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

描述(申请人提供)：线粒体功能障碍可能是非酒精性脂肪性肝病(NAFLD)的发病和发展的原因，这种疾病仅在美国就影响了7100多万人。线粒体功能受损可能导致氧化处置减少导致肝脏甘油三酯的初始积累，以及由于氧化磷酸化所需的过多氧化还原反应引起的氧化应激增加而导致脂肪性肝炎的转变。因此，我们认为轻度脂肪变性(被认为是良性疾病)和脂肪性肝炎(NASH)可能在线粒体代谢方面存在显著差异。脂肪肝炎是NAFLD的一种进行性和病态形式。这笔赠款的目标将是使用新开发的、非侵入性的、基于体内核磁共振的稳定同位素方法来确定肝脏线粒体功能障碍在NAFLD发展中的作用，以及这些变化如何与胰岛素抵抗和NASH的发展相关。使用标准的质谱学技术或经典的放射性示踪剂很难或不可能进行这样的测量。这项建议的第一个目的是确定在胰岛素抵抗和NAFLD中观察到的糖异生增加的速度是否与通过柠檬酸(TCA)循环产生的能量增加有关，柠檬酸循环是线粒体功能的一个组成部分。我们已经观察到TCA循环中的能量产生和来自乳酸和丙氨酸等前体的糖异生之间的联系，这表明这些过程是能量联系的。在这项建议的第二个目标中，我们将确定从平淡的脂肪变性到NASH的进展是否与线粒体功能的第二个组成部分-酮体生成的进行性下降有关。多篇报道显示NAFLD患者肝脏FA合成异常增加，提示线粒体FA2-氧化通过丙二酰辅酶A对肉碱棕榈酰转移酶的影响而受到抑制。肝脏2-氧化的减弱可能与外周输出酮的减少有关，有利于局部能量的产生，以支持肝细胞内的细胞过程。在最终目标中，将量化二甲双胍--一种治疗NAFLD的建议疗法--增强NAFLD患者肝脏线粒体功能的能力。拟议研究的好处有几个方面：第一，提高对NAFLD发病机制和进展中相互作用的代谢紊乱的了解，将使我们能够更好地临床洞察和重点治疗；第二，我们的方法可能提供一种简单、非侵入性的方法来确定NASH患者，他们有最大的进展性肝病风险；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人。

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.