembled into chylomicrons (CMs), which are secreted into the lymph and subsequently enter the blood.1 The adenosine triphosphate (ATP)–binding cassette protein (ABCA1) modulates the flow of cholesterol out of enterocytes.6 ABCA1 = protéine de liaison à l’adénosine triphosphate ; ACAT = acyl-coenzyme A/cholestérol acyltransférase ; CM = chylomicron D’après Champe PC, Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.

5 Lipoprotéines : LDL Les LDL proviennent des lipoprotéines de très basse densité (VLDL) Les LDL transportent le cholestérol vers les tissus périphériques - Elles déposent le cholestérol libre sur les membranes cellulaires - Elles se lient à des récepteurs membranaires spécifiques et sont internalisées par endocytose Un taux élevé de Cholestérol-LDL est un facteur de risque important de maladie coronaire (MC) Slide 5 The primary function of low-density lipoprotein (LDL) is to transport cholesterol to peripheral tissues by depositing free cholesterol on cell membranes and by binding to specific membrane receptors. The bound LDL is then internalized as intact particles by endocytosis.1 LDL is derived from very-low-density lipoprotein (VLDL) through reactions in the plasma. As VLDL molecules pass through the circulation, triacylglycerol is removed by lipoprotein lipase, and surface components, including apolipoproteins C (apoC) and E (apoE), are transferred to high-density lipoprotein (HDL). Cholesterol esters are transferred from HDL to VLDL. LDL has high concentrations of cholesterol and cholesterol esters.1 High levels of LDL-cholesterol (LDL-C) constitute a significant risk factor for coronary heart disease (CHD). Lowering LDL-C reduces the risk of CHD.7 D’après Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994; Expert Panel.JAMA 2001;285(19):

6 Lipoprotéines : HDL HDL naissant Foie C Récepteur HDL TISSUS
cholestérol libre (C) C Récepteur HDL TISSUS PERIPHERiQUES Lécithine : cholestérol acyltransférase Slide 6 A reservoir for apoE and apoC-II, HDL regulates the exchange of proteins and lipids between various lipoproteins in the blood.2 HDL is synthesized in the liver, and to a lesser extent in the intestine, and released into the bloodstream by exocytosis.1,2 HDL removes excess cholesterol from cells and transports it back to the liver through “reverse cholesterol transport.” Excess cholesterol in the plasma membranes of cells and in plasma lipoproteins is esterified to a fatty acid by lecithin:cholesterol acyltransferase (LCAT), an enzyme produced in the liver and bound to HDL in plasma. LCAT is activated by apoA-I, another component of HDL. The cholesterol ester generated in the reaction catalyzed by LCAT is highly hydrophobic and diffuses into the HDL core, where it is trapped and transported back to the liver. HDL particles are taken up by the liver by means of receptor-mediated endocytosis, and cholesterol esters are degraded. Cholesterol released in this manner can be repackaged into lipoproteins, converted into bile acids, or secreted into the bile for removal from the body. The liver is the only organ able to metabolize and excrete cholesterol.1,2 Ester Cholestérol + Apo HDL HDL = lipoprotéines de haute densité D’après Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.

7 Equilibre du cholestérol
Organes extrahépatiques Foie Intestin Cholestérol alimentaire et biliaire LDL VLDL Cholestérol Cholestérol HMG-CoA réductase Slide 7 The liver, intestine, and extrahepatic tissues all help to regulate the balance of cholesterol absorbed in the intestine from dietary and biliary sources. Intestinal mucosal cells secrete triglyceride-rich CMs that are transported to the liver and extrahepatic tissues.1,2 LDL carries cholesterol synthesized in the liver to extrahepatic tissues,1 and HDL carries cholesterol back from peripheral tissues to the liver.2 Cholesterol suppresses its own synthesis by inhibiting HMG-CoA reductase. Activation of ACAT promotes esterification and storage of excess cholesterol and suppresses the synthesis of LDL receptors, thus protecting cells from excess accumulation of cholesterol.8 HDL Acétyl-CoA Stérols fécaux Cholestérol synthétisé D’après Dietschy JM Am J Clin Nutr 1997;65:1581S-1589S.

