Metabolic Origins of Nonalcoholic Steatohepatitis

非酒精性脂肪性肝炎(NASH)在超过70%的肥胖和II型糖尿病患者中普遍存在 (T2 DM)患者，是肝移植的主要原因。肝脏胰岛素抵抗与炎症 线粒体氧化通量(β-氧化、三羧酸[TCA]循环和 线粒体呼吸)，在啮齿动物模型和患有单纯性脂肪变性的人类中。这项提案将确定新的 线粒体氧化通量功能障碍与NASH发生的机制。这项提议将 检验假设肝细胞炎症的严重程度和活性氧(ROS)的产生 将与线粒体氧化通量的速率成正比。因此，氧化助熔剂的衰减将提供一个 有望缓解NASH和T2 DM患者的炎症和氧化应激。目标一号将测试 在从单纯性脂肪变性到NASH的转变过程中线粒体氧化通量的变化与 ROS的产生、炎症和氧化应激。这将在喂食高果糖的小鼠模型中进行测试， 从单纯性脂肪变性逐渐过渡到NASH的高反式脂肪饮食，与人类非常相似 疾病。目标2将研究支链氨基酸慢性升高的新机制 肝脏胰岛素抵抗期间的支链氨基酸(BCAA)将破坏线粒体的氧化通量，维持脂肪生成。目标 3将利用一种新的小鼠模型，该模型具有临床相关的NADH脱氢酶亚单位的多态。 2(mt-ND2A)等位基因。这一独特的动物模型将有助于确定上调的抗氧化防御 Mt-Nd2A等位基因的有益作用将减轻线粒体氧化功能障碍 纳什。核磁共振和质谱学中最新的代谢谱技术 将与肝脏中ROS产生和氧化应激的测量相结合。直接测量 通过TCA循环的氧化通量相对于肝脏中的ATP周转将导致一个新的指数 线粒体偶联效率，这将对人类研究具有很高的翻译价值。总之， 识别减弱线粒体氧化通量的关键机制将为治疗提供更好的范例 NASH和减少T2 DM中未调控的糖异生。

Nonalcoholic steatohepatitis (NASH) is prevalent in over 70% of the obese and type II diabetes mellitus (T2DM) patients and is a leading cause of liver transplantation. Hepatic insulin resistance and inflammation mirror alterations in mitochondrial oxidative flux (beta-oxidation, tri-carboxylic acid [TCA] cycle and mitochondrial respiration), in rodent models and humans with simple steatosis. This proposal will identify new mechanisms leading to dysfunctional mitochondrial oxidative flux and development of NASH. The proposal will test the hypothesis that the severity of hepatocyte inflammation and reactive oxygen species (ROS) generation will be proportional to the rates of mitochondrial oxidative flux. Thus, attenuation of oxidative flux will provide a promising strategy to alleviate inflammation and oxidative stress in NASH and T2DM. Aim 1 will test whether altered mitochondrial oxidative flux during the transition from simple steatosis to NASH parallel an increase in ROS production, inflammation and oxidative stress. This will be tested in a mouse model fed high fructose, high trans-fat diet which gradually transitions from simple steatosis to NASH, closely resembling human disease. Aim 2 will investigate a novel mechanism by which chronic elevation of branched chain amino acids (BCAAs) during hepatic insulin resistance will disrupt mitochondrial oxidative flux and sustain lipogenesis. Aim 3 will utilize a novel mouse model with a clinically relevant polymorphism in the NADH dehydrogenase subunit 2 (mt-Nd2A) allele. This unique animal model will help identify whether the upregulated antioxidant defense resulting from the beneficial effects of the mt-Nd2A allele will attenuate mitochondrial oxidative dysfunction in NASH. State-of-the-art metabolic profiling techniques in nuclear magnetic resonance and mass spectrometry will be combined with measures of ROS production and oxidative stress in liver. Direct measurements of oxidative flux through the TCA cycle relative to ATP turnover in the liver will result in a novel index of mitochondrial coupling efficiency, which will have high translational value for human studies. In conclusion, identifying key mechanisms to attenuate mitochondrial oxidative flux will provide a better paradigm to treat NASH and decrease unregulated gluconeogenesis in T2DM.