EFFECT OF HIGH FRUCTOSE CORN SYRUP FEEDING IN NONALCOHOLIC FATTY LIVER DISEASE

高果糖玉米糖浆喂养对非酒精性脂肪肝的影响

• 批准号: 8817285
• 负责人: Shelby A Sullivan
• 金额: $ 16.94万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8817285
• 关键词: Acute; Address; Adult; Affect; Apolipoproteins; Applications Grants; Award; Biopsy; Carbohydrates; Cardiovascular Diseases; Chronic; Clinical; Consultations; Consumption; Data; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Eicosanoid Production; Environment; Epidemiologic Studies; Euglycemic Clamping; Fasting; Food Supply; Fructose; Functional disorder; Funding; Gastroenterologist; Glucose; Glucose Clamp; Goals; Hepatic; Hypertension; Incidence; Inflammatory; Infusion procedures; Ingestion; Institution; Insulin; Insulin Resistance; Intake; Investigation; Isotopes; K-Series Research Career Programs; Kinetics; Knowledge; Lipids; Liver; Liver diseases; Magnetic Resonance Spectroscopy; Measures; Medical; Mentors; Metabolic; Metabolism; Methods; Molecular Analysis; Muscle; Myocardial Infarction; Obesity; Organ; Pathogenesis; Patients; Persons; Physiological; Plasma; Population; Procedures; Program Development; Prospective Studies; Research; Research Personnel; Research Project Grants; Resources; Role; Scientist; Severities; Skeletal Muscle; Source; Staging; Sucrose; Tissue Sample; Tracer; Training; Training Programs; Triglycerides; United States; United States National Institutes of Health; Very low density lipoprotein; Weight Gain; Work; career; career development; cytokine; experience; fatty acid oxidation; feeding; high risk; human subject; in vivo; insight; insulin sensitivity; insulin signaling; intrahepatic; lipid biosynthesis; lipid metabolism; mathematical model; non-alcoholic fatty liver; nutrition; oral glucose tolerance; public health relevance; response; skills; stable isotope; sugar; tool; very low density lipoprotein triglyceride

DESCRIPTION (provided by applicant): This proposal describes a 3-year training program for the development of an academic research career, which completes the training started during a KL2 Career Development Award. The PI is a gastroenterologist who has previous experience in stable isotope tracer methods for determining metabolic processes in vivo with a focus on nutrition and obesity. She is currently expanding her scientific skills in investigation of the pathogenesis of Nonalcoholic Fatty Liver Disease (NAFLD) in relation to consumption of an increased high fructose corn syrup diet in obese persons without NAFLD compared to obese persons with NAFLD. Dr. Samuel Klein, the primary mentor for this proposal, has considerable expertise in evaluating substrate metabolism in vivo in human subjects, particularly the metabolic abnormalities associated with obesity, and has an established record of training independent scientists. To complete the investigator's scientific development, Dr. Nada Abumrad, an expert in molecular analysis, and Dr. Bruce Patterson an expert in isotope tracer methods and mathematical modeling will be secondary mentors. This proposal also includes consultation from Dr. Ken Schechtman, a biostatistician, who will provide statistical analysis support. The environment at the PI's institution provides a rich network of intellectual and investigational resources to support her career development. The proposed research focuses on a carbohydrate source that is prevalent in the United States food supply, high fructose corn syrup (HFCS), and its role in the pathogenesis of NAFLD. NAFLD affects approximately one-third of the adult population in the United States and is associated with serious cardiometabolic complications. Several lines of evidence suggest that HFCS in the diet affects triglyceride storage, lipid kinetics, and insulin sensitivity in the liver, and epidemiologic studies have correlated consumption of HFCS with incidence and severity of NAFLD and insulin resistance. However, many studies conducted in people have involved overfeeding fructose in persons with normal intrahepatic triglyceride content, which does not address the weight gain independent effect of consuming HFCS in a high-risk population. Isocaloric fructose feeding studies have shown some but not all of the metabolic changes seen in hypercaloric fructose feeding studies, and no studies have prospectively fed HFCS to obese adults with NAFLD and compared their response to HFCS to people without NAFLD. The goal of this proposal is to provide new insights into the in vivo metabolic effects of HFCS in subjects with NAFLD compared to subjects without NAFLD, clarifying the role of HFCS in the increased hepatic triglyceride storage and lipid kinetics as well as decreased multi-organ insulin sensitivity seen in patients with NAFLD. Scientific tools including magnetic resonance spectroscopy, stable isotope tracer infusions, hyperinsulinemic euglycemic clamp procedure, and molecular analysis of skeletal muscle tissue samples will assist in addressing the affect of a 4-week isocaloric diet high in HFCS in non-NAFLD obese adults compared to obese adults with NAFLD on: 1) intrahepatic triglyceride content, 2) hepatic lipid metabolism, and 3) multi-organ insulin sensitivity. The larger goal of th application and this mentored research grant is for the PI to develop the knowledge and skill sets required to become an independent investigator with R01 funding and ask relevant questions that aid in our understanding of the pathophysiology of NAFLD.

