SCHWARZ, JEAN-MARC & HAVEL, PETER J
1R01HL107256-01A1

FATTY ACID SOURCES OF FRUCTOSE AND HFCS-INDUCED POSTPRANDIAL HYPERTRIGLYCERIDEMIA

The parent study for this proposed ancillary study is an NIH/NHLBI-funded investigation comparing the effects of consuming sweetened beverages for 2 weeks in young (18-40 years), normal weight and overweight/obese adults (5R01HL091333-02: Effects of 2wk fructose & HFCS consumption on lipid dysregulation & insulin resistance). Baseline experimental procedures (including 24-h serial blood sampling) are conducted while subjects reside as inpatients at the CTSC-funded Clinical Research Center (CCRC) for 3.5 days and consume an energy-balanced, high complex carbohydrate diet. Subjects then consume sweetened beverages providing 25% of energy requirements as fructose, glucose, or high fructose corn syrup (HFCS); or 0, 10, or 17.5% of energy as fructose or HFCS along with their usual ad libitum diet. At the end of the 2-week intervention, subjects return to the CCRC and the same experimental procedures are performed while subjects consume an energy-balanced diet, which includes the assigned sweetened beverages. The early results from this investigation indicate that consumption of HFCS-sweetened beverages at 25% of energy results in significant increases of late-night postprandial triglyceride (TG) concentrations, and of fasting LDL cholesterol and apolipoprotein-B (ApoB) concentrations that are comparable in magnitude to those observed after consumption of beverages sweetened with 100% fructose. Consumption of glucose-sweetened beverages does not alter these parameters. There is considerable evidence to support the hypothesis that postprandial hypertriglyceridemia is a key metabolic disturbance that gives rise to the lipid dysregulation characteristic of metabolic syndrome and type 2 diabetes. The purpose of this proposal is to investigate the mechanisms that contribute to the postprandial hypertriglyceridemia induced by fructose and HFCS consumption by quantifying the absolute and proportional contributions of fatty acids derived from de novo lipogenesis (DNL), diet, and free fatty acids (FFA) from adipose TG lipolysis to fasting and postprandial levels of triglyceride-rich lipoproteins (TRL). Stable isotopes will be administered (via oral consumption and 26-h intravenous infusions) to subsets of subjects during the 24-h serial blood sampling protocols that are conducted in all study participants during consumption of energy-balanced, high complex carbohydrate meals at baseline, and meals consumed with beverages sweetened with HFCS, fructose, glucose or aspartame at the end of intervention. The specific objective of these studies is to test the hypothesis that 2 weeks of fructose or HFCS consumption will increase the absolute and proportional contributions of fatty acids derived from DNL to late-night increases of TRL, and that the increases of DNL-fatty acid will be a critical determinant of the increases of fasting LDL and ApoB concentrations. A second objective is to determine the doses of HFCS that increase the absolute and proportional contributions of DNL-fatty acids to postprandial TRL. PUBLIC HEALTH RELEVANCE: There is evidence to suggest that consumption of high sugar diets is associated with increased incidence of cardiovascular disease and diabetes, and the early results from the parent study indicate that consumption of beverages sweetened with high fructose corn syrup (HFCS) at 25% of energy requirement for 2 weeks increases risk factors for cardiovascular disease, including late-night triglyceride (TG) concentrations, and fasting LDL-cholesterol and apolipoprotein-B concentrations. Scientific evidence suggests that increased plasma TG concentrations after meals lead to the increases of other risk factors, and studies are proposed to mechanistically investigate the late-night postprandial increase of TG induced by consumption of HFCS and fructose. These studies will help to determine how sugar consumption may promote increased risk for cardiovascular and related metabolic diseases. 