8 Rôle du foie dans le contrôle du cholestérol
Synthèse hépatique De novo dans le foie Cholestérol synthétisé dans les tissus extra-hépatiques Cholestérol alimentaire HDL Régulation par HMG-CoA réductase Pool de cholestérol hépatique Régulation du récepteur LDL Sécrétion de HDL et VLDL Slide 8 The liver plays a primary role in the regulation of cholesterol levels. HMG-CoA reductase is the primary site for control of cholesterol biosynthesis in the liver. Cholesterol inhibits its own metabolism by a feedback mechanism that involves both inhibition and inactivation of this enzyme. Suppression of cholesterol synthesis resulting from high plasma levels involves LDL-bound cholesterol that undergoes endocytosis by means of specific LDL receptors.2 The liver clears cholesterol in three ways: (1) excretion in the bile as free cholesterol and after conversion to bile salts; (2) esterification and storage in the liver as cholesterol esters; and (3) incorporation into lipoproteins (VLDL and LDL), which are then secreted into the circulation.2 Transformation en acides/sels biliaires Cholestérol libre sécrété dans la bile D’après Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994.

9 (Chélateurs des acides biliaires)
Cibles biochimiques pour le contrôle du cholestérol : 1) synthèse et excrétion Foie LDL VLDL Cholestérol R-LDL Synthèse Excrétion Slide 9 Serum cholesterol levels can be controlled in several ways. Treatment with HMG-CoA reductase inhibitors regulates the rate-limiting step in cholesterol synthesis, the conversion of HMG-CoA to MVA. This causes increases in the expression of LDL receptors by hepatocytes and stimulates receptor-mediated LDL clearance from the circulation.3 A second approach is to interfere with reabsorption of bile acids (an end product of cholesterol metabolism) in the intestine with the use of bile acid–binding resins such as cholestyramine and colestipol. The resultant compensatory increase in bile-acid synthesis and upregulation of LDL-receptor production by hepatocytes enhance clearance of LDL cholesterol from the circulation.3 (Statines) (Chélateurs des acides biliaires) R-LDL = Récepteur LDL D’après Dietschy JM Am J Clin Nutr 1997;65:1581S-1589S

10 Cibles biochimiques pour le contrôle du cholestérol : 2) absorption
Slide 10 Another option for regulating cholesterol levels is to block/inhibit uptake from the intestine, thus reducing the amount of cholesterol delivered to the liver, upregulating LDL receptors, and increasing LDL clearance from the circulation.4 Ezetimibe, a new, potent, and selective inhibitor of cholesterol absorption, is active at or near the brush border at the outer-cell membrane of the intestinal epithelium.8 Other agents that inhibit cholesterol absorption from the intestine include stanols and sterols, synthetic saponins, neomycin, surformer, sucrose polyester, ACAT inhibitors, and microsomal triglyceride transfer protein inhibitors.10 MTP = protéine de transfert des triglycérides microsomiaux D’après Champe PC, Harvey RA Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994; Miettinen TA Int J Clin Pract 2001;55(10): ; Brown WV Am J Cardiol 2001;87(suppl 5A):23B-27B.

11 References 1. Champe PC, Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994. 2. Glew RH. Lipid metabolism II: Pathways of metabolism of special lipids. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002: 3. Ginsberg HN, Goldberg IJ. Disorders of lipoprotein metabolism. In: Fauci AS et al, eds. Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998: 4. Shepherd J. The role of the exogenous pathway in hypercholesterolaemia. Eur Heart J Suppl 2001;3:(suppl E):E2-E5. Hopfer U. Digestion and absorption of basic nutritional constituents. In: Devlin TM, ed. Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002: Ostlund RE Jr. Cholesterol absorption. Curr Opin Gastroenterol 2002;18: 7. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA 2001;285(19): 8. Cotran RS, Kumar V, Collins T. Genetic disorders. In Robbins Pathologic Basis of Disease. 6th ed. Philadelphia: Saunders, 1999: 9. Brown WV. Novel approaches to lipid lowering: What is on the horizon? Am J Cardiol 2001;87(suppl 5A):23B-27B. 10. Miettinen TA. Cholesterol absorption inhibition: A strategy for cholesterol-lowering therapy. Int J Clin Pract 2001;55: Avant de prescrire, veuillez vous référer au résumé des caractéristiques du produit Before prescribing, please consult full manufacturer’s prescribing information. Copyright © 2003 MSP Singapore Company LLC. All rights reserved EZT 2003-W SS Printed in USA