描述（由申请人提供）：该提案描述了一项为期三年的学术研究职业培训计划，该计划完成了KL2职业发展奖的培训。 PI是一位胃肠病学家，他以前在稳定的同位素示踪剂方法上有经验，用于确定体内代谢过程，重点是营养和肥胖。与患有NAFLD的肥胖者相比，她目前正在扩大自己的科学技能，以调查与没有NAFLD的肥胖者的肥胖者的高果糖玉米糖浆饮食的消费有关。该提案的主要指导者塞缪尔·克莱因（Samuel Klein）博士在评估人类受试者体内底物代谢方面具有丰富的专业知识，尤其是与肥胖相关的代谢异常，并具有培训独立科学家的既定记录。为了完成研究者的科学发展，分子分析专家Nada Abumrad博士和同位素示踪方法和数学建模专家Bruce Patterson博士将是次要导师。该建议还包括生物统计学家肯·施赫赫特曼（Ken Schechtman）博士的咨询，他将提供统计分析支持。 PI机构的环境提供了丰富的知识和研究资源网络，以支持其职业发展。拟议的研究重点是在美国粮食供应，高果糖玉米糖浆（HFC）及其在NAFLD发病机理中的作用。 NAFLD影响了美国大约三分之一的成年人口，并且与严重的心脏代谢并发症有关。几条证据表明，饮食中的HFC会影响肝脏中甘油三酸酯的储存，脂质动力学和胰岛素敏感性，并且流行病学研究与HFC的消耗与NAFLD和胰岛素抵抗的发病率和严重程度相关。但是，许多对人进行的研究都涉及过度喂养肝内甘油三酸酯含量正常的果糖，这并不能解决高危人群中消耗HFC的体重增加的独立效应。等量平衡的果糖喂养研究表明，在高平衡果糖喂养研究中看到的一些但并非所有代谢变化，没有任何研究前瞻性地将HFC喂给了患有NAFLD的肥胖成年人，并将其对HFC的反应与没有NAFLD的人进行了比较。该提案的目的是与没有NAFLD的受试者相比，对HFC在患有NAFLD受试者中的体内代谢作用的新见解，阐明HFC在NAFLD患者中可见的HFC在增加的肝甘油三酸酯储存和脂质胰岛素动力学增加以及降低的多层胰岛素胰岛素敏感性方面的作用。科学工具在内的科学工具，包括磁共振光谱，稳定的同位素示踪剂输注，高胰岛素血糖夹夹程序以及对骨骼肌组织样品的分子分析，将有助于解决4周的异常饮食的影响，以解决非肥胖成年人与肥胖成人相比，HFC高度的HFC中的HFC高度与肥胖成人相比。脂质代谢和3）多器官胰岛素敏感性。应用程序的更大目标和这项受过指导的研究赠款是让PI发展成为R01资金的独立调查员所需的知识和技能，并提出相关问题，以帮助我们理解NAFLD的病理生理学。