Sulfur Amino Acid Metabolism in NAFLD

描述(申请人提供)：非酒精性脂肪性肝病(NAFLD)在人类中已经成为一个日益严重的公共健康问题，与肥胖、II型糖尿病的增加以及饮食和活动模式的变化相平行。NAFLD的范围包括单纯性肝脂肪变性到脂肪性肝炎、纤维化和肝硬变。已发表的数据和我们初步研究的数据表明，全身性胰岛素抵抗和脂类流量增加是人类NAFLD的主要特征。更多的脂肪酸流入肝脏会导致更高的脂肪酸氧化速率，产生活性氧物种(ROS)，增加谷胱甘肽的消耗，最终导致线粒体功能障碍和疾病的传播。我们假设，肝脏胰岛素抵抗和高脂肪酸流入肝脏，再加上氧化应激增加，导致高甲基化需求、高蛋氨酸转硫率和谷胱甘肽合成。基因多态引起的叶酸代谢改变，以及激素、细胞因子和营养缺乏的改变，可能会加剧蛋氨酸代谢的这些变化。我们将使用稳定的同位素示踪剂，通过量化肝脏脂肪变性和脂肪性肝炎患者的甲基化和硫化转化率以及谷胱甘肽合成率来检验这些假说。此外，我们还将研究营养和脂肪酸对谷胱甘肽合成速率的影响。这些数据将与临床和实验室数据、系统性胰岛素抵抗的测量和亚甲基四氢叶酸还原酶多态性相关。提出的假设是基于强有力的初步数据和文献中公布的数据。这些研究将提供对NAFLD进展的机械性洞察，并将确定疾病中可以实施和评估有针对性干预的具体时间。公共卫生相关性：非酒精性脂肪性肝病已迅速成为全球成年人中最常见的肝病。它被认为是肥胖、II型糖尿病和与胰岛素抵抗相关的作用的并发症。拟议的研究旨在检查与疾病进展有关的代谢机制，以便能够确定和评估与疾病阶段相关的特定靶向干预策略。

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.