Sulfur Amino Acid Metabolism in NAFLD

NAFLD 中的硫氨基酸代谢

• 批准号: 7653996
• 负责人: SATISH C KALHAN
• 金额: $ 56.95万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7653996
• 关键词: Adult; Animal Model; Calorimetry; Cirrhosis; Clinical; Complication; Consumption; Cysteine; Data; Deposition; Development; Diet Habits; Disease; Disease Progression; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Fibrosis; Frequencies; Functional disorder; Generations; Genes; Genetic Polymorphism; Glutathione; Glutathione Metabolism Pathway; Glycine; Hepatic; Hormones; Human; Incidence; Injury; Insulin; Insulin Resistance; Intervention; Intravenous; Kinetics; Label; Laboratories; Lead; Lecithin; Lipids; Literature; Liver; Liver diseases; Mass Spectrum Analysis; Measures; Membrane Potentials; Metabolic; Metabolism; Methionine; Methionine Metabolism Pathway; Methylation; Methylenetetrahydrofolate reductase (NADPH); Micronutrients; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Oxidation-Reduction; Oxidative Stress; Patients; Pattern; Phosphatidylethanolamine; Plasma; Population; Process; Public Health; Publishing; Reactive Oxygen Species; Regulation; Resistance; Staging; Steatohepatitis; Sulfur Amino Acids; Time; Tracer; Very low density lipoprotein; base; cytokine; fatty acid oxidation; folic acid metabolism; insight; lipid metabolism; micronutrient deficiency; mitochondrial dysfunction; mitochondrial membrane; non-alcoholic fatty liver; nonalcoholic steatohepatitis; patient population; phosphatidylethanolamine; public health relevance; respiratory; response; transmethylation; very low density lipoprotein triglyceride

DESCRIPTION (provided by applicant): Nonalcoholic fatty liver disease (NAFLD) in humans has become an increasing public health problem paralleling the increase in obesity, type II diabetes, and changing dietary and activity patterns. The spectrum of NAFLD includes simple hepatic steatosis to steatohepatitis, fibrosis and cirrhosis. Published data and those from our preliminary studies suggest systemic insulin resistance and increased lipolytic flux are the major hallmarks of NAFLD in humans. An increased influx of fatty acids into the liver results in a higher rate of fatty acid oxidation, generation of a reactive oxygen species (ROS), increased glutathione consumption, and ultimately leads to mitochondrial dysfunction and propagation of disease. We hypothesize that hepatic insulin resistance and high fatty acid flux into the liver, in combination with increased oxidative stress, results in high methylation demands, a high rate of methionine transsulfuration, and glutathione synthesis. These changes in methionine metabolism may be exacerbated by altered folate metabolism as a result of gene polymorphism and by changes in hormones, cytokines and nutrient deficiency. We will examine these hypotheses by quantifying the rates of transmethylation and transsulfuration of methionine, and rate of glutathione synthesis in a well characterized population of hepatic steatosis and steatohepatitis patients using stable isotopic tracers. In addition, we will examine the responses to nutrient and fatty acid administration on the rate of glutathione synthesis. These data will be related to clinical and laboratory data, with measures of systemic insulin resistance and with methylenetetrahydrofolate reductase polymorphism. The proposed hypotheses are based upon strong preliminary data and published data in the literature. These studies will provide a mechanistic insight into the progression of NAFLD and will identify specific times in the disease when targeted interventions can be implemented and evaluated. PUBLIC HEALTH RELEVANCE: Nonalcoholic fatty liver disease has rapidly become the most common liver disease in the adult population worldwide. It has been recognized as the complication of obesity, type II diabetes and associated resistance to insulin action. The proposed studies are aimed at examining the metabolic mechanisms involved in the progression of this disease, so that specific targeted intervention strategies related to the stage of the disease can be identified and evaluated.

描述（由申请人提供）：人类中的非酒精性脂肪肝病（NAFLD）已成为越来越多的公共卫生问题，该问题与肥胖，II型糖尿病以及饮食和活动模式变化的增加相似。 NAFLD的光谱包括简单的肝脂肪变性到脂肪性肝炎，纤维化和肝硬化。已发布的数据以及我们的初步研究的数据表明，全身性胰岛素抵抗和脂溶性通量增加是人类NAFLD的主要标志。脂肪酸涌入肝脏的涌入会导致脂肪酸氧化的速率更高，活性氧（ROS）的产生（ROS），增加的谷胱甘肽消耗量增加，并最终导致线粒体功能障碍和疾病的传播。我们假设肝胰岛素抵抗和高脂肪酸通量与氧化应激的增加相结合，导致甲基化需求高，蛋氨酸转硫化率高和谷胱甘肽合成。由于基因多态性以及激素，细胞因子和营养缺乏症的变化，叶酸代谢的改变可能会加剧蛋氨酸代谢的这些变化。我们将通过使用稳定的同位素截止剂来量化甲基化和谷胱甘肽合成速率的经甲基化和转硫的速率以及谷胱甘肽合成的速率来检验这些假设。此外，我们将研究对谷胱甘肽合成速率的营养和脂肪酸给药的反应。这些数据将与临床和实验室数据有关，并具有全身性胰岛素抵抗和甲基化酸酸还原酶多态性的测量。提出的假设基于强大的初步数据和文献中发布的数据。这些研究将提供对NAFLD进展的机械洞察力，并在可以实现和评估有针对性的干预措施时确定疾病中的特定时间。公共卫生相关性：非酒精性脂肪肝疾病已迅速成为全球成年人群中最常见的肝病。它被认为是肥胖，II型糖尿病和对胰岛素作用的抗药性的并发症。拟议的研究旨在检查该疾病发展所涉及的代谢机制，以便可以鉴定和评估与疾病阶段有关的特定靶向干预策略。