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United States Department of Agriculture

Agricultural Research Service

Research Project: LIPOPROTEINS AND NUTRITION

Location: Human Nutrition Research Center on Aging

2012 Annual Report


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.


4.Accomplishments
1. Diet and Coronary Heart Disease (CHD) Risk Reduction. CHD is a leading cause of death and disability, and major CHD risk factors include age, high blood pressure, smoking, diabetes, elevated low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol. Being overweight or obese predisposes to all these risk factors except for age and smoking. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts have developed and tested a therapeutic lifestyle program in150 overweight or obese men and women with CHD. They have documented that this 12 class telephone program, delivered to groups of 10 or less can be very effective in prompting weight loss, exercise, and heart disease risk reduction. The USDA has the mandate to specify diets for chronic disease prevention, and such a program if widely implemented could significantly reduce both CHD and obesity in America.

2. Low Adiponectin and Elevated Lipoprotein (a) as Risk Factors for CHD. CHD is a leading cause of death and disability, and major CHD risk factors include age, high blood pressure, smoking, diabetes, elevated low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol. Two additional emerging risk factors include low serum adiponectin, made in fat and said to be a marker of subcutaneous fat and not deleterious visceral fat, and elevated lipoprotein (a), an LDL-like lipoprotein with a unique protein known as apo(a) attached to it. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts measured determined adiponectin and Lp (a) levels In over 3,000 subjects followed for more ten years, and documented that decreased plasma adiponectin elevated plasma lipoprotein (a) levels are significant independent predictors of CHD risk, and that measurement of apo (a) isoforms, and Lp (a) cholesterol does not add significant additional information about CHD risk. The USDA has the mandate to specify diets for chronic disease prevention. The measurement of these risk factors can improve prediction of CHD, and can also be used to target subjects for weight loss for low adiponectin and /or niacin treatment for high LP (a) to optimize these risk factors and reduce CHD risk.

3. CHD is a leading cause of death and disability, and major CHD risk factors include age, high blood pressure, smoking, diabetes, elevated low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol. The cornerstone of CHD risk reduction remains dietary modification by restricting animal fat and sugars, and increasing dietary essential omega 6 and omega 3 fatty acids. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts have examined the effects of diets restricted in animal fat and cholesterol either rich or low in omega 3 fatty acids as found in fish on lipoprotein metabolism using stable isotope methods in middle and elderly subjects. The diet poor in fish lowered LDL apolipoprotein B-100 by about 20% all due to enhanced fractional catabolism, while the diet high in fish also lowered the levels of apoB-100 and apoB-48 in triglyceride-rich lipoproteins by lowering their production, but also enhanced the conversion of apoB-100 to LDL, so the LDL-C reduction was only about 10%. The USDA has the mandate to specify diets for chronic disease prevention, and these data indicate that adding fish to cholesterol therapeutic cholesterol diets is most beneficial in those with elevated serum triglyceride levels. Such diets if widely implemented could significantly reduce CHD risk in America.

4. Predicting Statin Induced LDL Cholesterol Lowering Response and Muscle Problems. CHD is a major cause of death and disability, and the use of statins, which inhibit cholesterol synthesis, has been shown to significantly reduce LDL cholesterol and CHD risk in many large scale randomized and placebo controlled prospective studies. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts have studied 6,000 elderly people and have shown that genetic variation at the solute carrier organic anion transporter 1B1 gene locus (SLCO1B1, the liver statin uptake transporter) has a significant effect on LDL cholesterol lowering response to pravastatin in the elderly. This genetic variation has also been linked to the risk of statin induced muscle problems. About 20% carry one variant allele and have a decreased LDL-C lowering response, while about 3% carry both alleles, resulting in a marked and significant decrease in statin induced LDL-C lowering. The USDA has the mandate to specify diets for chronic disease prevention along with other treatments. Our overall findings have important implications for ways to lower the risk of CHD, especially in the elderly.

5. Statins Increase Insulin Resistance and Diabetes Risk. CHD is a major cause of death and disability, and the use of statins, which inhibit cholesterol synthesis, has been shown to significantly reduce LDL cholesterol and CHD risk in many large scale randomized and placebo controlled prospective studies, but they can also increase the risk of developing diabetes. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts have documented that maximal statin treatment with either atorvastatin or rosuvastatin increases insulin resistance in patients receiving this therapy, which may explain why statins can increase the risk of developing type 2 diabetes, despite their beneficial effects of lowering heart disease risk. The USDA has the mandate to specify diets for chronic disease prevention along with other treatments. This information is useful in monitoring patients on statin therapy.

6. Cholesterol Ester Transfer Protein Inhibition Lowers Intestinal Lipoprotein Production. CHD is a major cause of death and disability, and low levels of HDL cholesterol are a major CHD risk factor. Cholesteryl ester transfer protein (CETP) acts to transfer cholesteryl ester from HDL to triglyceride-rich lipoproteins in exchange for triglyceride, and inhibiting CETP significantly raises HDL cholesterol. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts have examined the effects of a CETP inhibitor torcetrapib on human lipoprotein metabolism and have documented that this treatment decreases apolipoprotein (apo) B-48 levels within triglyceride-rich lipoproteins of intestinal origin by decreasing their production, and also enhances the clearance of apoB-100 lipoproteins, and decreases the clearance of HDL apoA-I. The USDA has the mandate to specify diets for chronic disease prevention along with other treatments. Our data indicate that CETP inhibition does not increase fecal excretion, and therefore may not be a useful treatment to reduce CHD risk.

7. Cell Studies Indicate that Omega 3 Fatty Acids Decrease HDL ApoA-I Gene Expression. CHD is a leading cause of death and disability, and major CHD risk factors include age, high blood pressure, smoking, diabetes, elevated low density lipoprotein (LDL) cholesterol, and decreased high density lipoprotein (HDL) cholesterol. Researchers at JMUSDA-HNRCA at Tufts University, Boston, Massachusetts have shown that docosahexaenoic acid (a major omega 3 fatty acid found in fish and fish oil) suppresses apolipolipoprotein (apo) A-I gene expression via hepatic nuclear receptor factor-3 beta. The USDA has the mandate to specify diets for chronic disease prevention along with other treatments. These cell studies indicate that omega 3 fatty acids have a variety of poorly understood effects on lipoprotein metabolism at the cellular level, which may have important implications for CHD risk reduction.


Last Modified: 8/22/2014
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