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United States Department of Agriculture

Agricultural Research Service


Location: Human Nutrition Research Center on Aging

2013 Annual Report

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. LIPID METABOLISM LAB: Dietary glycemic index affects plasma lipids and inflammatory status in overweight and obese subjects. Obesity is very prevalent in the Unites States and Western countries and is associated with an increased risk of diabetes and heart disease. Our study shows that, over a period of 12 weeks, compared to a high glycemic index (GI) diet, a low GI diet was associated with greater weight loss, significant reductions in plasma insulin levels greater changes in fasting levels of triglycerides, high density lipoprotein cholesterol, and C reactive protein. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts data indicates that low glycemic index diets promote reductions in insulin resistance, glucose, CRP, and triglycerides, and are therefore useful in preventing diabetes.

2. LIPID METABOLISM LAB: Novel model for the prediction of diabetes. Diabetes is a major risk factor for heart disease. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts have developed a new diabetes risk model based on follow-up studies over about 10 years on over 3,100 male and female participants (mean age 58 years) in the Framingham Offspring Study. In this model the following parameters were statistically significant:.
1)fasting serum glucose,.
2)body mass index,.
3)percent serum glycated albumin,.
4)plasma adiponectin,.
5)parental history of diabetes,.
6)fasting serum triglycerides, and.
7)use of cholesterol lowering medications (statins and niacin). Age, gender, insulin, HDL cholesterol, blood pressure, and C reactive protein (CRP) did not predict the risk of diabetes in our model. The C statistic, a measure of the accuracy and precision in risk prediction was 0.924 with the full model.

3. LIPID METABOLISM LAB: The metabolism of C reactive protein is regulated by cholesterol biosynthesis inhibition. Inflammation plays a very important role in the initiation and progression of coronary heart disease. C-reactive protein(CRP) is a protein produced and secreted mainly by the liver in response to inflammation stimuli and therefore its plasma levels are a marker of inflammation status. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts conducted a study to assess the association between CRP production and clearance with plasma lipoprotein production and clearance. We found that a slower clearance of triglyceride-rich lipoproteins (TRL), which is a common feature of obesity and type 2 diabetes mellitus, was associated with a slower clearance of CRP. In addition, we found that inhibition of cholesterol biosynthesis by atorvastatin reduced plasma CRP levels by 28%, accompanied by a 40% increase in plasma CRP clearance and no change in CRP production suggesting that statin treatment lowers CRP levels by increasing its plasma clearance.

4. CARDIOVASCULAR NUTRITION LAB: Positive association between circulating cis-palmitoleic acid and heart disease risk. Although previous studies have suggested associations between plasma palmitoleic acid, a monounsaturated fatty acid, and heart disease risk factors, including blood pressure, inflammation and insulin resistance, little is known about the relation of palmitoleic acid and heart disease risk. In collaboration with researchers at Harvard Medical School, Boston, MA, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts found that higher levels of circulating levels of cis-palmitoleic acid was associated with higher heart disease risk. These data suggest that not all fatty acids within a class, in this case monounsaturated fatty acids, should be assumed to have similar effects on heart disease risk. These data also suggest that in addition to dietary intake, in vitro synthesis/modification of fatty acids may influence fatty acid profiles.

5. CARDIOVASCULAR NUTRITION LAB: Plasma biomarkers of food intake are better predictors of heart disease risk than self-reported data. Diet quality is an important determinant of heart disease risk. Uncertainty in estimating food intake can affect heart disease risk estimates and obscure disease-risk associations. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts demonstrated that higher plasma levels of dihydrophylloquinone (marker for partially-hydrogenated fat/trans fatty acids), saturated fat (marker for meat and dairy fat) and very long chain omega-3 fatty acid (marker for fish) were more robust predictors of heart disease risk than similar measures determined using self-reported food frequency questionnaires. These data support efforts to increase fish intake and develop alternative vegetable oils that can replace partially-hydrogenated fat in the diet.

6. CARDIOVASCULAR NUTRITION LAB: Postprandial lipid response to standard carbohydrates challenges. Prior studies assessing the metabolic effects of different types of dietary carbohydrate have focused on their glycemic response and plasma glucose without taking other cardiometabolic risk factors into consideration. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts demonstrated that a sugar solution (glucose) resulted in higher plasma glucose concentrations and more rapid decline in plasma glucose concentrations than white bread, with little difference in plasma postprandial total cholesterol, LDL-cholesterol and HDL-cholesterol concentrations. These data suggest that with regard to heart disease risk factors there was little difference between the two types of refined carbohydrate, glucose and white bread. These data also suggest that more emphasis should be placed on other less refined sources of carbohydrate in the diet.

