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)
1. Beneficial Effects of Margarine versus Butter on Heart Disease Risk Factors. Heart disease is a major cause of death and disabilty in our society. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have shown that non-trans margarines have much more beneficial effects on lowering low density lipoprotein cholesterol particles (the bad cholesterol) and inflammation markers and increasing cholesterol transfer to high density lipoprotein (the good cholesterol) as compared to butter in people studied in the free-living state. Our data indicates that non-trans margarines are the spreads of choice for heart disease risk reduction, and should replace butter.
2. Detrimental Effects of Dietary Fructose are not Related to Changes in Non-Fasting Glucose Both sugar and high fructose corn syrup contain approximately equal amounts of fructose and glucose. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have shown that fructose has much more detrimental effects on blood sugar and cholesterol levels and liver fat amount than does dietary glucose, and that these deleterious effects are not related to 24 hour changes in glucose and insulin levels. Our data indicates that efforts should be made to restrict both sugar and high fructose corn syrup in the diet in order to reduce heart disease risk.
3. Beneficial Effects of Fish Intake to Prevent Bone Loss in the Elderly Bone loss and osteoporosis is a major cause of hip fractures and disability in the elderly. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have shown that increased intake of fish is associated with prevention of bone loss and promotes increased bone density Our results indicate that fish intake is not only good for heart disease prevention, but also prevention of bone loss in the elderly.
4. Controlling Lipids is Important for Preventing Complication of Type 1 Diabetes Type 1 diabetes is associated with kidney, eye, and nerve disease over time. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have shown that patients with type 1 diabetes who have optimal total cholesterol and HDL cholesterol levels, and follow a prudent diet and exercise on a regular basis, can live for more than 50 years without developing kidney, eye, or nerve disease. Our results indicate that control of cholesterol, diet, and exercise are critical to prevent the complications of type 1 diabetes.
5. Cholesterol Synthesis Inhibition Lowers Cholesterol and C Reactive Protein Levels, but can increase Diabetes risk Heart disease is a leading cause of death and disability in our society, and lowering cholesterol by inhibiting cholesterol synthesis can decerase heart disease risk greatly. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have shown that inhibition of cholesterol synthesis with statins significantly lower levels of C reactive protein, but can modestly increase insulin levels and insulin resistance, resulting in enhanced risk of developing diabetes. Our data indicate that subjects on statins for heart disease prevention need to be monitored for new onset diabetes.
6. Measurement of High Density Lipoprotein (HDL) Particles provides More Information about Heart disease Risk than Measuring HDL cholesterol. Heart disease is a leading cause of death and disability in our society, and low HDL is a major risk factor for this disease. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have documented measuring HDL particles by two dimensional gel electrophoresis provides substantially more information about heart disease risk than HDL cholesterol alone. Moreoever the particles have different functions and metabolism and can be very favorably modified by weight loss in the obese, and by niacin treatment. Our data indicate that optimizing HDL particles with lifestyle and niacin is important for preventing future heart disease events.
7. Diets High in Animal Fat and Cholesterol Cause Clogging of Arteries in Mice that Have High Cholesterol Levels Heart disease is a leading cause of death and disability in our society, and is caused by cholesterol deposits in certain types of white blood cells known as macrophages in the artery wall. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have shown that when mice with very high cholesterol levels (LDL receptor negative mice) are fed diets high in animal fat and cholesterol they have increased cholesterol deposits and inflammation in macrophages in their artery walls. These data in animals support human studies indicating that diets restricted in animal fat and cholesterol are beneficial in terms of reducing the cholesterol content of cells found in the artery wall.
8. Fish Oils Fats Suppress HDL production in the Liver Low levels of HDL are a major risk factor for heart disease, the leading cause of death and disability in our society, and use of fish oil has been shown to reduce heart disease risk. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, have shown that feeding liver cells (HepG2) with a major fatty acid found in fish (docosahexaenoic acid) results in suppression of the gene and protein expression of apolipoprotein A-I (the major protein of high density lipoproteins) by a direct action on hepatic nuclear factor-3 (beta). Our data provide a mechanistic explanation for why fish supplementation reduces HDL apoA-I production rate in humans. This mechanistic knowledge will help in developing better and more specific dietary strategies to reduce the risk of heart disease.