1a. Objectives (from AD-416):
LAB: LIPID METABOLISM 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 free-living 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. LAB: CARDIOVASCULAR NUTRITION 1. Assess the relationship between plasma biomarkers of nutrient intake and heart health. 2. Characterize the relationship between plasma markers of cholesterol homeostasis, dietary intake and intestinal cholesterol absorption protein genotypes, and heart health. 3. Assess the value of glycemic index (GI) as a component of dietary guidance to promote heart health and decrease the risk of chronic diseases associated with aging. 4. Assess the relationship between the red blood cell fatty acid profiles and indicators of heart health in subjects consuming diets enriched in trans fatty acids derived from ruminant fat and partially-hydrogenated vegetable oils. 5. Assess the efficacy of a comprehensive family centered lifestyle modification program – Family Weight Study (FamWtStudy) – using biomarkers of nutrient intake and cardiovascular risk factors in family member pairs (female parent/guardian and child) after initiation of a comprehensive year long program. 6. Assess the influence in human subjects of dietary 16- and 18-carbon fatty acids on cardiovascular risk factors.
1b. Approach (from AD-416):
LAB: LIPID METABOLISM 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. LAB: CARDIOVASCULAR NUTRITION In the next 5 years the Cardiovascular Nutrition Laboratory will assess the relationship between cardiovascular health and biomarkers of nutrient intake relative to food frequency data using Women’s Health Initiative samples by measuring nutrient intake biomarkers (plasma phospholipid trans fatty acids, eicosapentaenoic acid and docosahexaenoic acid, and phylloquinone and dihydrophylloquinone) and relating these data to cardiovascular health; identifying dietary patterns from food frequency questionnaire data and relating to cardiovascular health; and developing an algorithm using these data that best predicates cardiovascular health; assess the relationship between biomarkers of cholesterol homeostasis and modifiers thereof using plasma samples from the Framingham Offspring Study by measuring plasma cholesterol absorption (sitosterol, campesterol, cholestanol) and biosynthesis (desmosterol, lathosterol, squalene) marker concentrations and relating these data to cardiovascular health as modified by dietary intake and selected genotypes; and evaluate glycemic index (GI) as a component of dietary guidance to decrease chronic diseases risk by determining the reproducibility and variability of GI value determinations in volunteers differing in BMI, age, and gender; assessing the effect of macronutrient amounts and combinations, and fiber on GI and glycemic load (GL) value determinations; and determining the effect of macronutrient composition (carbohydrate, fat, and protein) of a prior meal (“second meal” effect) on GI and GL value determinations.
3. Progress Report:
This progress report includes the work of two subordinate projects at the HNRCA funded through a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information and progress reports, see 1950-51000-072-01S (Lipoproteins and nutrition) and 1950-51000-072-02S (Diet and biomarkers of cardiovascular health)
1. LAB: Lipid metabolism: 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 JMUSDAHNRCA at Tufts University, Boston, MA have developed and tested a therapeutic lifestyle program in 150 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. LAB: Lipid metabolism: 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, MA 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. LAB: Lipid metabolism: 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, MA 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. LAB: Lipid metabolism: 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, MA 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. LAB: Lipid metabolism: 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, MA 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. LAB: Lipid metabolism: 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, MA 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. LAB: Lipid metabolism: 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, MA 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.
8. LAB: Cardiovasuclar Nutrition: Women’s Health Initiative Observational Study predicts disease risk through diet patterns. Heart disease is the leading cause of death in women. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, addressed the experimental question of whether habitual dietary patterns are predictive of heart disease risk in post-menopausal women. Analyzed were diet records of 2448 women, half of whom were diagnosed with heart disease and half of whom were similar in age and race/ethnicity, and did not have heart disease at baseline. We found that women whose dietary patterns were characterized by higher intakes of vegetables and fruits and took supplemental calcium and vitamin D were at the lowest risk of developing heart disease. These data support efforts to increase vegetable and fruit intake in the U.S. population.
9. LAB: Cardiovasuclar Nutrition: Changes in cholesterol homeostasis modify the response of F1B hamsters to dietary very long chain n-3 and n-6 polyunsaturated fatty acids. Fish derived n-3 fatty acids have been associated with decreased risk of heart disease in humans. To define the mechanism associated with these beneficial effects of n-3 fatty acids, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, compared the effects of fish derived n-3 fatty acids with vegetable oil derived n-6 fatty acids in a common animal model, the F1B hamster. Our results indicated that in contrast to previous assumptions the F1B hamster does not respond to dietary fatty acids in a manner similar to humans. To determine the mechanisms by which n-3 fatty acids decrease heart disease risk in humans an alternate experimental model must be developed.
Sorci-Thomas, M., Zabalawi, M., Bharadwaj, M., Wilhelm, A., Owen, J., Asztalos, B., Bhat, S., Thomas, M. 2012. Dysfunctional HDL containing L159R apoA-I leads to exacerbation of atherosclerosis in hyperlipidemic mice. Biochimica et Biophysica Acta. 1821(3):502-512.