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.
Hepatic insulin resistance and fatty liver disease is associated with altered mitochondrial energy metabolism, a factor that may play a causative role in hepatocellular damage. This project tests whether abnormal mitochondrial energetics and related oxidative stress/inflammation are metabolically mediated by biosynthetic pathways that draw on the energetic capacity of the liver. We will identify energetically demanding biosynthetic pathways that are altered by insulin resistance. We will determine whether increased mitochondrial biosynthetic and energetic fluxes are necessary for oxidative stress and inflammation. We will determine whether altered cell signaling pathways during insulin resistance are sufficient to initiate the biosynthetic and therefore energetic environment that can lead to hepatocellular damage.
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