Factors Controlling Metabolic Flux in the Liver

项目摘要： 肝细胞能量产生用于支持生物合成、分解代谢和无效途径， 消耗ATP或还原当量。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： 抵抗和肥胖改变了通过能量昂贵的生物合成途径的通量。我们建议 这些途径的变化改变了线粒体的明显功能，导致氧化损伤增加， 肝脏该项目在我们先前的发现基础上取得了进展，即（i）胰岛素抵抗/NAFLD导致 动物模型和人类的肝脏氧化通量;（ii）增加的氧化通量与氧化 应激和炎症;（iii）抑制新生血管生成防止氧化代谢升高， 氧化应激和炎症。本项目检验了肝脏胰岛素抵抗影响 通过改变耗费能量的生物合成途径来影响线粒体代谢。因此，似乎 不相关的中间代谢可能对线粒体功能产生继发性影响， NAFLD中的氧化应激和炎症等因素。为了验证这个假设，我们将使用最先进的 稳定同位素示踪方法、NMR和MS，以评价代谢通量和条件性功能获得/丧失 小鼠建立机制。特别强调的是确定能量依赖 胰岛素抵抗期间肝脏能量代谢变化的途径， 信号通路有助于这些变化，并决定是否阻止改变生物合成 在胰岛素抵抗和脂肪肝疾病期间，足以保护免受氧化损伤。

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.