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Metabolic Origins of Nonalcoholic Steatohepatitis

非酒精性脂肪性肝炎的代谢起源

基本信息

批准号：
9906207
负责人：
Nishanth Sunny
金额：
$ 34.2万
依托单位：
UNIV OF MARYLAND, COLLEGE PARK
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-07 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9906207
关键词：
Acute Address Affect Age Alleles Animal Model Antioxidants Attenuated Branched-Chain Amino Acids Cardiovascular Diseases Cell Respiration Ceramides Chronic Cirrhosis Citric Acid Cycle Clinical Coupling Cytochrome c Reductase Defect Deposition Development Diet Diglycerides Etiology Fatty Liver Fructose Generations Genetic Polymorphism Genetic Risk Gluconeogenesis Goals Hepatic Hepatocyte Human Impairment In Vitro Inflammation Insulin Resistance Keto Acids Link Lipids Liver Liver Mitochondria Liver diseases Mass Spectrum Analysis Measurement Measures Mediating Metabolic Metabolism Mitochondria Modeling Morphology Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Magnetic Resonance Obesity Oxidative Stress PPAR alpha PPAR gamma Pathogenicity Patients Phosphorus Plasma Production Public Health Reactive Oxygen Species Research Personnel Resistance Respiration Respiratory Chain Rodent Model Severities Steatohepatitis Techniques Testing Tissues Trans Fats Work acylcarnitine attenuation clinically relevant clinically translatable hepatic gluconeogenesis high risk human disease in vivo indexing lipid biosynthesis liver transplantation metabolic profile mitochondrial oxidative dysfunction mouse model nonalcoholic steatohepatitis novel oxidation prevent

项目摘要

Nonalcoholic steatohepatitis (NASH) is prevalent in over 70% of the obese and type II diabetes mellitus (T2DM) patients and is a leading cause of liver transplantation. Hepatic insulin resistance and inflammation mirror alterations in mitochondrial oxidative flux (beta-oxidation, tri-carboxylic acid [TCA] cycle and mitochondrial respiration), in rodent models and humans with simple steatosis. This proposal will identify new mechanisms leading to dysfunctional mitochondrial oxidative flux and development of NASH. The proposal will test the hypothesis that the severity of hepatocyte inflammation and reactive oxygen species (ROS) generation will be proportional to the rates of mitochondrial oxidative flux. Thus, attenuation of oxidative flux will provide a promising strategy to alleviate inflammation and oxidative stress in NASH and T2DM. Aim 1 will test whether altered mitochondrial oxidative flux during the transition from simple steatosis to NASH parallel an increase in ROS production, inflammation and oxidative stress. This will be tested in a mouse model fed high fructose, high trans-fat diet which gradually transitions from simple steatosis to NASH, closely resembling human disease. Aim 2 will investigate a novel mechanism by which chronic elevation of branched chain amino acids (BCAAs) during hepatic insulin resistance will disrupt mitochondrial oxidative flux and sustain lipogenesis. Aim 3 will utilize a novel mouse model with a clinically relevant polymorphism in the NADH dehydrogenase subunit 2 (mt-Nd2A) allele. This unique animal model will help identify whether the upregulated antioxidant defense resulting from the beneficial effects of the mt-Nd2A allele will attenuate mitochondrial oxidative dysfunction in NASH. State-of-the-art metabolic profiling techniques in nuclear magnetic resonance and mass spectrometry will be combined with measures of ROS production and oxidative stress in liver. Direct measurements of oxidative flux through the TCA cycle relative to ATP turnover in the liver will result in a novel index of mitochondrial coupling efficiency, which will have high translational value for human studies. In conclusion, identifying key mechanisms to attenuate mitochondrial oxidative flux will provide a better paradigm to treat NASH and decrease unregulated gluconeogenesis in T2DM.

非酒精性脂肪性肝炎（NASH）在70%以上的肥胖和II型糖尿病患者中普遍存在（T2 DM）患者，并且是肝移植的主要原因。肝脏胰岛素抵抗与炎症线粒体氧化通量（β-氧化、三羧酸[TCA]循环和线粒体呼吸），在啮齿动物模型和患有单纯性脂肪变性的人类中。该提案将确定新的导致线粒体氧化通量功能障碍和NASH发展的机制。该提案将检验肝细胞炎症的严重程度和活性氧（ROS）的产生将与线粒体氧化通量的速率成比例。因此，氧化通量的衰减将提供有希望的策略，减轻NASH和T2 DM的炎症和氧化应激。目标1将测试从单纯性脂肪变性向NASH转变过程中线粒体氧化通量的改变与 ROS产生、炎症和氧化应激。这将在喂食高果糖的小鼠模型中进行测试，高反式脂肪饮食，从单纯性脂肪变性逐渐转变为NASH，非常类似于人类疾病目的2将探讨支链氨基酸慢性升高的新机制，在肝胰岛素抵抗期间，支链氨基酸（BCAA）将破坏线粒体氧化通量并维持脂肪生成。目的 3将利用一种新的小鼠模型，该模型在NADH脱氢酶亚基中具有临床相关的多态性。 2（mt-Nd 2A）等位基因。这种独特的动物模型将有助于确定是否上调抗氧化防御由mt-Nd 2A等位基因的有益作用引起的线粒体氧化功能障碍，纳什核磁共振和质谱分析中最先进的代谢分析技术将与肝脏中ROS产生和氧化应激的测量相结合。直接测量通过TCA循环的氧化通量相对于肝脏中的ATP周转率将导致一种新的指数，线粒体偶联效率，这将对人类研究具有很高的翻译价值。最后，我谨指出，确定减少线粒体氧化通量的关键机制将提供更好的治疗模式， NASH和减少T2 DM中不受调节的新生血管生成。