Dietary Fructose and Redox Effects in Pediatric Nonalcoholic Fatty Liver Disease

描述(由申请人提供)： 非酒精性脂肪性肝病(NAFLD)是一种与肥胖和胰岛素抵抗密切相关的慢性肝病。由于肥胖的流行，NAFLD已成为儿童和成人最常见的肝病。从成人自然史研究推断，在接下来的几十年里，NAFLD可能会导致超过15万名当今儿童的终末期肝病。在美国，卡路里甜味剂的摄入量在过去30年里急剧增加，导致果糖的日摄入量增加，果糖是一种主要在肝脏代谢的单糖。在动物模型中，果糖会导致脂肪肝、高脂血症、氧化应激、肥胖和高血压。因此，果糖诱导的脂肪肝与人类NAFLD的特征非常相似。目前尚不清楚果糖是否会导致儿童脂肪肝、血脂异常和氧化应激。我们假设，饮食中的果糖在易感肥胖儿童NAFLD的诱导中起着关键作用。长期目标是在预防和治疗肥胖相关的儿童NAFLD方面通过优化营养来改善健康。这些特定研究的目的是确定饮食中的果糖是否会增加NAFLD儿童的血浆甘油三酯和氧化应激。这些研究是创新的，因为尽管儿童摄入果糖的量很高，但尚未对患有NAFLD的儿童进行果糖研究。这些结果将对公共健康具有重大意义，因为果糖消费非常普遍，可以进行修改以在社会层面上改善健康。申请者是一位已完成公共卫生理学硕士学位的儿科肝病专家，她是一位杰出的候选人，具有公认的儿科非酒精性脂肪肝和营养学方面的研究重点。她得到了两名资深研究人员的指导，他们在翻译研究和与这些研究相关的营养方面拥有丰富的经验。计划在生物化学、营养学、稳定同位素示踪研究和新的肝脏和代谢物成像方面进行未来的培训。这种有指导的研究经验将有助于她发展成为一名成功的独立内科科学家。 公共卫生相关性：这项研究将提高人们对果糖在儿童非酒精性脂肪性肝病中所起作用的认识，这种疾病在美国有300多万儿童受到影响。这些研究旨在改善儿童NAFLD的治疗和预防，从而改善数百万儿童的健康。

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease closely associated with obesity and insulin resistance. Because of the obesity epidemic, NAFLD has become the most common liver disease in children and adults. Extrapolating from adult natural history studies, in the next several decades, NAFLD may cause end-stage liver disease in over 150,000 of today's children. In the United States, caloric sweetener consumption has increased dramatically over the past 3 decades resulting in higher daily consumption of fructose, a monosaccharide that is metabolized primarily in the liver. In animal models, fructose induces fatty liver as well as hyperlipidemia, oxidative stress, obesity and hypertension. Thus, fructose-induced fatty liver closely mimics features of human NAFLD. It is unknown if fructose induces fatty liver, dyslipidemia and oxidative stress in children. We hypothesize that dietary fructose plays a critical role in the induction of NAFLD in susceptible obese children. The long range goal is to improve health by optimizing nutrition in the prevention and treatment of obesity-associated pediatric NAFLD. The objective of these specific studies is to determine if dietary fructose increases plasma triglycerides and oxidative stress in children with NAFLD. These studies are innovative as fructose has not been studied in children with NAFLD despite the fact that children have a high consumption of fructose. These results will be significant for public health because fructose consumption is pervasive and could be modified to improve health on a societal level. The applicant is a pediatric hepatologist who has completed a Masters of Science in Public Health She is an outstanding candidate with a proven focus of research in pediatric NAFLD and nutrition. She is mentored by two senior investigators with extensive experience in translational research and nutrition relevant to these studies. Future training in biochemistry, nutrition, stable isotope tracer studies and novel hepatic and metabolite imaging is planned. This mentored research experience will facilitate her development into a successful independent physician scientist. PUBLIC HEALTH RELEVANCE: This research will improve knowledge about the role of fructose in pediatric nonalcoholic fatty liver disease, a disease that affects over 3 million children in the United States. These studies are designed to lead to improved treatment and prevention of NAFLD in children, thus improving the health of millions of children.