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United States Department of Agriculture

Agricultural Research Service

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Location: Jean Mayer Human Nutrition Research Center On Aging

2010 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.

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 project 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.

4. Accomplishments
1. LAB: LIPID METABOLISM. Increased Fat and Cholesterol Absorption Increases the Risk of Developing Heart Disease. ARS-funded researchers from Tufts University in Boston, MA have shown that specific fat-rich particles made in the intestine after a fat-rich meal are much more likely to increase in overweight and obese subjects, as well as in those with baseline elevated blood cholesterol levels. These findings are corroborated by observations by these same researchers in the Framingham Offspring Study that those with elevated markers of cholesterol absorption are at increased risk of developing heart disease. These findings support the guidelines to restrict dietary cholesterol and animal fat in the diet for heart disease prevention. Moreover this same overabsorption occurs in families with premature heart disease. These findings support the guidelines to restrict dietary cholesterol and animal fat in the diet for heart disease prevention, and indicate that diet plays a very key role in heart disease risk.

2. Increased Small Dense Low Density Lipoprotein (LDL) Cholesterol is a Better Heart Disease Risk Marker than Total LDL Cholesterol. Elevated blood cholesterol levels have been identified as a major risk factor for heart disease. These elevations are usually due to increases in the low density lipoprotein or LDL cholesterol. ARS-funded researchers from Tufts University in Boston, MA have shown in the Framingham Offspring Study that a specific type of LDL, known as small dense LDL, is a better predictor of heart disease than is total LDL. Moreover these investigators have shown that increases in small dense LDL are related to markers of intestinal cholesterol overabsorption. These findings support the guidelines to restrict dietary cholesterol and animal fat in the diet for heart disease prevention.

3. A High Fructose Diet Increases Heart Disease Risk Factors More than a High Glucose Diet. ARS-funded researchers from Tufts University in Boston, MA, in collaboration with researchers from the University of California, Davis, have shown that dietary fructose at 25% of calories is much more likely to increase the blood triglyceride and small dense low density lipoprotein (LDL) cholesterol levels, and to lower levels of the high density lipoproteins (or good cholesterol) than is a diet containing 25% of calories as glucose. Not only have increased consumption of dietary animal fats and cholesterol been linked to heart disease, but so has increased intake of refined carbohydrate (especially table sugar and high fructose corn syrup). Moreover the high fructose diet also increased the risk of developing diabetes, and promoted excess fat deposition in the abdomen. These findings support the guidelines to reduce heart disease risk by restricting sugars especially table sugar and high fructose corn syrup, which both contain about 50% of carbohydrate as fructose.

4. LAB: CARDIOVASCULAR NUTRITION. Both long chain omega-6 and omega-3 polyunsaturated fatty acids decrease inflammatory response. Dietary long chain polyunsaturated fatty acids, both omega-3 (fish derived) and omega-6 (vegetable oil derived), are thought to have unique benefits with respect to heart disease prevention. Using a macrophage cell culture system, ARS-funded researchers from Tufts University in Boston, MA studied the mechanisms by which these polyunsaturated fatty acids alter inflammatory response and cholesterol accumulation. Exposure to long chain omega-6 and omega-3 polyunsaturated fatty acids elicited less inflammatory response than control cells or cells treated with saturated fatty acids, as indicated by lower levels of mRNA and secretion of inflammatory factors. In response to the various fatty acids, differences in cholesterol accumulation after exposure to minimally modified-LDL (source of cholesterol) and proteins controlling cellular cholesterol flux were modest. The results of this study confirm that diets rich in long chain polyunsaturated fatty acids, both from fish and vegetable oils, is beneficial in heart disease prevention.

5. Altering the ratio of dietary amino acids has little effect on heart disease risk factors. Information is conflicting about the effect of different dietary protein types on heart disease risk factors. One variable among protein types is their amino acid profile. Interest has focused on two amino acids, lysine and arginine, and the ratio of one to the other (termed Lys:Arg ratio). ARS-funded researchers from Tufts University in Boston, MA provided individuals with each of 2 diets in random order, one with a high Lys:Arg ratio and the other with a low Lys:Arg ratio. Most protein sources for the low Lys:Arg ratio diet was from plant foods, mainly nuts and legumes, and for the high Lys:Arg ratio diet was from animal foods, including dairy products, fish, eggs, poultry and beef. No significant differences were observed in plasma lipids or vascular function. The results of this study demonstrate that altering protein type has little effect on heart disease risk factors. These observations indicate researchers should direct their efforts to determining alternate diet modifications that will reduce heart disease risk.