7. CARDIOVASCULAR NUTRITION LAB: Cholesterol homeostasis markers are not predictors of heart disease risk and differ on the basis of sex. Available data are inconsistent regarding the predictive value of cholesterol homeostasis markers and heart disease risk. To address this issue, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts measured plasma cholesterol homeostasis marker concentrations in the Framingham Offspring cohort (cycle.
6)and related the values to incident heart disease events. They determined that the markers, both absorption and synthesis, were not predictive of heart disease events in either women or men. They found that there were significant sex differences in the 10-year prognostic value of cholesterol synthesis markers and heart disease, indicating the need for judicious interpretation of these marker data.

8. CARDIOVASCULAR NUTRITION LAB: Relationship between stearidonic acid and heart disease risk. Current recommendations for heart disease risk reduction include consuming at least two fish meals per week to ensure adequate intake of the very long chain n-3 fatty acids, eicosapentaenoic acid (EPA) and docosapentaenoic acid. A large proportion of individuals in the U.S. do not comply with this recommendation. A strain of soybeans has recently been developed that is rich in stearidonic acid (SDA), a plant-based n-3 fatty acid. Some of the SDA can be converted to EPA. In collaboration with researchers at Harvard Medical School, Boston, MA, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, at Boston, Massachusetts addressed the question of whether conversion from SDA to EPA is necessary by assessing the association between circulating SDA levels and heart disease risk. They found no significant relationship, suggesting that for SDA to be biologically active it has to first be converted, in vivo, to EPA. This work supports a potential role of the newly developed high SDA soybean oils and heart disease risk reduction.

Review Publications
Matthan, N., Lichtenstein, A., Zhu, L., D'Agnostino, R., Schaefer, E., Pencina, M. 2013. Sex specific differences in the predictive value of cholesterol homeostasis markers and 10-Year CVD event rate in Framingham Offspring Study participants. Journal of the American Heart Association. 2(1):e005066.

Vega-Lopez, S., Ausman, L., Matthan, N., Lichtenstein, A. 2013. Postprandial lipid responses to standard carbohydrate challenges used to determine glycemic index values. British Journal of Nutrition. DOI:10.1017/S000711451300130X.

Richard, C., Couture, P., Desroches, S., Lichtenstein, A., Lamarche, B. 2013. Effect of an isoenergetic traditional Mediterranean diet on apolipoprotein A-I kinetic in men with metabolic syndrome. Nutrition. 12:76.

Matsumoto, C., Matthan, N., Lichtenstein, A., Wilk, J., Gaziano, J., Djousse, L. 2012. Erythrocyte stearidonic acid and other n-3 fatty acids and CHD in the Physicians’ Health Study. British Journal of Nutrition. 109:2044-2049.

Thongtang, N., Ai, M., Otokozawa, S., Van Himbergen, T.M., Asztalos, B.F., Nakajima, K., Stein, E., Jones, P.H., Schaefer, E.J. 2011. Effects of maximal atorvastatin and rosuvastatin treatment on markers of glucose homeostasis and inflammation. American Journal of Cardiology. 107(3):387-392.

Thongtang, N., Diffenderfer, M.R., Ooi, E.M., Asztalos, B.F., Dolnikowski, G.G., Lamon-Fava, S., Schaefer, E.J. 2013. Effects of atorvastatin on human c reactive protein metabolism. Atherosclerosis. 226:466-470.

Schaefer, E.J. 2012. Nutrition in the prevention of Coronary Heart Disease and the management of lipoprotein disorders. In: Ross, Catharine A. New York, NY. Lippincott Williams & Wilkins. Modern Nutrition in Health and Disease. 11th edition, p. 862-876.

Kristo, A., Matthan, N., Lichtenstein, A. 2013. Effects of diets differing in glycemic index and glycemic load on cardiovascular risk factors: review of randomized controlled-feeing trials. Nutrients. 5(4):1071-1080.

Ooi, E.M., Lichtenstein, A.H., Millar, J.S., Diffenderfer, M.R., Lamon-Fava, S., Rasmussen, H., Welty, F.K., Barrett, P.R., Schaefer, E.J. 2013. Effects of therapeutic lifestyle change diets high and low in dietary fish-derived fatty acids on lipoprotein metabolism in middle-aged and elderly subjects. Journal of Lipid Research. 53(9):1958-1967.

Last Modified: 8/1/2014
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