Imaging Hepatic Energy Metabolism in NAFLD/NASH

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Project Summary There is an urgent need for development of metabolic imaging methods that are sensitive to nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), and to the transition linking the two pathophysiological states. We will develop magnetic resonance based metabolic imaging using hyperpolarized 13C and thermally polarized 2H-labeled substrates. Our testbed is the C57Bl/6N mouse, and diet induced and genetic models of the disease states. The approach assays both carbohydrate and fatty acid metabolism, which are known to be altered in these diseases. Aim 1. Using hyperpolarized [1-13C] and [2-13C]pyruvate and [2-13C]dihydroxyacetone, we will produce a multi-parametric assessment of hepatic pyruvate oxidation and anaplerosis, as well as pyruvate cycling. Aim 2. Using uniformly deuterated fatty acids, we will determine rates of β-oxidation and changes in redox biology in the same models. The combination of these approaches will yield the most comprehensive analysis of energy metabolism to date in these well-accepted models of the human disease. Aim 3. We will confirm both carbohydrate and fatty acid metabolism imaging assays using knock out mice that test the assumptions underlying our paradigms. The pyruvate carboxylase knockout mouse downregulates pyruvate anaplerosis. The fumarate hydratase knockout mouse is a model of downregulated metabolism that will test our sensitivity to changes in Krebs cycle turnover. The acetyl-CoA carboxylase knockout mouse will upregulate fatty acid oxidation. All three pathways have been hypothesized as essential elements of the pathogenesis and progression of NAFLD and NASH. Relevance NAFLD and NASH are now a worldwide epidemic, with some estimates of NAFLD prevalence as high as 24% of the world population. NASH is expected to surpass hepatitis as the number one cause of liver transplant in the United States within the next 5 years. Over the next 10 years, this disease is projected to be a 1 trillion dollar burden to the healthcare system. While imaging of fibrosis is somewhat diagnostic of NASH progression, there is no metabolic imaging technique that is sensitive to the inflammation endemic to the transition of NAFLD to NASH. Current stepwise paradigms for identifying NASH lack the sensitivity to correctly classify early development. When NASH is diagnosed, clinical management of the disease changes dramatically, becoming much more expensive. Development of a metabolic imaging method for diagnosis and staging of NASH would significantly enhance healthcare practice, with prospects for improving patient care and decreasing costs.