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Cholesterol and Heart Disease Plaques • Buildup in arteries is composed of proteins, lipids, and cholesterol • When blood vessels are plugged up, you get heart attacks or strokes. • 1.5 million deaths per year from heart attacks • 600,000 deaths from cancer Deaths in Thousands 1200 1000 800 600 400 200 0 00 10 20 30 40 50 60 70 80 90 00 06 Years Deaths from cardiovascular disease (United States: 1900–2006 preliminary). Source: NCHS and NHLBI.3 100 85.9 Percent of Population 90 80 73.3 72.6 79.3 70 60 50 37.9 38.5 40 30 20 10 15.9 7.8 0 20-39 40-59 60-79 Men 80+ Women Prevalence of CVD in adults age 20 and older by age and sex (NHANES: 2005-2006). Source: NCHS and NHLBI. These data include coronary heart disease, heart failure, stroke and hypertension. 4 16 Per 1,000 Persons 14 12 10 8 6 4 2 0 35-44 White Men 45-54 Black Men 55-64 White Women 65-74 Black Women Annual rate of first heart attack by age, sex and race. (ARIC Surveillance:1987-2004). Source: NHLBI. 5 15.1 16 Prevalence (%) 14 11.4 12 10.4 10 8.3 8 6 5.1 7.9 8.6 6.2 5.6 5.1 3.6 4 2.2 2 0 All 1971-75 Women 1976-1980 1988-1994 Men 1999-2002 Prevalence of low CHD risk, overall and by sex, ages 25-74 (NHANES :1971-2002). Source:Personal communication with NHLBI 6/28/07. “Low risk” is defined as SBP <120 mm Hg and DBP<80 mm Hg; cholesterol < 200 mg/dL and BMI <25 kg/m2 and currently not smoking cigarettes and no prior MI or DM. 6 Cholesterol • What is it used for? – Lipid bi-layer – half of all lipids in your cell membranes are cholesterol, half of all your cholesterol in your body is in cell membranes – You liver uses it to create bile that helps digest fats • Where does it come from? – Diet – eggs, butter, etc – Endogenous synthesis – your liver makes it Cholesterol • Cholesterol is too waxy to move through the blood, so it is esterified • Low density lipoproteins (LDL) – Very large particles – 220 angstroms – 1600 cholesterols • High density lipoprteins (HDL) • Very low density lipoproteins (VLDL) LDLR PDB code: 1N7D • The low-density lipoprotein receptor mediates cholesterol homeostasis through endocytosis of lipoproteins. • Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. • The LDL receptor gene is located on the short arm of chromosome 19, and the protein is composed of 860 amino acids. LDL receptors • Liver normally clears out 75% of cholesterol to bring the level down through a regulatory process • It also produces cholesterol – Acetic acid -> HMG CoA reductase -> cholesterol Acetyl-CoA-> HMG CoA reductase -> cholesterol Cholesterol Liver Bile Acids Cholesterol Diet LDL extracellular space cytosol receptor-mediated endocytosis LDL receptor Cholesterol Familial Hypercholesterolemia • Hypercholesterolemia – too much cholesterol in the blood • Familial – transmitted in families – +/+ normal people 150mg/deciliter • Heart att – +/- you got the mutation from one of your parents 300 mg/deciliter – -/- you got the mutation from both of your parents 600 mg/deciliter Background • In 1972, Michael S. Brown and Joseph L. Goldstein hypothesized that surmised that cholesterol overproduction results from defect in the control mechanisms that normally regulate cholesterol biosynthesis. • In 1974, Brown and Goldstein demonstrated that the lesion in FH cells is a defect in LDL binding to a receptor on the surface. What is your solution • Reduce cholesterol in diet – If reduce drastically, you only get a 10% reduction in -/- patients • Your body is more efficient at using cholesterol • Your liver produces more when the level decreases • Feed people bile acid-binding resins – Your liver will then up regulate its LDL receptors, and use more cholesterol from the blood stream – Get 20-25% reduction, but liver still increases production Solutions? • You could give them HMG CO-A reductase inhibitors that stop the liver from producing cholesterol – Statin drugs inhibit pathway to producing cholesterol – When combined with diet and bile acid-binding resins +/- patients are reduced to normal levels – This same strategy helps people that arent FH – The only people who don’t benefit are FH -/- What about FH -/• Gene therapy – Since the liver regenerates quickly, you can take out some cells, fix the mutation and inject them back and they will have the correct receptor