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

• 批准号: 8231420
• 负责人: JEFFREY D BROWNING
• 金额: $ 41.79万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 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/8231420
• 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

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. PUBLIC HEALTH RELEVANCE: Accumulation of fat in the liver due to obesity and diabetes is termed non-alcoholic fatty liver disease (NAFLD), with over 71 million individuals in the USA afflicted with this disorder. Such fat accumulation can lead to inflammation and progressive liver disease in some individuals. The goal of this proposal is to determine if impaired mitochondrial function contributes to the pathogenesis and progression of NAFLD using non-invasive techniques based on stable isotope tracers and nuclear magnetic resonance spectroscopy, techniques that have the potential to immediately impact clinical care by providing a method to identify individuals at risk for progressive liver disease, heretofore only possible by liver biopsy.

描述（由申请人提供）：线粒体功能障碍可能是非酒精性脂肪肝病 (NAFLD) 的发病机制和进展的原因，这种疾病仅在美国就影响了超过 7100 万人。线粒体功能受损可能导致氧化处理减少而导致肝甘油三酯最初积累，以及由于氧化磷酸化所需的过多氧化还原反应导致氧化应激增强而转变为脂肪性肝炎。因此，我们认为，轻度脂肪变性（被认为是良性病症）和脂肪性肝炎（NASH）（NAFLD 的一种进行性病态形式）个体之间的线粒体代谢可能存在显着差异。这笔赠款的目标是使用新开发的、非侵入性的、基于体内 NMR 的稳定同位素方法来确定肝线粒体功能障碍在 NAFLD 发展中的作用，以及这些改变与胰岛素抵抗和 NASH 的发展之间的关系。使用标准质谱技术或经典放射性示踪剂很难或不可能进行此类测量。该提案的第一个目标是确定在胰岛素抵抗和 NAFLD 中观察到的糖异生率增加是否与柠檬酸 (TCA) 循环（线粒体功能的一个组成部分）产生的能量增加有关。我们观察到 TCA 循环中的能量产生与乳酸和丙氨酸等前体发生的糖异生之间存在关联，表明这些过程在能量上是相关的。在该提案的第二个目标中，我们将确定从轻度脂肪变性到 NASH 的进展是否与线粒体功能第二个组成部分（生酮作用）的逐渐下降有关。一些报告表明，患有 NAFLD 的受试者肝脏中 FA 合成不适当地增加，这意味着线粒体 FA 2-氧化通过丙二酰辅酶 A 对肉碱棕榈酰转移酶的作用而受到抑制。肝脏 2-氧化的减弱可能与酮向外周输出的减少有关，有利于局部能量生成以支持肝细胞中的细胞过程。最终目标是对二甲双胍（一种拟议的 NAFLD 疗法）增强 NAFLD 患者肝线粒体功能的能力进行量化。这项研究的好处是多方面的：首先，加深对 NAFLD 发病机制和进展中代谢紊乱的了解，将有助于更好的临床洞察力和有针对性的治疗方法；其次，我们的方法可以提供一种简单、非侵入性的方法来识别 NASH 患者，他们患进展性肝病的风险最大；第三，更好地了解二甲双胍治疗 NAFLD 的作用机制将使这种疗法能够针对最有可能受益的个体。 公共健康相关性：由于肥胖和糖尿病而导致的肝脏脂肪堆积被称为非酒精性脂肪肝病 (NAFLD)，在美国有超过 7100 万人患有这种疾病。这种脂肪堆积会导致某些人出现炎症和进行性肝病。该提案的目标是使用基于稳定同位素示踪剂和核磁共振波谱的非侵入性技术来确定线粒体功能受损是否会导致 NAFLD 的发病和进展，这些技术有可能立即影响临床护理，提供一种方法来识别有进展性肝病风险的个体，迄今为止只能通过肝活检来实现。