6. More efficient absorbers of cholesterol are at increased risk of developing heart disease. Cholesterol balance is determined by the rate of cholesterol absorption and synthesis. The balance of the two can alter heart disease risk. In humans, it is difficult to directly measure these factors. ARS-funded researchers from Tufts University in Boston, MA measured validated surrogate markers of cholesterol absorption and synthesis in the Framingham Offspring Study Cycle-6 participants diagnosed with heart disease and matched control subjects. Plasma LDL-cholesterol concentrations were similar between the two groups. Cholesterol absorption markers were significantly higher, whereas cholesterol synthesis markers were significantly lower, in cases compared to controls. The results of this work indicate that some individuals are at increased risk of developing heart disease because they have high cholesterol absorption rates and do not adequately compensate by decreasing cholesterol synthesis rates. These findings indicate future work should be directed towards developing methods to identify this subgroup of the population early in life and identifying effective dietary approaches to decrease their heart disease risk.

Review Publications
Van Himbergen, T.M., Otokozawa, S., Matthan, N.R., Schaefer, E.J., Buchsbaum, A., Ai, M., Van Tits, L.J., De Graaf, J., Stalenhoef, A.F. 2010. Familial combined hyperlipidemia is associated with alterations in the cholesterol synthesis pathway. Arteriosclerosis Thrombosis and Vascular Biology. 30:113-120.

Millar, J.S., Brousseau, M.E., Diffenderfer, M.R., Barrett, H.R., Welty, F.K., Cohn, J.S., Wilson, A., Wolfe, M.L., Martsupha, C., Schaefer, P.M., Digenio, A.G., Mancuso, J.P., Dolnikowski, G.G., Schaefer, E.J., Rader, D.J. 2008. Effects of the cholesteryl ester transfer protein inhibitor torcetrapib on VLDL apolipoprotein E metabolism. Journal of Lipid Research. 49:543-549.

Polisecki, E., Muallem, H., Maeda, N., Peter, I., Robertson, M., Mcmahon, A.D., Ford, I., Packard, C., Shepherd, J., Westendorp, R.G., De Crean, A.J., Buckley, B.M., Ordovas, J.M., Schaefer, E.J., Jukema, J. 2008. Genetic variation at the LDL receptor and HMG-CoA reductase gene loci, lipid levels, statin response, and cardiovascular disease incidence in PROSPER. Atherosclerosis. 200:109-114.

Polisecki, E., Peter, I., Robertson, M., Mcmahon, A.D., Ford, I., Packard, C., Shepherd, J., Jukema, J., Biauw, G.J., Westendrop, R.G., De Crean, A.J., Trompet, S., Buckley, B.M., Murphy, M.B., Ordovas, J.M., Schaefer, E.J. 2008. Genetic variation at the PCSK9 locus, low density lipoproteins, response to pravastatin and coronary heart disease: results from PROSPER. Atherosclerosis. 200:95-101.

Otokozawa, S., Ai, M., Diffenderfer, M.R., Asztalos, B.F., Tanaka, A., Lamon-Fava, S., Schaefer, E. 2009. Fasting and post-prandial apolipoprotein B-48 levels in healthy, obese, and hyperlipidemic subjects. Metabolism: Clinical and Experimental. 58:1536-1542.

Brousseau, M.E., Millar, J.S., Diffenderfer, M.R., Nartsupha, C., Asztalos, B.F., Wolfe, M.L., Mancuso, J.P., Digenio, A.G., Rader, D.J., Schaefer, E.J. 2009. Effects of cholesteryl ester transfer protein inhibition on apolipoprotein A-II-containing HDL subspecies and apoA-II metabolism. Journal of Lipid Research. 50(7):1456-1462.

Miller, M., Ginsberg, H.N., Schaefer, E.J. 2008. Relative atherogenicity and predictive value of non-high-density lipoprotein cholesterol for coronary heart disease. American Journal of Cardiology. 101(7):1003-1008.

Santos, R.D., Schaefer, E., Asztalos, B.F., Polisecki, E., Wang, J., Hegele, R.A., Martinez, L.R., Miname, M.H., Rochitte, C.E., Daluz, P.L., Maranhao, R.C. 2007. Characterization of high density lipoprotein particles in familial apolipoprotein A-I deficiency. Journal of Lipid Research. 49:349-357.

