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 3 年的学术研究职业发展培训计划，该计划完成了 KL2 职业发展奖期间开始的培训。 PI 是一位胃肠病学家，之前在稳定同位素示踪剂方法方面拥有丰富的经验，用于确定体内代谢过程，重点关注营养和肥胖问题。她目前正在扩大她的科学技能，研究非酒精性脂肪肝病 (NAFLD) 的发病机制，与患有 NAFLD 的肥胖者相比，未患 NAFLD 的肥胖者增加高果糖玉米糖浆饮食的摄入量有关。该提案的主要导师 Samuel Klein 博士在评估人类受试者体内底物代谢，特别是与肥胖相关的代谢异常方面拥有丰富的专业知识，并且拥有培训独立科学家的良好记录。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 博士将担任第二导师。该提案还包括生物统计学家 Ken Schechtman 博士的咨询，他将提供统计分析支持。 PI 所在机构的环境提供了丰富的知识和研究资源网络来支持她的职业发展。拟议的研究重点关注美国食品供应中普遍存在的碳水化合物来源——高果糖玉米糖浆（HFCS）及其在 NAFLD 发病机制中的作用。 NAFLD 影响着美国大约三分之一的成年人口，并与严重的心脏代谢并发症有关。多项证据表明，饮食中的 HFCS 会影响肝脏中甘油三酯的储存、脂质动力学和胰岛素敏感性，并且流行病学研究将 HFCS 的摄入量与 NAFLD 和胰岛素抵抗的发生率和严重程度相关联。然而，许多针对肝内甘油三酯含量正常的人进行的研究都涉及过量喂食果糖，这并没有解决高风险人群中食用高果糖玉米糖浆对体重增加的独立影响。等热量果糖喂养研究显示了高热量果糖喂养研究中看到的一些但不是全部代谢变化，并且没有研究前瞻性地向患有 NAFLD 的肥胖成人喂养 HFCS，并将他们对 HFCS 的反应与未患 NAFLD 的人进行比较。该提案的目标是提供关于 HFCS 对 NAFLD 受试者与非 NAFLD 受试者体内代谢影响的新见解，阐明 HFCS 在增加肝脏甘油三酯储存和脂质动力学以及减少多器官胰岛素中的作用NAFLD 患者的敏感性。科学工具包括磁共振波谱、稳定同位素示踪剂输注、高胰岛素正常血糖钳夹程序和骨骼肌组织样本的分子分析，将有助于解决与肥胖成人相比，为期 4 周的高 HFCS 等热量饮食对非 NAFLD 肥胖成人的影响成人 NAFLD 的影响：1) 肝内甘油三酯含量，2) 肝脏脂质代谢，3) 多器官胰岛素敏感性。该申请和这项指导性研究资助的更大目标是让 PI 发展成为 R01 资助的独立研究者所需的知识和技能，并提出有助于我们理解 NAFLD 病理生理学的相关问题。