Targeting Uric Acid as a Therapeutic for NASH

以尿酸为靶标治疗 NASH

基本信息

批准号：
10364671
负责人：
Eric Eugene Kelley
金额：
$ 33.69万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10364671
关键词：
Acids Anti-Inflammatory Agents Benign Cardiovascular Diseases Catabolism Cholesterol Chronic Kidney Failure Cirrhosis Clinical Complex Data Diet Disease Dyslipidemias Enzymes Epidemic FDA approved Fatty Liver Fatty acid glycerol esters Fibrosis Fructose Functional disorder Generations Genetic Models Hepatic Hyperuricemia Increased Uric Acid Level Inflammation Inflammatory Injury Insulin Resistance Isomerism Knowledge Liver Failure Liver diseases Malignant Neoplasms Mediating Mediator of activation protein Metabolic Diseases Metabolic syndrome Metabolism Mitochondria Modeling Mus Nitrogen Dioxide Non-Insulin-Dependent Diabetes Mellitus Obesity Oleic Acids Outcome Pathogenesis Pathogenicity Pathologic Pathway interactions Pharmaceutical Preparations Pharmacology Phase II Clinical Trials Phenotype Play Production Property Publications Purines Reactive Oxygen Species Research Risk Risk Factors Role Scheme Stress System Testing Therapeutic Urate Oxidase Uric Acid Xanthine Oxidase adult obesity analog chronic liver disease fast food febuxostat feeding improved insulin sensitivity metabolome mitochondrial dysfunction non-alcoholic fatty liver disease nonalcoholic steatohepatitis novel novel therapeutics overexpression prevent protective effect response simple steatosis

项目摘要

Non-alcoholic fatty liver disease (NAFLD) is the most prevalent chronic liver disease. The most common risk factors associated with NAFLD are obesity, type 2 diabetes and dyslipidemia, with 80-90% of obese adults developing NAFLD. Simple steatosis is generally inert pathologically but in the presence of inflammation, defined as non-alcoholic steatohepatitis (NASH), is a gateway to more severe forms of liver disease including cirrhosis and liver failure. As waistlines continue to expand, NAFLD is now considered the next global epidemic, as it is associated with increased risk of metabolic syndrome, cardiovascular disease and cancer. Two of the largest untargeted metabolome studies revealed uric acid (UA) as the most significant metabolite associated with obesity and is a better predictor than the next six metabolites combined. UA is generated solely from xanthine oxidase (XO) during the catabolism of purines. Recent publications and preliminary data herein reveal that XO activity is increased in conjunction with UA in obesity and in clinical and experimental NAFLD. During this catabolism of purines by XO, toxic reactive oxygen species (ROS) are generated that can damage biomolecules and contribute to injury. Indeed, the current dogma is that ROS generated from XO are directly responsible for this enzyme’s injurious role in inflammation and injury. However, this dogma ignores the fact that UA also is a toxic species that induces inflammation, mitochondrial dysfunction and ROS generation in other diseases. Whether or not UA plays a similar deleterious role in NAFLD remains unclear. Elucidating whether ROS or UA is the predominant XO-derived toxic metabolite in NAFLD pathogenesis fills critical gaps in knowledge and reveals new therapeutic options. A longitudinal mouse study revealed that a fast food diet (FFD) consisting of high- fat, -fructose and - cholesterol recapitulates the NASH phenotype observed clinically. It is believed that fructose metabolism activates the purine catabolism pathway (via XO) resulting in the culmination of UA although the exact mechanism is unclear. Therefore, we will test the hypothesis this fast food diet leads to hyperuricemia and promotes the progression of NAFLD to NASH. To test this hypothesis, these aims will be tested: (1)- Determine whether hyperuricemia is causally responsible for mitochondrial stress, insulin resistance and hepatic steatosis in experimental NAFLD/NASH; and (2)-Determine whether pharmacologically targeting XO is sufficient enough to slow the progression from NAFLD to NASH. Understanding the pathophysiology of hyperuricemia and whether it directly causes mitochondrial dysfunction resulting in the progression of NAFLD to NASH will fill critical knowledge gaps. Additionally, successful outcomes will determine if inhibiting XO (novel target) with febuxostat is sufficient enough to protect against NAFLD/NASH or a one drug-multiple target approach using nitro-oleic acid will provide better responses for diseases that display complex, multifactorial pathogenesis such as NASH.

非酒精性脂肪肝病（NAFLD）是最常见的慢性肝病，也是最常见的风险。与 NAFLD 相关的因素有肥胖、2 型糖尿病和血脂异常，其中 80-90% 的成年人肥胖单纯性脂肪变性在病理上通常是惰性的，但存在炎症，定义为非酒精性脂肪性肝炎 (NASH)，是导致更严重的肝病的途径，包括随着腰围不断扩大，NAFLD 现在被认为是下一个全球性的疾病。流行病，因为它与代谢综合征、心血管疾病和癌症的风险增加有关。两项最大的非靶向代谢组研究表明尿酸（UA）是最重要的代谢物与肥胖相关，并且是比接下来的六种代谢物组合更好的预测因子。仅来自嘌呤分解代谢过程中的黄嘌呤氧化酶（XO）。最近的出版物和初步数据。本文揭示，在肥胖症以及临床和实验中，XO 活性与 UA 一起增加 NAFLD 在 XO 分解代谢过程中，会产生有毒的活性氧 (ROS)。事实上，当前的教条是 XO 生成的 ROS 是然而，这种教条忽视了这种酶在炎症和损伤中的有害作用。事实上，UA 也是一种有毒物质，会引起炎症、线粒体功能障碍和 ROS UA 是否在 NAFLD 中发挥类似的有害作用尚不清楚。阐明 ROS 或 UA 是否是 NAFLD 发病机制中主要的 XO 衍生有毒代谢物知识的关键差距并揭示新的治疗选择。一项纵向小鼠研究表明，快餐饮食 (FFD) 包含高脂肪、果糖和胆固醇概括了临床上观察到的 NASH 表型，据认为与果糖代谢有关。激活嘌呤分解代谢途径（通过 XO），导致 UA 达到顶峰，尽管确切的因此，我们将检验快餐饮食导致高尿酸血症的假设。促进 NAFLD 进展为 NASH。为了检验这一假设，将检验以下目标：(1)- 确定高尿酸血症是否与线粒体应激、胰岛素抵抗和实验性 NAFLD/NASH 中的肝脂肪变性；以及 (2)-确定药物靶向 XO 是否有效足以减缓从 NAFLD 到 NASH 的进展。高尿酸血症及其是否直接导致线粒体功能障碍导致病情进展此外，NAFLD 到 NASH 将填补关键的知识空白。用非布索坦抑制 XO（新靶点）足以预防 NAFLD/NASH 或使用硝基油酸的一种药物多靶点方法将为以下疾病提供更好的反应显示复杂、多因素的发病机制，例如 NASH。