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: We have successfully developed a group based lifestyle intervention program consisting of 12 classes by group run by our research dietitian, which can be done by telephone conference calls. The program has been designed to teach middle aged and elderly people how to modify their lifestyle long term 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 and cholesterol, and enriched in essential fatty acids and vegetables, along with omega 3 fatty acid supplementation, as well as calorie restriction when indicated. The next step is to put the program on the web as well. This is now being implemented. The program has been very successful in promoting weight loss. as well as improvement in heart disease risk factors such as high blood pressure, high cholesterol, and diabetes. We are also carefully examining the effects of individual purified fats found in fish known as the omega 3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in humans in order to understand why they reduce the risk of heart disease. We have also collaborated with others to examine the effects of gastric bypass surgery on heart disease risk factors, and to look at the effects of dietary glucose and fructose on plasma glucose levels in the non-fasting state. (NP 107-3B) Human Population Studies: We have completed all biochemical studies in the Framingham Heart Study and all genetic studies in elderly participants in PROSPER (Prospective Study of Pravastatin in Elders at Risk). and in the Framingham Heart Study and the Framingham Offspring Study we have completed all bioichemical analysis. We are now in the active data analysis, write up and publication phase to assess the usefulness of various blood tests and genetic markers in determining risk of heart disease, cognitive decline, all-cause dementia, and Alzheimer’s disease. (NP 107-4A) Human Metabolic Studies: We are currently 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 has been strongly linked to heart disease risk.(NP 107-4A) In Vitro Tissue Culture Studies: We have now completed all cell culture studies examining the effects of individual fats on cell cholesterol metabolism. The data are currently being analyzed and written up. (NP-107-2B)