Factors controlling metabolic flux in the liver - Supplement Revision

项目总结： 肝细胞能量生产被用来支持生物合成、分解代谢和无效的途径 消耗三磷酸腺苷或降低当量。除了质子泄漏和解偶联，线粒体 功能必须符合这些要求。这个项目是基于这样一个科学前提：肝脏胰岛素 抵抗力和肥胖改变了通过耗费能量的生物合成途径的流量。我们建议 这些途径的变化改变了线粒体的表观功能，导致脑内氧化损伤增加 肝脏。该项目在我们先前发现的基础上取得了进展，即(I)胰岛素抵抗/非酒精性脂肪肝会导致 动物模型和人类的肝脏氧化通量；(Ii)氧化通量的增加与氧化有关 应激和炎症；(Iii)抑制糖异生防止氧化代谢升高， 氧化应激和炎症。这个项目测试了肝脏胰岛素抵抗影响的假说 通过改变耗费能量的生物合成途径对线粒体新陈代谢的影响。因此，似乎 不相关的中间代谢可能会对线粒体功能产生次要影响，并有助于 非酒精性脂肪肝的氧化应激和炎症等因素。为了检验这一假设，我们将使用最先进的 稳定同位素示踪法、核磁共振和质谱法评估代谢流量和条件功能获得/丧失 小鼠建立机制。特别强调的是识别能量依赖的 解释胰岛素抵抗期间肝脏能量代谢变化的途径，确定哪些 信号通路有助于这些变化，并决定是否阻止改变的生物合成 在胰岛素抵抗和脂肪肝疾病期间，DIVE足以防止氧化损伤。

Project Summary: Hepatocellular energy production is used to support biosynthetic, catabolic and futile pathways that consume ATP or reducing equivalents. With the exception of proton leak and uncoupling, mitochondrial function must match these requirements. This project is based on the scientific premise that hepatic insulin resistance and obesity alter flux through energetically costly biosynthetic pathways. We propose that changes in these pathways alter apparent mitochondrial function, resulting in increased oxidative damage in liver. The project advances on our previous findings that (i) insulin resistance/NAFLD results in elevated hepatic oxidative flux in animal models and humans; (ii) increased oxidative flux is associated with oxidative stress and inflammation; (iii) suppressing gluconeogenesis prevented elevated oxidative metabolism, oxidative stress and inflammation. This project tests the hypothesis that hepatic insulin resistance impinges on mitochondrial metabolism by altering energetically costly biosynthetic pathways. Hence, seemingly unrelated intermediary metabolism could have secondary effects on mitochondrial function and contribute to factors like oxidative stress and inflammation in NAFLD. To test the hypothesis, we will use state-of-the-art stable isotope tracer methods, NMR and MS to evaluate metabolic flux, and conditional gain/loss of function mice to establish mechanism. Particular emphasis is placed on identifying the energetically dependent pathways that account for changes in hepatic energy metabolism during insulin resistance, identifying which signaling pathways contribute to these changes and determining whether preventing altered biosynthesis during is sufficient to protect against oxidative damage during insulin resistance and fatty liver disease.