Imaging Hepatic Energy Metabolism in NAFLD/NASH

项目摘要 迫切需要开发对非酒精性代谢敏感的代谢成像方法。 脂肪性肝病（NAFLD）和非酒精性脂肪性肝炎（NASH），以及两者之间的过渡 病理生理状态。我们将开发基于磁共振的代谢成像， 13 C和热极化2 H标记的底物。我们的实验平台是C57 B1/6 N小鼠，并且饮食诱导和 疾病状态的遗传模型。该方法测定碳水化合物和脂肪酸代谢， 已知这些疾病会发生改变。目标1.使用超极化的[1- 13 C]和[2- 13 C]丙酮酸盐， [2- 13 C]二羟基丙酮，我们将对肝脏丙酮酸氧化进行多参数评估， 回补，以及丙酮酸循环。目标2.使用均匀氘代脂肪酸，我们将确定 在相同的模型中，β-氧化和氧化还原生物学的变化。这些方法的结合将 在这些广为接受的模型中，产生迄今为止最全面的能量代谢分析。 人类疾病目标3.我们将确认碳水化合物和脂肪酸代谢成像分析， 敲除老鼠来测试我们模式的基础假设。丙酮酸羧化酶敲除 小鼠下调丙酮酸回补。富马酸水合酶敲除小鼠是一种模型， 这将测试我们对克雷布斯循环周转变化的敏感性。乙酰-coa 羧化酶敲除小鼠将上调脂肪酸氧化。所有这三种途径都被假设为 作为NAFLD和NASH发病机制和进展的基本要素。 相关性 NAFLD和NASH现在是一种世界性的流行病，一些人估计NAFLD的患病率高达 占世界人口的24%。NASH预计将超过肝炎，成为肝脏疾病的第一大病因。 在未来5年内在美国进行移植。在接下来的10年里，这种疾病预计将成为 1万亿美元的负担给医疗保健系统。虽然纤维化成像在一定程度上可以诊断NASH， 进展，没有代谢成像技术是敏感的炎症地方性的， NAFLD向NASH的转变。目前用于鉴别NASH的逐步范例缺乏正确鉴别NASH的敏感性。 分类早期发展。当NASH被诊断时，疾病的临床管理发生变化 戏剧性地，变得更加昂贵。代谢显像诊断和治疗糖尿病的新方法 NASH的分期将显著提高医疗实践，改善患者护理的前景， 降低成本。

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.