Pathophysiology and Characterisation of NAFLD

NAFLD 的病理生理学和特征

• 批准号: 7211326
• 负责人: MICHAEL R CHARLTON
• 金额: $ 30.05万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211326
• 关键词: Pathophysiology; Characterisation; NAFLD

DESCRIPTION (provided by applicant): Non-alcoholic fatty liver disease (NAFLD) is the most common form of liver disease in the United States. The high prevalence of NAFLD is largely on the basis of relentless increases in the prevalences of obesity and insulin resistance. The basis of progressive histological injury in a proportion of patients with NAFLD is poorly understood. The overall goals of this project are to 1) develop a model to identify patients with more histologically severe grades of NAFLD and 2) better define the pathophysiological basis of histological progression of NAFLD. Two hypotheses and specific aims have been developed to achieve these goals. Our first hypothesis is that indices of insulin sensitivity, hyperinsulinemia and/or subclinical inflammation can be used to generate a model capable of identifying patients at increased risk for more histologically severe grades of NAFLD. The first specific aim is to prospectively screen a panel of biological parameters for their ability to identify patients at risk for histologically severe NAFLD, as measured by NAFLD grade. In a pilot study of patients with varying degrees of severity of NAFLD, we found that more histologically severe NAFLD is independently associated with greater percent body fat, higher C-reactive protein and fasting insulin levels. Strong trends for an association with severity of NAFLD grade were also seen for higher IGFBP-1 levels, % truncal fat, HGH levels, and continuous glucose monitoring profiles. We now propose to carry out detailed assessments of these and other markers of subclinical inflammation, insulin sensitivity, insulin-like growth factor axis and assessments of anthropometry in patients with grades 1-3 of NAFLD and in controls. Our second hypothesis is that the inflammation and progressive fibrosis that can occur in NAFLD are substantially due to increased oxidative stress. The second specific aim is to determine the mechanism and effects of increased oxidative stress in NAFLD. Oxidative stress is thought to be central to hepatocellular injury in NAFLD. Our preliminary data demonstrate a possible pre-transcriptional basis of increased oxidative stress in patients with more histologically progressive NASH. In a logical extension of these experiments, we now propose to use high-throughput mass spectrometry analysis, using an ICAT tagging technique, to measure differential hepatic protein abundance, including of peroxisomal proteins, in patients with NAFLD grades 1-3, and also in controls. We believe that these experiments will generate mechanistic insight into the cause and effects of increased oxidative stress in patients with histologically progressive NAFLD.

描述（由申请人提供）：非酒精性脂肪肝病 (NAFLD) 是美国最常见的肝病形式。 NAFLD 的高患病率很大程度上是由于肥胖和胰岛素抵抗患病率的不断增加。部分 NAFLD 患者进行性组织学损伤的基础尚不清楚。该项目的总体目标是 1) 开发一个模型来识别组织学级别更严重的 NAFLD 患者，2) 更好地定义 NAFLD 组织学进展的病理生理学基础。为了实现这些目标，我们提出了两个假设和具体目标。我们的第一个假设是，胰岛素敏感性、高胰岛素血症和/或亚临床炎症指数可用于生成一个模型，该模型能够识别组织学上更严重级别的 NAFLD 风险增加的患者。第一个具体目标是前瞻性筛选一组生物参数，以确定其是否能够识别具有组织学严重 NAFLD 风险的患者（按 NAFLD 等级衡量）。在一项针对不同严重程度的 NAFLD 患者的初步研究中，我们发现组织学上更严重的 NAFLD 与更高的体脂百分比、更高的 C 反应蛋白和空腹胰岛素水平独立相关。较高的 IGFBP-1 水平、躯干脂肪百分比、HGH 水平和连续血糖监测曲线也显示出与 NAFLD 严重程度相关的强烈趋势。我们现在建议对 1-3 级 NAFLD 患者和对照组的这些和其他亚临床炎症标志物、胰岛素敏感性、胰岛素样生长因子轴以及人体测量学评估进行详细评估。我们的第二个假设是 NAFLD 中可能发生的炎症和进行性纤维化主要是由于氧化应激增加所致。第二个具体目标是确定 NAFLD 中氧化应激增加的机制和影响。氧化应激被认为是 NAFLD 肝细胞损伤的核心。我们的初步数据表明，组织学进展程度较高的 NASH 患者氧化应激增加可能存在转录前基础。在这些实验的逻辑扩展中，我们现在建议使用高通量质谱分析，使用 ICAT 标记技术来测量 1-3 级 NAFLD 患者以及对照组的差异肝蛋白丰度，包括过氧化物酶体蛋白。我们相信，这些实验将深入了解组织学进展型 NAFLD 患者氧化应激增加的原因和影响。