1. EZT 2003-W-166089-SSSlide 1 Cholesterol From Two Sources Copyright © 2003 MSP Singapore Company, LLC. All rights reserved.

2. Slide 2 EZT 2002-W-6017-SS Liver Two Sources of Cholesterol Fecal bile acids and neutral sterols Extrahepatic tissues Dietary cholesterol (~300–700 mg/day) Intestine Adapted from 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, 2002:728-777; Ginsberg HN, Goldberg IJ. In Harrison’s Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:2138-2149; 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, 2002:1082-1150. Biliary cholesterol (~1000 mg/day) ~700 mg/day Synthesis (~800 mg/day)

3. Slide 3 EZT 2002-W-6017-SS Cholesterol Synthesis Adapted from Dietschy JM Am J Clin Nutr 1997;65:1581S-1589S. Acetyl-CoAAcetoacetyl-CoAHMG-CoA Mevalonate Cholesterol HMG-CoA reductase Hepatocyte

4. Slide 4 EZT 2002-W-6017-SS Cholesterol Absorption ABCA1=adenosine triphosphate–binding cassette protein; ACAT=acyl-coenzyme A:cholesterol acyltransferase; CM=chylomicron Adapted from Champe PC, Harvey RA. Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994. ABCA1

5. Slide 5 EZT 2002-W-6017-SS Lipoproteins: LDL LDL is derived from very-low-density lipoprotein (VLDL) LDL transports cholesterol to peripheral tissues –Deposits free cholesterol on cell membranes –Binds to specific membrane receptors and is internalized by endocytosis High LDL-cholesterol (LDL-C) is a significant risk factor for coronary heart disease (CHD) Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994; Expert Panel JAMA 2001;285(19):2486-2497.

6. Slide 6 EZT 2002-W-6017-SS Lipoproteins: HDL HDL=high-density lipoprotein Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994. HDL recepto r Lecithin: cholesterol acyltransferase Liver Cholesterol ester HDL + C Nascent HDL PERIPHERAL TISSUES Apo Free cholesterol (C)

7. Slide 7 EZT 2002-W-6017-SS Cholesterol Balance Adapted from Dietschy JM Am J Clin Nutr 1997;65:1581S-1589S. Synthesized cholesterol Fecal sterols Extrahepatic organs Dietary and biliary cholesterol LiverIntestine Cholesterol Acetyl-CoA HMG-CoA reductase LDLVLDL HDL

8. Slide 8 EZT 2002-W-6017-SS Role of the Liver in Cholesterol Control Adapted from Champe PC, Harvey RA. Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994. Dietary cholesterol Liver cholesterol pool De novo synthesis in liver Cholesterol synthesized in extrahepatic tissue HMG-CoA reductase regulation LDL-receptor regulation Conversion to bile acids/salts Free cholesterol secreted in bile Secretion of HDL and VLDL HD L

9. Slide 9 EZT 2002-W-6017-SS Biochemical Targets for Cholesterol Control: Synthesis and Excretion LDL-R=LDL receptor Adapted from Dietschy JM Am J Clin Nutr 1997;65:1581S-1589S. (Bile-acid sequestrants) Liver Cholesterol LDLVLDL SynthesisExcretion (Statins) LDL-R

10. Slide 10 EZT 2002-W-6017-SS Biochemical Targets for Cholesterol Control: Absorption MTP=microsomal triglyceride transfer protein Adapted from Champe PC, Harvey RA Lippincott’s Illustrated Reviews: Biochemistry. 2nd ed. Philadelphia: Lippincott-Raven, 1994; Miettinen TA Int J Clin Pract 2001;55(10):710-716; Brown WV Am J Cardiol 2001;87(suppl 5A):23B-27B. StanolsSterols Synthetic saponins NeomycinSurformer Sucrose polyester Ezetimibe MTP inhibitor Dietary cholesterol Biliary cholesterol ACAT inhibitor ABCA1

11. Slide 11 EZT 2002-W-6017-SS Before prescribing, please consult full manufacturer’s prescribing information.