Impact of Fructose on Metabolism, Energy Homeostasis and MR biomarkers in NAFLD

果糖对 NAFLD 代谢、能量稳态和 MR 生物标志物的影响

• 批准号: 8219268
• 负责人: MANAL F. ABDELMALEK
• 金额: $ 29.69万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8219268
• 关键词: Accounting; Acute; Address; Biological Markers; Biopsy; Biotechnology; Chronic; Clinical; Cohort Studies; Consumption; Data; Deposition; Development; Diagnostic; Diet; Dietary Intervention; Disease; Disease Progression; Distant; Dose; Energy Metabolism; Fatty Liver; Fibrosis; Fructokinases; Fructose; Genetic Transcription; Goals; Hepatic; Hepatocyte; Histologic; Histology; Homeostasis; Hour; Human; Image; Injury; Insulin Resistance; Intervention Studies; Knowledge; Lipids; Liver; Liver diseases; Longitudinal Studies; Magnetic Resonance; Magnetic Resonance Imaging; Measurement; Measures; Metabolic; Metabolism; Methodology; Modification; Morbidity - disease rate; Obesity; Pathologic; Patients; Prevalence; Process; Protocols documentation; Public Health; Randomized; Recovery; Reporting; Risk Factors; Serum; Severities; Steatohepatitis; Surrogate Markers; Techniques; Tissue Banking; Tissue Banks; United States National Institutes of Health; Uric Acid; Variant; Water; Work; base; chronic liver disease; clinically relevant; cohort; disease diagnosis; energy balance; improved; liver imaging; liver metabolism; mortality; multidisciplinary; non-alcoholic fatty liver; nonalcoholic steatohepatitis; novel; spectroscopic imaging; tool; volunteer

DESCRIPTION (provided by applicant): To define the mechanism(s) by which fructose may contribute to nonalcoholic fatty liver disease (NAFLD) progression and assess whether such factors can be measured using magnetic resonance (MR) biomarkers and modified with dietary fructose restriction. Background: NAFLD is a major public health concern which is anticipated to surpass the morbidity and mortality of other forms of chronic liver disease by 2020. Both the prevalence and severity of NAFLD have been associated with increased consumption of fructose. We have reported that increased fructose consumption is associated with decreased hepatic steatosis, liver injury (necroinflammation and hepatocyte ballooning) and fibrosis in a dose-dependent manner. The unique metabolism of fructose, one which depletes hepatic ATP, increases uric acid, and worsens features of insulin resistance, is a potential mechanism that may account for fructose-related liver injury in NAFLD. Given the changes which occur with fructose exposure, fructose is an ideal diagnostic "tool" by which to induce and/or amplify changes in quantitative MR-based biomarkers and "target" for dietary intervention studies for the treatment of NAFLD. Hypothesis: We hypothesize that fructose is a risk factor for hepatic steatosis, steatohepatitis, and advanced fibrosis and that acute and chronic fructose exposure will worsen the metabolic, energy homeostatic and associated MR-based biomarkers features of NAFLD. Further, we hypothesize that dietary fructose restriction will improve these metabolic and energy homeostatic derangements. Approach: Quantitative MR biomarkers of hepatic metabolites and energy homeostasis will be evaluated before, during, and after acute/chronic fructose challenges. We will characterize the pathophysiologic changes which occur with fructose exposure using multi-parametric analysis of MRI and 1H and 31P and spectroscopic imaging data to measures of metabolism and energy homeostasis and relate these to the histologic features of NAFLD. Impact: This work addresses the following significant gaps in knowledge: 1) whether acute and chronic fructose exposure alters metabolism, energy homeostasis, and is associated with liver injury in patients with/without NAFLD and 2) whether modification of fructose consumption could improve the clinical and pathologic features of NAFLD. The successful completion of the proposed studies will provide novel and clinically relevant information regarding the pathophysiologic and pathologic mechanism underlying fructose-related liver injury in humans. The proposed studies will be the first to correlate the dynamic measures of non-invasive MR-based biomarkers and energy homeostasis with the clinical, metabolic and histologic features of NAFLD. The integration of these biomarkers in a cross-sectional and longitudinal study will characterize their use for measuring changes associated with fructose-related liver injury and facilitate the development of non-invasive biomarkers for NAFLD diagnosis and progression. PUBLIC HEALTH RELEVANCE: The goal of this project is to define the mechanism(s) by which fructose may contribute to nonalcoholic fatty liver disease (NAFLD) progression, assess whether such factors can be measured using dynamic MRI/MRS biomarkers and whether these factors can be modified with dietary fructose restriction.

描述（由申请方提供）：旨在定义果糖可能导致非酒精性脂肪性肝病（NAFLD）进展的机制，并评估这些因素是否可以使用磁共振（MR）生物标志物进行测量并通过饮食果糖限制进行调整。背景资料：NAFLD是一个主要的公共卫生问题，预计到2020年将超过其他形式的慢性肝病的发病率和死亡率。NAFLD的患病率和严重程度都与果糖消费量的增加有关。我们已经报道了果糖消耗量的增加与肝脂肪变性、肝损伤（坏死性炎症和肝细胞气球样变）和纤维化的减少呈剂量依赖性相关。果糖的独特代谢，消耗肝脏ATP，增加尿酸，并破坏胰岛素抵抗的特征，是NAFLD中果糖相关肝损伤的潜在机制。考虑到果糖暴露发生的变化，果糖是一种理想的诊断“工具”，通过它可以诱导和/或放大定量MR生物标志物的变化，并为治疗NAFLD的饮食干预研究提供“目标”。假设：我们假设果糖是肝脂肪变性、脂肪性肝炎和晚期纤维化的危险因素，急性和慢性果糖暴露将恶化NAFLD的代谢、能量稳态和相关的基于MR的生物标志物特征。此外，我们假设饮食果糖限制将改善这些代谢和能量稳态紊乱。方法：将在急性/慢性果糖激发前、激发期间和激发后评价肝脏代谢物和能量稳态的定量MR生物标志物。我们将使用MRI和1H和31P的多参数分析以及光谱成像数据来表征果糖暴露所发生的病理生理变化，以测量代谢和能量稳态，并将这些与NAFLD的组织学特征相关联。影响：这项工作解决了以下知识方面的重大空白：1）急性和慢性果糖暴露是否会改变代谢，能量稳态，以及是否与NAFLD患者的肝损伤有关; 2）果糖摄入量的改变是否可以改善NAFLD的临床和病理特征。拟议研究的成功完成将提供有关人类果糖相关肝损伤的病理生理学和病理学机制的新的临床相关信息。拟议的研究将是第一个将非侵入性基于MR的生物标志物和能量稳态的动态测量与NAFLD的临床，代谢和组织学特征相关联的研究。在横断面和纵向研究中整合这些生物标志物将表征其用于测量与果糖相关的肝损伤相关的变化，并促进非侵入性生物标志物的开发，用于NAFLD诊断和进展。 公共卫生相关性：该项目的目标是确定果糖可能导致非酒精性脂肪性肝病（NAFLD）进展的机制，评估这些因素是否可以使用动态MRI/MRS生物标志物进行测量，以及这些因素是否可以通过饮食果糖限制进行修改。