Ai, M., Otokozawa, S., Schaefer, E.J., Asztalos, B.F., Nakajima, K., Shrader, P., Kathiresan, S., Meigs, J.B., Williams, G., Nathan, D.M. 2009. Glycated albumin and direct low density lipoprotein cholesterol levels in type 2 diabetes mellitus. Clinica Chimica Acta. 406:71-74.

Polisecki, E., Peter, I., Hegele, R., Robertson, M., Ford, I., Shepard, J., Packard, C., Jukema, W.J., De Craen, A., Westendorph, R.G., Buckley, B.M., Schaefer, E.J. 2010. Genetic variation at the NPC1L1 gene locus, plasma lipoproteins, and heart disease risk in the elderly. Journal of Lipid Research. 51:1201-1207.

Berson, E.L., Rosner, B., Sandberg, M.A., Weigel-Difranco, C., Brockhurst, R.J., Hayes, K.C., Johnson, E.J., Anderson, E.J., Johnson, C.A., Gaudio, A.R., Willett, W.C., Schaefer, E.J. 2010. Clinical trial of lutein in patients with retinitis pigmentosa receiving vitamin A treatment. Archives of Ophthalmology. 128(4):403-411.

Schaefer, E.J., Gleason, J.A., Dansinger, M.L. 2009. Dietary fructose and glucose differentially affect lipid and glucose homeostasis. Journal of Nutrition. 139(6):1257-1262.

Welsh, P., Polisecki, E., Robertson, M., Jahn, S., Buckley, B.M., De Crean, J., Ford, I., Jukema, J., Macfarlane, P.W., Packard, C.J., Stott, D.J., Westendrop, R.G., Sheperd, J., Hingorani, A.D., Smith, G., Schaefer, E.J., Sattar, N. 2009. Unraveling the directional link between adiposity and inflammation: a bidirectional Mendelian randomization approach. Journal of Clinical Endocrinology and Metabolism. 95(1):93-99.

Schaefer, E. 2009. Limitations of automated remnant lipoprotein cholesterol assay for diagnostic use. Clinical Chemistry. 55(11):2061-2062.

Wang, S., Wu, D., Lamon-Fava, S., Matthan, N.R., Honda, K.L., Lichtenstein, A.H. 2009. In vitro fatty acid enrichment of macrophages alters inflammatory response and net cholesterol accumulation. British Journal of Nutrition. 102:497-501.

Vega-Lopez, S., Matthan, N.R., Ausman, L.M., Ai, M., Otokozawa, S., Schaefer, E., Lichtenstein, A.H. 2009. Substitution of vegetable oil for a partially-hydrogenated fat favorably alters cardiovascular disease risk factors in moderately hypercholesterolemic postmenopausal women. Atherosclerosis. 207(1):208-212.

Matthan, N., Resteghini, N., Robertson, M., Ford, I., Shepherd, J., Packard, C., Buckley, B.M., Jukema, J., Lichtenstein, A.H., Schaefer, E. 2009. Cholesterol absorption and synthesis markers in individuals with and without a CHD event during pravastatin therapy: Insights from the PROSPER trial. Journal of Lipid Research. 51:202-209.

Lichtenstein, A., Vega-Lopez, S., Matthan, N., Ausman, L., Harding, S., Rideout, T., Ai, M., Otokozawa, S., Freed, A., Kuvin, J., Karas, R., Jones, P., Schaefer, E. 2009. Altering dietary lysine: arginine ratio has little effect on cardiovascular risk factors and vascular reactivity in moderately hypercholesterolemic adults. Atherosclerosis. 210(2):555-562.

Matthan, N., Pencina, M., Larocque, J., D'Agostino, R.B., Jacques, P.F., Ordovas, J.M., Schaefer, E.J., Lichtenstein, A.H. 2009. Alterations in cholesterol absorption and synthesis characterize Framingham offspring study participants with coronary heart disease. Journal of Lipid Research. 50:1927-1935.

Pittas, A.G., Chung, M., Trikalinos, T., Mitri, J., Brendel, M., Patel, K., Lichtenstein, A.H., Lau, J., Balk, E. 2010. Vitamin D and cardiometabolic outcomes: a systematic review. Annals Of Internal Medicine. 152(5):307-314.

Last Modified: 07/24/2017
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