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 telephone classes, run by our research dietitian. The program has been designed to teach middle aged and elderly people how to modify their lifestyle, in the long-term, to promote heart disease risk reduction and weight loss. The program consists 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, and calorie restriction when indicated. The next step is to put the program on the web as well. 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. Human Population Studies: We have completed all genetic studies on 5802 elderly participants in PROSPER (Prospective Study of Pravastatin in Elders at Risk), an in the Framingham Study we have completed all bioichemical analysis. 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. 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 prepared for publication. For publications relating to this project, see parent project #1950-51000-072-00D.
1. Increased Fat and Cholesterol Absorption Increases the Risk of Developing Heart Disease ARS-funded researchers from Tufts University in Boston, MA have shown that specific fat-rich particles made in the intestine after a fat-rich meal are much more likely to increase in overweight and obese subjects, as well as in those with baseline elevated blood cholesterol levels. These findings are corroborated by observations by these same researchers in the Framingham Offspring Study that those with elevated markers of cholesterol absorption are at increased risk of developing heart disease. These findings support the guidelines to restrict dietary cholesterol and animal fat in the diet for heart disease prevention. Moreover this same overabsorption occurs in families with premature heart disease. These findings support the guidelines to restrict dietary cholesterol and animal fat in the diet for heart disease prevention, and indicate that diet plays a very key role in heart disease risk.
2. Increased Small Dense Low Density Lipoprotein (LDL) Cholesterol is a Better Heart Disease Risk Marker than Total LDL Cholesterol Elevated blood cholesterol levels have been identified as a major risk factor for heart disease. These elevations are usually due to increases in the low density lipoprotein or LDL cholesterol. ARS-funded researchers from Tufts University in Boston, MA have shown in the Framingham Offspring Study that a specific type of LDL, known as small dense LDL, is a better predictor of heart disease than is total LDL. Moreover these investigators have shown that increases in small dense LDL are related to markers of intestinal cholesterol overabsorption. These findings support the guidelines to restrict dietary cholesterol and animal fat in the diet for heart disease prevention.
3. A High Fructose Diet Increases Heart Disease Risk Factors More than a High Glucose Diet ARS-funded researchers from Tufts University in Boston, MA, in collaboration with researchers from the University of California, Davis, have shown that dietary fructose at 25% of calories is much more likely to increase the blood triglyceride and small dense low density lipoprotein (LDL) cholesterol levels, and to lower levels of the high density lipoproteins (or good cholesterol) than is a diet containing 25% of calories as glucose. Not only have increased consumption of dietary animal fats and cholesterol been linked to heart disease, but so has increased intake of refined carbohydrate (especially table sugar and high fructose corn syrup). Moreover the high fructose diet also increased the risk of developing diabetes, and promoted excess fat deposition in the abdomen. These findings support the guidelines to reduce heart disease risk by restricting sugars especially table sugar and high fructose corn syrup, which both contain about 50% of carbohydrate as fructose.