SCHWARZ, JEAN-MARC
5R01DK078133-04

DE NOVO LIPOGENESIS IN THE PATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE

DESCRIPTION: Fatty liver - steatosis - affects about one third of the population. Its prevalence is rising and seems to parallel the global increase in obesity and type-2 diabetes. The mechanisms underlying steatosis and leading to non-alcoholic fatty liver disease are poorly understood. We propose that the hepatic conversion of carbohydrates (CHO) to lipids (de novo lipogenesis, DNL) is a key factor in the accumulation of excess liver fat and the accompanying dyslipidemia and that suppressing DNL by diet will reduce liver fat and improve the metabolic profile in patients with steatosis. These hypotheses are based on studies in which we and others have established that fractional hepatic DNL can vary dramatically depending on the diet and/or health status of a subject; and, in particular, that dietary fructose is a potent lipogenic stimulus. In this proposal we will perform Clinical Research Center (CRC) based studies to compare the rates of DNL and VLDL kinetics in steatotic and matched non-steatotic controls and evaluate their relationship to lipid profiles (Aim 1). The steatotic individuals whose habitual intake of fructose and other simple sugars exceeds 15% of total energy intake will then be randomized to consume one of two low-fat diets that differ only in CHO type to determine whether diet-induced changes in DNL affect liver fat flux, content (Aim 2). We hypothesize that a diet that is rich in complex CHO will achieve greater decreases in DNL and liver fat than one that contains typical amounts of simple CHO, including fructose. This dietary intervention study includes a 6-week 25% energy restriction outpatient phase to promote moderate weight loss and improve insulin sensitivity, followed by a week weight maintenance with the last 5 days as an inpatient stay during which all of the studies performed at baseline (Aim 1) will be repeated. State-of-the-art stable isotope techniques will be used to assess hepatic DNL, apoB100 turnover, VLDL-TG fluxes, and lipolysis under fasting and fed conditions. Liver fat will be measured by proton magnetic resonance spectroscopy. These studies will allow us to evaluate the importance of DNL as a mechanism modulating liver fat content and flux, and the significance of CHO quality in dietary guidance for steatotic patients.

SCHWARZ JEAN-MARC
5R01DK089216-02

METABOLIC IMPACT OF FRUCTOSE RESTRICTION IN OBESE CHILDREN

The past 30 years have seen a dramatic increase in the proportion of children with from obesity, diabetes, and metabolic syndrome, which drive up health care costs and contribute to premature mortality. The etiology(ies) of metabolic syndrome remain(s) unknown. The racial/ethnic presentations of metabolic syndrome differ, especially in children. Obese Latino children exhibit the highest prevalence of dyslipidemia, visceral adiposity, and non-alcoholic fatty liver disease (NAFLD); African American children present instead with hypertension, worsened insulin resistance, and glucose intolerance. Understanding these variations in presentation of metabolic syndrome holds the key to understanding its pathogenesis and, therefore, its prevention and treatment. Evidence for both genetic and environmental differences in symptom prevalence abound, and suggest a gene/race-diet interaction. One likely contributor to the etiology of metabolic syndrome is fructose. The secular trend in fructose consumption parallels the triple epidemics of obesity, type 2 diabetes, and metabolic syndrome in children. Fructose stimulates hepatic de novo lipogenesis, which we have demonstrated contributes to dyslipidemia and NAFLD; and hepatic uric acid synthesis, thought to be important in hypertension. We hypothesize that racial/ethnic differences in fructose metabolism contribute to the observed racial/ethnic differences in presentation of the metabolic syndrome: that in Latinos, fructose is primarily converted to TG by DNL, which leads to an increase in liver fat content, VLDL-TG output, and TG levels; but in African Americans, a greater proportion of fructose is converted to glucose, which leads to increased glycemia and insulin resistance. We further hypothesize that 10 days of isocaloric fructose restriction will decrease DNL and IHL and improve lipid profiles in Latinos; and improve glucose control, insulin sensitivity, and blood pressure in African Americans. We will examine insulin sensitivity and glucose disposal (by OGTT), de novo lipogenesis and triglyceride-rich lipoprotein kinetics (by stable isotope measurement), lipid partitioning within tissues (by magnetic resonance spectroscopy), and nitric oxide metabolites (by HLPC and ELISA) in children with metabolic syndrome, stratified by race and gender; and then again after 10 days fructose restriction. We anticipate that comorbidities will improve in a race/ethnic specific fashion. The results of this study will have immediate impact on: 1) reasons for racial/ethnic differences in insulin resistance and obesity; 2) alterations of nutritional information and the Food Pyramid; 3) public health efforts regarding prevention and treatment of obesity, diabetes, and metabolic syndrome around the world; and 4) the regulation of food industry claims and food advertising.