The Effectiveness of NanoSOD in Ameliorating Ethanol-induced Liver Injury in Obesity

NanoSOD 在改善肥胖者乙醇引起的肝损伤方面的功效

• 批准号: 9388032
• 负责人: Saraswathi Viswanathan
• 金额: $ 18.11万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2019-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9388032
• 关键词: Adipose tissue; Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Antioxidants; Attention; Attenuated; Body Weight; C57BL/6 Mouse; CYP2E1 gene; Calories; Cells; Chronic; Cirrhosis; Cytochrome P450; Data; Development; Diet; Disease; Drug Stability; Effectiveness; Environmental Risk Factor; Enzymes; Ethanol; Ethanol Metabolism; Exhibits; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Generations; Goals; Half-Life; HepG2; Hepatocyte; Impairment; Inflammation; Inflammatory; Injury; Kupffer Cells; Lead; Link; Linoleic Acids; Liver; Liver diseases; Macrophage Activation; Measures; Mediating; Metabolism; Molecular; Mus; Nanotechnology; Nonesterified Fatty Acids; Obesity; Oxidative Stress; Pathogenesis; Pathologic; Pharmacology; Physiological; Play; Polyunsaturated Fatty Acids; Prevalence; Process; Production; Proteins; Rattus; Reporting; Research; Role; Severities; Signal Transduction; Source; Steatohepatitis; Stimulus; Superoxides; Therapeutic; Therapy Clinical Trials; Vitamins; antioxidant enzyme; antioxidant therapy; attenuation; base; copper zinc superoxide dismutase; enzyme therapy; experimental study; fatty acid oxidation; hepatoma cell; improved; in vivo; insight; lipid metabolism; liver development; liver injury; member; mouse model; nanoencapsulated; nanomedicine; non-alcoholic fatty liver; novel; novel therapeutics; prevent; problem drinker; superoxide dismutase 1; therapeutic target

Project Summary Alcoholic liver disease (ALD) encompasses a spectrum of injury, ranging from simple steatosis to serious cirrhosis. Obesity and excess body weight is strongly associated with the severity of ALD. Ethanol-induced oxidative stress is a major mechanism by which ethanol induces liver injury. Increased CYP2E1 and reduced SOD1 activity leads to increased levels of superoxide in ethanol-fed conditions. Although oxidative stress appears to be a common mechanism linking obesity with ALD, the role of oxidative stress initiated by superoxide in modulating the pathogenesis of obesity-linked ALD is unclear. Moreover, the potential role of antioxidants in modulating the progression of ALD in obesity remains largely unknown. We recently reported that nanoformulated copper/zinc superoxide dismutase (nanoSOD) attenuates adipose tissue inflammation and non-alcoholic fatty liver disease (NAFLD) in obesity. Our preliminary data show that a combination of ethanol and linoleic acid (LA), a dietary polyunsaturated fatty acid, induced oxidative stress in primary hepatocytes and CYP2E1 over-expressing HepG2 cells. Our data also show that ethanol and LA in combination evoked profound increase in oxidative stress in steatotic hepatocytes derived from HF diet-fed rats, indicating that the presence of NAFLD can exacerbate ethanol-induced liver injury. We also provide evidence that primary hepatocytes derived from chronic ethanol-fed rats displayed increased oxidative stress compared to control which was attenuated by nanoSOD. Finally, we provide evidence for a possible role of AMPK signaling in mediating the anti-steatotic effects of nanoSOD. Together, these data suggest that delivery of SOD to hepatocytes is effective in ameliorating superoxide-induced liver injury. Because the metabolism of ethanol and FFAs generate superoxide radicals, we hypothesize that ethanol in the presence of obesity enhances superoxide generation, resulting in enhanced liver injury, and that delivery of SOD in a novel nano- encapsulated form attenuates obesity-associated ALD. The studies proposed in this application will take physiological, pharmacological, and molecular approaches to investigate how reduction of superoxide using nanoSOD will impact the development of ALD with or without obesity. In Specific Aim 1, we will determine the role of nanoSOD in delivering active SOD to hepatocytes and in scavenging ethanol plus LA-induced superoxide in hepatocytes. In Specific Aim 2, we will determine the impact of hepatocyte SOD1 deletion on the progression of ALD with or without obesity and the effectiveness of nanoSOD in ameliorating ethanol and/or obesity-induced ALD. The findings will be relevant to define the role of superoxide in modulating the pathogenesis of obesity-linked ALD and the therapeutic potential of nanoformulated antioxidant enzymes in treating ALD in the presence or absence of obesity.

项目摘要 酒精性肝病（ALD）包括一系列损伤，从简单的脂肪变形到严重 肝硬化。肥胖和体重过剩与ALD的严重程度密切相关。乙醇引起的 氧化应激是乙醇诱导肝损伤的主要机制。增加CYP2E1并减少 SOD1活性导致乙醇喂养条件下的超氧化物水平升高。虽然氧化应激 似乎是将肥胖与ALD联系起来的常见机制，是由氧化应激的作用 超氧化物调节肥胖连接ALD的发病机理尚不清楚。而且， 调节肥胖症中ALD进展的抗氧化剂在很大程度上未知。我们最近报道 纳米制造的铜/锌超氧化物歧化酶（纳米编码）减弱了脂肪组织炎症 肥胖症中的非酒精性脂肪肝病（NAFLD）。我们的初步数据表明 乙醇和亚油酸（LA）是一种饮食多不饱和脂肪酸，诱导原代氧化应激 肝细胞和CYP2E1过表达HEPG2细胞。我们的数据还表明乙醇和洛杉矶 联合诱发了来自HF饮食喂养的脂肪变性肝细胞中氧化应激的大幅增加 大鼠表明NAFLD的存在会加剧乙醇诱导的肝损伤。我们也提供 证据表明源自慢性乙醇喂养大鼠的原发性肝细胞表现出增加的氧化应激 与对照相比，该对照被纳米编码减弱。最后，我们提供证据证明 AMPK信号传导在介导纳米编码的抗溶木作用时。这些数据一起表明交付 肝细胞的SOD可有效改善超氧化物诱导的肝损伤。因为 乙醇和FFA会产生超氧化物自由基，我们假设在肥胖存在的情况下乙醇 增强超氧化物的产生，从而增加肝损伤，并在新型纳米中递送SOD 封装形式减弱了与肥胖相关的ALD。本应用程序中提出的研究将进行 生理，药理和分子方法研究如何使用超氧化物的还原 纳米编号会影响有或没有肥胖症的ALD的发展。在特定目标1中，我们将确定 纳米录在将肝细胞和清除乙醇加LA诱导的肝细胞的活性SOD中的作用 肝细胞中的超氧化物。在特定目标2中，我们将确定肝细胞SOD1删除对 有或没有肥胖症的ALD的进展以及纳米编码在改善乙醇中的有效性 和/或肥胖引起的ALD。这些发现将与定义超氧化物在调节该的作用有关 肥胖连锁ALD的发病机理和纳米成型抗氧化剂在中的治疗潜力 在存在或不存在肥胖症的情况下治疗ALD。