The Role of Mitochondrial Dysfunction in Non-Alcoholic Fatty Liver Disease

线粒体功能障碍在非酒精性脂肪肝中的作用

基本信息

批准号：
8401182
负责人：
JEFFREY D BROWNING
金额：
$ 44.29万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-23 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8401182
关键词：
Acetoacetates Affect Alanine Benign Biological Assay Carnitine Cell physiology Cirrhosis Citrates Citric Acid Cycle Clinical Data Development Diabetes Mellitus Disease Effectiveness Fasting Fatty Acids Fatty acid glycerol esters Fingerprint Generations Gluconeogenesis Glucose Goals Grant Hepatic Hepatocyte Histologic Human Hydroxybutyrates Impairment Individual Inflammation Insulin Resistance Ketones Lead Link Liver Liver Mitochondria Liver diseases Malonyl Coenzyme A Mass Spectrum Analysis Measurement Measures Metabolic Metabolism Metformin Methodology Methods Mitochondria NMR Spectroscopy Nuclear Magnetic Resonance Obesity Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathogenesis Patients Peripheral Pharmaceutical Preparations Population Process Production Propionates Rattus Reaction Reporting Research Risk Rodent Role Skeletal Muscle Staging Steatohepatitis Techniques Testing Time Tissues Tracer Transferase Triglycerides attenuation base clinical care fatty acid oxidation glucose metabolism glucose production glycogenolysis improved in vivo insight ketogenesis liver biopsy mitochondrial dysfunction non-alcoholic fatty liver nonalcoholic steatohepatitis oxidation public health relevance radiotracer response stable isotope

项目摘要

DESCRIPTION (provided by applicant): Mitochondrial dysfunction may be responsible for the pathogenesis and progression of non-alcoholic fatty liver disease (NAFLD), a condition that affects over 71 million individuals in the U.S. alone. Impaired mitochondrial function could lead to both the initial accumulation of hepatic triglycerides via decreased oxidative disposal, as well as the transition to steatohepatitis due to enhanced oxidative stress originating from the plethora of redox reactions required for oxidative phosphorylation. As a result, we believe that there may be significant differences in mitochondrial metabolism between individuals with bland steatosis, presumed to be a benign condition, and steatohepatitis (NASH), a progressive and morbid form of NAFLD. The goal of this grant will be to use newly-developed, non-invasive, in vivo NMR-based stable isotope methodologies to define the role of hepatic mitochondrial dysfunction in the development of NAFLD and how these alterations relate to the development of insulin resistance and NASH. Such measurements are difficult or impossible to do using standard mass spectrometry techniques or classic radiotracers. The first aim of this proposal seeks to determine if the increased rates of gluconeogenesis observed in insulin resistance and NAFLD are associated with increased energy generation via the citric acid (TCA) cycle, a component of mitochondrial function. We have observed an association between energy generation in the TCA cycle and gluconeogenesis occurring from precursors such as lactate and alanine, suggesting that these processes are energetically linked. In the second aim of this proposal we will determine if progression from bland steatosis to NASH is associated with a progressive decline in a second component of mitochondrial function, ketogenesis. Several reports demonstrate that FA synthesis in liver is inappropriately increased in subjects with NAFLD, implying that mitochondrial FA 2-oxidation is inhibited via the effect of malonyl-CoA on carnitine palmitoyl transferase. Attenuation of hepatic 2-oxidation may be associated with decreased export of ketones to the periphery in favor of local energy generation to support cellular processes in the hepatocyte. In the final aim, the ability of metformin, a proposed therapy for NAFLD, to augment hepatic mitochondrial function in individuals with NAFLD will be quantified. The benefits of the proposed research are several-fold: First, improved understanding of the metabolic derangements complicit in the pathogenesis and progression of NAFLD will allow better clinical insight and focused approaches to therapy; Second, our methodologies may provide a simple, non-invasive method to identify individuals with NASH, who are at greatest risk of progressive liver disease; and Third, a better understanding of the mechanism of action of metformin in the treatment of NAFLD will allow this therapy to be targeted to individuals most likely to derive benefit.

描述（由申请人提供）：线粒体功能障碍可能导致非酒精性脂肪肝病（NAFLD）的发病机理和进展，这种疾病仅影响美国超过7100万个人。线粒体功能受损可能会导致肝甘油三酸酯的初始积累，以及由于氧化应激增强而引起的氧化应激引起的氧化应激引起的氧化磷酸磷酸化所需的大量氧化还原反应引起的过渡。结果，我们认为，平淡无变的个体之间的线粒体代谢可能存在显着差异，假定是一种良性疾病，而脂肪性肝炎（NASH）是NAFLD的进行性和病态形式。该赠款的目的是在基于体内NMR的新开发的，无创的，非侵入性的稳定同位素方法论来定义肝线粒体功能障碍在NAFLD开发中的作用，以及这些变化与胰岛素抵抗和NASH的发展如何相关。使用标准质谱技术或经典的放射性示例，难以或不可能进行此类测量。该提案的第一个目的旨在确定在胰岛素抵抗和NAFLD中观察到的糖异生速率是否与通过柠檬酸（TCA）循环增加的能量产生有关，这是线粒体功能的组成部分。我们已经观察到在TCA循环中产生能量的关联与乳酸和丙氨酸等前体产生的糖异生，这表明这些过程在能量上是有能量联系的。在该提案的第二个目的中，我们将确定从平淡的脂肪变性到纳什的进展是否与线粒体功能第二个成分酮生成的第二个成分的逐渐下降有关。几份报告表明，NAFLD受试者中肝脏中的FA合成不当，这意味着线粒体FA 2-氧化是通过丙二酰-COA对carnitine Palmitoyl转移酶的影响而抑制的。肝2-氧化的衰减可能与向周围的酮出口减少有关，以支持局部能量产生以支持肝细胞中的细胞过程。在最终目的中，将量化二甲合身蛋白（一种针对NAFLD的疗法）增强NAFLD个体肝线粒体功能的能力。拟议研究的好处是多个：首先，对NAFLD的发病机理和进展的代谢危险同谋的了解，将有助于更好的临床见解和专注的治疗方法；其次，我们的方法可能会提供一种简单的非侵入性方法来识别纳什（Nash）患有最大风险的纳什人。第三，更好地理解二甲双胍在NAFLD治疗中的作用机理将使该疗法成为最有可能获得益处的个体的目标。