Factors Controlling Metabolic Flux in the Liver

控制肝脏代谢通量的因素

• 批准号: 10585716
• 负责人: Shawn C Burgess
• 金额: $ 50.87万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10585716
• 关键词: Acute; Amino Acids; Antioxidants; Catabolism; Citric Acid Cycle; Closure by clamp; Consumption; Cre driver; Development; Energy Metabolism; Equilibrium; Functional disorder; Gene Expression; Gluconeogenesis; Hepatocyte; Histology; Homeostasis; Immunohistochemistry; Individual; Inflammation; Insulin; Insulin Resistance; Ischemia; Knockout Mice; Link; Lipids; Liver; Liver Mitochondria; Liver diseases; Lobular; Lobule; LoxP-flanked allele; Malates; Mediating; Metabolic; Metabolic Control; Metabolism; Methods; Mitochondria; Modeling; Molecular; Mus; NADP; Nutrient; Obese Mice; Obesity; Obesity associated liver disease; Outcome; Oxidation-Reduction; Oxidative Stress; Oxidoreductase; Pathway interactions; Phosphoenolpyruvate Carboxylase; Physiological; Play; Predisposition; Process; Production; Pyruvate; Pyruvate Carboxylase; Reaction; Recycling; Regulation; Role; Signal Transduction; Testing; Tracer; Vision; conditional knockout; cost; human disease; improved; in vitro Assay; in vivo; insight; knock-down; liver function; liver injury; malic enzyme; metabolomics; mitochondrial dysfunction; mitochondrial metabolism; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; obesity development; respiratory; stable isotope; tool; trafficking; urea cycle; western diet

Project Summary: It is widely accepted that mitochondrial metabolism contributes to the development and progression of non- alcoholic fatty liver disease (NAFLD), but the mechanisms of this process are poorly understood. Hepatocellular mitochondria are unique in their ability and requirement to support biosynthetic, catabolic, and substrate trafficking pathways. These functions are mediated by anaplerosis, non-oxidative pathways of the TCA cycle that allow its intermediates to produce and recycle substrates. The downstream pathways that require anaplerosis (e.g., gluconeogenesis and urea cycle function) are energetically costly. They are also notably dysregulated by obesity and insulin resistance, but it is unknown how mitochondrial anaplerotic function impinges on the progress of liver disease. It is suspected that changes in anaplerotic pathways of liver mitochondria alter apparent mitochondrial function, redox state, and antioxidant capacity. This project tests the hypothesis that the equilibrium between anaplerosis and downstream pathways impinge on antioxidant capacity by modulating redox-mediated reactions in liver. Hence, seemingly unrelated intermediary metabolism may 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 knockout mice to establish mechanism. Emphasis is placed on identifying how TCA cycle intermediates modulate antioxidant function and the role of metabolic compartmentation. In the process, we will develop new tools and concepts that can be tested and applied against human disease.

项目概要： 广泛认为线粒体代谢有助于非细胞性白血病的发生和发展， 酒精性脂肪肝（NAFLD），但这一过程的机制知之甚少。 肝细胞线粒体在其支持生物合成、分解代谢 和底物运输途径。这些功能是由回补、非氧化途径介导的 TCA循环允许其中间体产生和再循环底物。下游通路 需要回补（例如，尿素生成和尿素循环功能）是能量昂贵的。他们是 肥胖和胰岛素抵抗也明显失调，但目前尚不清楚线粒体的回补作用是如何发生的。 功能影响肝病的进展。人们怀疑，回补途径的变化， 肝线粒体改变表观线粒体功能、氧化还原状态和抗氧化能力。这个项目 检验了回补和下游途径之间的平衡冲击的假设， 通过调节肝脏中氧化还原介导的反应来提高抗氧化能力。因此，看似无关 中间代谢可能对线粒体功能有继发性影响， 比如氧化应激和炎症为了验证假设，我们将使用最先进的稳定 同位素示踪方法、NMR和MS来评估代谢通量，以及条件性基因敲除小鼠来建立 机制重点放在确定如何TCA循环中间体调节抗氧化功能 以及代谢区室化的作用。在此过程中，我们将开发新的工具和概念， 可以测试并应用于人类疾病。