Consumption of Fructose and Markers of Cardiovascular Disease Risk among US Adolescents with Nonalcoholic Fatty Liver Disease Open Access

Jin, Ran (2014)

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Nonalcoholic fatty liver disease (NAFLD), the hepatic manifestation of metabolic syndrome, is the most common cause of chronic liver disease in western countries. Adults with NAFLD have increased morbidity and mortality rate from cardiovascular disease (CVD), and more importantly, adolescents with NAFLD demonstrate early signs of subclinical atherosclerosis. Dietary fructose has been proposed as a culprit in the development and progression of NAFLD, and fructose-induced metabolic abnormalities are likely to be associated with increased CVD risk seen in NAFLD. Adolescents are reported to have the highest fructose intake (primarily from fructose-sweetened beverages); however, little is known about the consumption of fructose and markers of CVD risk among U.S. adolescents with NAFLD.

In the body of research for this dissertation, we hypothesized that fructose could be a modifiable dietary factor to ameliorate CVD risk in NAFLD. Thus we implemented a series of studies to 1) determine whether fructose consumption could acutely alter/exacerbate the lipid profile, glycemic status, and other CVD risk factors in adolescents with NAFLD, 2) to determine if fructose restriction could improve hepatic steatosis, lipids, insulin resistance, and other markers related to CVD risk in adolescents with NAFLD, and 3) to evaluate whether endotoxin could be a mediator through which fructose induces NAFLD and associated CVD risk in adolescents.

Through these studies, we found that in adolescents with NAFLD, fructose acutely induced the postprandial dyslipidemia (a high-triglyceride, low-high density lipoprotein pattern), an important risk factor in the pathogenesis of atherosclerosis. In addition, by performing a calorie-matched, randomized controlled trial, we found that fructose reduction for 4 weeks resulted in an improved cardiometabolic profile, including increased insulin sensitivity, reduced inflammation and LDL oxidation. This improvement could be possibly mediated by the fructose-induced endotoxemia. Further research is needed to evaluate potential benefits of fructose restriction in a longer intervention period, and to fully investigate the underlying biological mechanisms of fructose in the early atherosclerotic lesions seen in pediatric NAFLD.

Table of Contents

Chapter I: Introduction...1
Chapter II: Literature Review...6
II.1. Nonalcoholic Fatty Liver Disease (NAFLD)...6
1.1 Definition...6
1.2 Epidemiology...7
1.3 Histopathology...10
1.4 Etiology...11
1.5 Therapeutics...13
1.6 Associated risk - cardiovascular disease...15
II.2. Dietary Fructose...17
2.1 Trend of consumption in general population...17
2.2 Increased consumption in NAFLD...18
2.3 Hepatic metabolism...18
2.4 Fructose-induced negative health outcomes...19
II.3. Purpose of Research...22
II.4. References...23

Chapter III: Children with NAFLD Are More Sensitive to the Adverse Metabolic
Effects of Fructose Beverages than Children without NAFLD...36

Chapter IV: Dietary Fructose Reduction Improves Markers of Cardiovascular

Disease Risk in Adolescents...74

Chapter V: Fructose Induced Endotoxemia in Pediatric Nonalcoholic Fatty Liver


Chapter VI: Conclusions, Future Directions, and Public Health Implications...131

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