Factors Controlling Metabolic Flux in the Liver

控制肝脏代谢通量的因素

• 批准号: 9437886
• 负责人: Shawn C Burgess
• 金额: $ 24.3万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9437886
• 关键词: Anabolism; Animal Model; Antioxidants; Cell Respiration; Citric Acid Cycle; Defect; Diet; Energy Metabolism; Environment; Equilibrium; Fatty Liver; Fatty acid glycerol esters; Gluconeogenesis; Hepatic; Hepatocellular Damage; Human; Inflammation; Insulin; Insulin Receptor; Insulin Resistance; Knockout Mice; Lead; Link; Lipid Synthesis Pathway; Liver; Liver Mitochondria; Liver diseases; Mediating; Metabolic; Metabolic Activation; Metabolism; Methods; Mitochondria; Modeling; Molecular; Mus; Obese Mice; Obesity; Oxidative Stress; Pathologic; Pathway interactions; Phosphorylation; Play; Production; Protein Biosynthesis; Protons; Role; Signal Pathway; Signal Transduction; Testing; Tracer; base; cost; insulin signaling; interest; ketogenesis; loss of function; mitochondrial dysfunction; mitochondrial metabolism; non-alcoholic fatty liver; oxidative damage; prevent; stable isotope

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, and tests whether this condition alters the apparent mitochondrial function and increases 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.

项目总结: