1a. Objectives (from AD-416):
1. To determine the effect of altering dietary composition by restricting carbohydrates, fats, glycemic load, or total calories on plasma lipoproteins, blood pressure, glucose homeostasis, and body weight, cardiovascular risk factors in overweight and obese subjects under controlled feeding conditions and in the freeliving state. 2. Develop and test an interactive program to provide an optimal diet and exercise program for middle-aged and elderly overweight and obese subjects for weight loss and heart disease reduction. 3. Observe the interactions of nutritional factors, especially intake of calories, types of fat, types of carbohydrate, level of physical activity, and different genetic factors on lipoprotein subspecies, obesity, metabolic syndrome, inflammatory markers, and heart disease risk in overweight and obese subjects and subjects with premature cardiovascular disease as compared to age- and gender-matched control subjects within populations. 4. Determine the in vitro and in vivo effects of dietary fatty acids, cholesterol, carbohydrates, hormone levels, hormonal replacement, B vitamins, cholesterol biosynthesis inhibition and cholesteryl ester transfer protein inhibition on lipoprotein metabolism and gene expression, and inflammation in human liver cells (HepG2) and in human subjects under metabolic ward conditions using stable isotopes.
1b. Approach (from AD-416):
In the next 5 years the Lipid Metabolism Laboratory will continue to test optimal lifestyle strategies for the prevention of coronary heart disease (CHD). Human intervention studies will assess effects of supplementation with omega 3 fatty acids and plant sterols versus placebo on CHD risk factors, caloric restriction in older overweight subjects using diet either low or high in glycemic load on CHD risk factors, and an aggressive lifestyle and omega 3 fatty acid supplementation program in overweight subjects with CHD versus usual care on CHD risk factors, cognitive function, and change in coronary atheroma. Population studies will examine the interaction of diet as assessed by questionnaires, genetics as assessed by genotyping, and biochemical markers of insulin resistance, inflammation, and alterations in lipoprotein particles on CHD risk and cognitive decline in participants in the Framingham Heart Study (original cohort and offspring). Human metabolic studies will examine the effects of diets low in animal fat and cholesterol with or without fish versus average American diets on lipoprotein metabolism. We will also examine the effects of estrogens and niacin on human plasma lipoprotein metabolism. Cell studies will examine the mechanisms of action of different fatty acids on the expression of specific genes involved in reverse cholesterol transport in human liver cells and in macrophages. Our overall objectives are to develop optimal lifestyle strategies for the prevention of CHD.
3. Progress Report:
Human Dietary Studies for Heart Disease Risk Reduction: Successfully developed a group based lifestyle intervention program consisting of 12 telephone classes (peer-group) run by our research dietitian. The program has been designed to teach middle aged and elderly people how to modify their lifestyle for the long-term in order to promote heart disease risk reduction and weight loss. The program consist of at least 30 minutes of exercise per day, a diet restricted in animal fat, cholesterol, and trans fats, and enriched in essential fatty acids, fiber, fruits, and vegetables, along with omega 3 fatty acid supplementation, as well as calorie restriction when indicated. The program has been very successful in promoting weight loss as well as improvement in heart disease risk factors such as high blood pressure, plasma lipoproteins, and glycosylated hemoglobin (diabetes marker). Human Population Studies: Completed all genetic studies on 5802 elderly participants in PROSPER (Prospective Study of Pravastatin in Elders at Risk), and in the Framingham Study we have completed all biochemical analysis. We are currently examining the relationship of these parameters with nutritional intake and risk of coronary heart disease and dementia. Human Metabolic Studies: Completed our studies assessing the effect of cholesterol lowering medications (cholesterol synthesis inhibitors) on the metabolism of large and small dense low density lipoprotein (LDL). Small dense LDL is catabolized much more slowly than large LDL, and has been strongly linked to heart disease risk. Statins markedly lower both large and small dense LDL by enhancing their fractional clearance or catabolism. Statins also lower levels of C reactive protein by enhancing its fractional catabolism. In Vitro Tissue Culture Studies: Completed all cell culture studies examining the effects of individual fats on cell cholesterol metabolism, as well as the role of individual HDL particles in promoting cellular cholesterol efflux and liver uptake. The data are currently being analyzed and written up. We are also currently examining the effects of fish oils, along with purified eicosapentaenoic acid and docosahexaenoic acid on white blood cell gene expression in cells isolated from human subjects who have received supplementation over 6 weeks.