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United States Department of Agriculture

Agricultural Research Service

Research Project: Nutrition and Cardiovascular Health

Location: Human Nutrition Research Center on Aging

2011 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 using samples from the Framingham Offspring Study.

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.

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: Lipoproteins and Nutrition. 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. LAB: Lipoproteins and Nutrition. 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. LAB: Lipoproteins and Nutrition. 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. LAB: Lipoproteins and Nutrition. 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. LAB: Lipoproteins and Nutrition. 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. LAB: Lipoproteins and Nutrition. 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. LAB: Lipoproteins and Nutrition. 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. LAB: Lipoproteins and Nutrition. 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.

9. LAB: Cardiovascular Nutrition. F1B Golden-Syrian Hamster assessed as a model for diet-induced atherosclerosis.(2A) Golden-Syrian hamsters have been used as an animal model to assess diet-induced atherosclerosis since the early 1980s, but little data are available on the extent to which diet induced changes alters lesion development. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, evaluated impact of two potential determinants of lesions development: background diet composition (semi-purified, non-purified) and dietary fat type (coconut oil, safflower oil) on plasma lipoproteins profiles and aortic cholesterol accumulation. The researchers found that hamsters fed non-purified diets had higher plasma non-HDL cholesterol and TG concentrations compared to hamsters fed the semi-purified diets. Dietary fat type had no significant effect on plasma lipoprotein concentrations when hamsters were fed the semi-purified diets, however, coconut oil feeding resulted in higher non-HDL cholesterol and triglyceride concentrations than safflower oil when hamsters were fed the non-purified diets. Regardless of lipoprotein profile, there was no evidence of diet induced aortic cholesterol accumulation in any of the hamster groups. These data suggest the F1B Golden Syrian hamster may not be a useful model to determine the mechanisms underlying diet-induced atherosclerosis.

10. LAB: Cardiovascular Nutrition. Long-Term Fatty Acids Stability in Human Serum.(2B) Fatty acid profiles of biological specimens from epidemiological/clinical studies can serve as biomarkers to assess potential relationships between diet and chronic disease risk. Limited data are available regarding fatty acid stability in archived specimens following long-term storage, a variable that could affect result validity. Using gas chromatography (GC) methodology ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, determined the effect of prolonged storage (8-10 years) at minus 80 degrees C on the fatty acid profiles of serum cholesteryl ester (CE), triglyceride (TG), and phospholipid (PL) fractions. The researchers found little change in fatty acid profiles over time. When differences were identified, they were quantitatively small and likely attributable to technical improvements in GC methodology rather than sample degradation. Therefore, storage at minus 80 degrees C up to 10 years does not significantly influence serum CE, TG, or PL fatty acid profiles, thus, the use of archived samples can provide valuable information on diet and chronic disease risk.

Review Publications
Matthan, N.R., Ip, B., Resteghini, N., Ausman, L., Lichtenstein, A.H. 2010. Long-term fatty acid stability in human serum cholesteryl ester, triglyceride, and phospholipid fractions. Journal of Lipid Research. 51:2826-2832.

Corcoran, M.P., Meydani, M., Lichtenstein, A.H., Schaefer, E.J., Dillard Hirschel, A., Lamon-Fava, S. 2010. Sex hormone modulation of proinflammatory cytokine and CRP expression in macrophages from older men and postmenopausal women. Journal of Endocrinology. 206(2):217-224.

Tybor, D., Lichtenstein, A., Dallal, G., Daniels, S., Must, A. 2011. Independent effects of age-related changes in waist circumference and BMI z scores in predicting cardiovascular disease risk factors in a prospective cohort of adolescent females. American Journal of Clinical Nutrition. 93:392-401. PMID 21147855.

Kuang, Y., Paulson, K., Lichtenstein, A., Matthan, N., Lamon-Fava, S. 2011. Docosahexaenoic acid suppresses apolipoprotein A-I gene expression through hepatocyte nuclear factor-3beta. American Journal of Clinical Nutrition. 94:1-8.

Chung, M., Balk, E.M., Ip, S., Lee, J., Terasawa, T., Raman, G., Trikalinos, T., Lichtenstein, A.H., Lau, J. 2010. Systematic review to support the development of nutrient reference intake values: challenges and solutions. American Journal of Clinical Nutrition. 92(2):273-276.

Corcoran, M., Lichtenstein, A., Meydani, M., Dillard, A., Schaefer, E., Lamon-Fava, S. 2011. The effect of 17 beta-estradiol on cholesterol in human macrophages is influenced by the lipoprotein milieu. Journal of Molecular Endocrinology. 47(1):109-117.

Dillard, A., Matthan, N., Lichtenstein, A. 2010. Appropriateness of the hamster as a model to study diet-induced atherosclerosis. Nutrition Metabolism and Cardiovascular Disease. 10:89. PMID 21143982.

Lichtenstein, A. 2010. Health claims and dietary guidance to reduced cardiovascular disease risk in the United States. In: Salminen, S., Kniefel, W., Ouwehand, A., editors. Lactic Acid Bacteria. New York, NY: Marcel Dekker, Inc.

Lichtenstein, A. 2011. Dietary effects on cardiovcascular risk factors. In: Grundy, S., editor. 5th Edition. Philadelphia, PA: Current Medicine, Inc.

Lichtenstein, A. 2010. Nutrition and CVD risk. In: Eckel, R., editor. Metabolic Risk for Cardiovascular Disease. Oxford, UK: Wiley-Blackwell.

Lamon-Fava, S., Asztalos, B.F., Howard, T., Reboussin, D.M., Horvath, K., Schaefer, E.J., Herrington, D.M. 2010. Association of polymorphisms in genes involved in lipoprotein metabolism with plasma concentrations of remnant lipoproteins and HDL subpopulations before and after hormone therapy in postmenopausal women. Clinical Endocrinology. 72(2):169-75.

Ai, M., Otokozawa, S., Asztalos, B.F., Ito, Y., Nakajima, K., White, C.C., Cupples, A.L., Wilson, P.W., Schaefer, E. 2010. Small dense low density lipoprotein cholesterol and coronary heart disease: results from the Framingham Offspring Study. Clinical Chemistry. 56(6):1-10.

Schaefer, E. 2010. Northern light: a commentary on the 2009 Canadian Guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in adults. Clinical Chemistry. 56(4):502-504.

Asztalos, B., Tani, M., Schaefer, E. 2011. Metabolic and functional relevance of HDL subspecies. Current Opinion in Lipidology. 22(3):176-185.

Last Modified: 4/18/2014
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