Targeting Uric Acid as a Therapeutic for NASH

以尿酸为靶标治疗 NASH

• 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
• 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

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.

非酒精性脂肪性肝病（NAFLD）是最常见的慢性肝病。最常见的危险 与NAFLD相关的因素是肥胖、2型糖尿病和血脂异常，80-90%的肥胖成年人 发展NAFLD。单纯性脂肪变性在病理学上通常是惰性的，但在存在炎症的情况下， 定义为非酒精性脂肪性肝炎（NASH），是更严重形式的肝病的门户，包括 肝硬化和肝功能衰竭。随着腰围继续扩大，NAFLD现在被认为是下一个全球性的 它是一种流行病，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学研究显示尿酸（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。UA生成 在嘌呤的催化过程中仅来自黄嘌呤氧化酶（XO）。近期出版物和初步数据 本文揭示了XO活性在肥胖症中以及在临床和实验中与UA一起增加 NAFLD。在XO对嘌呤的这种催化过程中，产生了有毒的活性氧物质（ROS）， 破坏生物分子并造成损伤。事实上，目前的教条是，从XO产生的ROS是 直接导致这种酶在炎症和损伤中的有害作用。然而，这种教条忽视了 UA也是一种毒性物质，可诱导炎症、线粒体功能障碍和ROS 在其他疾病中。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XO衍生的毒性代谢产物， 关键的知识差距，并揭示了新的治疗选择。 一项纵向小鼠研究显示，由高脂肪、高果糖和高脂肪组成的快餐饮食（FFD） 胆固醇概括了临床上观察到的NASH表型。据信果糖代谢 激活嘌呤catalysts途径（通过XO），导致UA的高潮，尽管确切的 机制尚不清楚。因此，我们将检验这种快餐饮食导致高尿酸血症的假设， 促进NAFLD向NASH的进展。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是线粒体应激、胰岛素抵抗和 实验性NAFLD/NASH中的肝脂肪变性;和（2）-确定是否靶向XO的β-内酰胺酶是 足以减缓从NAFLD到NASH的进展。了解的病理生理学 高尿酸血症以及它是否直接导致线粒体功能障碍，从而导致 NAFLD到NASH将填补关键的知识空白。此外，成功的结果将决定 用非布司他抑制XO（新靶点）足以保护免受NAFLD/NASH或 使用硝基油酸的一药多靶方法将为 表现出复杂的多因素发病机制，如NASH。