Targeting Uric Acid as a Therapeutic for NASH

以尿酸为靶标治疗 NASH

• 批准号: 10152586
• 负责人: Eric Eugene Kelley
• 金额: $ 33.75万
• 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/10152586
• 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

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。最常见的风险 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 发展非酒精性脂肪肝。单纯性脂肪变性在病理上通常是惰性的，但在存在炎症的情况下， 被定义为非酒精性脂肪性肝炎(NASH)，是导致更严重形式的肝病的门户，包括 肝硬变和肝功能衰竭。随着腰围的持续扩大，NAFLD现在被认为是下一个全球 流行，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显示尿酸(UA)是最重要的代谢物 与肥胖有关，比接下来的六种代谢物加起来更能预测。已生成UA 在嘌呤的分解代谢过程中，仅由黄嘌呤氧化酶(XO)引起。近期出版物和初步数据 这揭示了XO活性在肥胖以及临床和实验中与尿酸一起增加。 NAFLD。在XO分解嘌呤的过程中，会产生有毒的活性氧(ROS)，它可以 破坏生物分子，造成伤害。事实上，当前的教条是，从XO生成的RO是 对这种酶在炎症和损伤中的有害作用负有直接责任。然而，这一教条忽视了 尿酸也是一种有毒物种，会导致炎症、线粒体功能障碍和ROS 在其他疾病中生成。UA是否在NAFLD中起着类似的有害作用尚不清楚。 阐明ROS或UA是NAFLD发病机制中主要的XO衍生毒性代谢物 关键的知识差距，并揭示了新的治疗选择。 一项纵向的老鼠研究表明，快餐饮食(FFD)由高脂肪、-果糖和- 胆固醇概括了临床观察到的Nash表型。据认为，果糖代谢 激活嘌呤分解代谢途径(通过XO)，导致UA达到顶峰，尽管准确的 机制尚不清楚。因此，我们将检验这种快餐饮食会导致高尿酸血症和 促进NAFLD向NASH的进展。为了验证这一假设，我们将测试以下目标：(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中的肝脏脂肪变性；以及(2)-确定药物靶向XO是否 足以减缓从NAFLD到NASH的进程。了解心绞痛的病理生理学 高尿酸血症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，成功的结果将决定是否 用非布索他汀抑制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对以下疾病提供更好的反应 表现为复杂、多因素的发病机制，如NASH。