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，从简单的脂肪变性到严重的脂肪变性。 肝硬化肥胖和超重与ALD的严重程度密切相关。乙醇诱导 氧化应激是乙醇诱导肝损伤的主要机制。CYP 2 E1增加和降低 SOD 1活性导致乙醇喂养条件下超氧化物水平增加。虽然氧化应激 这似乎是一个共同的机制，肥胖与ALD，氧化应激的作用，引发的 超氧化物在调节肥胖相关ALD发病机制中的作用尚不清楚。此外， 抗氧化剂在调节肥胖症ALD进展中的作用在很大程度上仍然未知。我们最近报道 纳米铜/锌超氧化物歧化酶（nanoSOD）可减轻脂肪组织炎症 和肥胖症中的非酒精性脂肪性肝病（NAFLD）。我们的初步数据显示， 乙醇和亚油酸（LA），膳食中的多不饱和脂肪酸，诱导氧化应激的主要 肝细胞和CYP 2 E1过表达的HepG 2细胞。我们的数据还表明，乙醇和LA在 联合诱导HF饮食喂养的脂肪变性肝细胞中氧化应激的显著增加 大鼠，表明NAFLD的存在可加重乙醇诱导的肝损伤。我们还提供 来自慢性乙醇喂养大鼠的原代肝细胞显示氧化应激增加的证据 与用nanoSOD减毒的对照相比。最后，我们提供了一个可能的作用证据， AMPK信号转导介导nanoSOD的抗脂肪变性作用。这些数据表明， SOD对肝细胞有明显的保护作用，可减轻超氧化物歧化酶诱导的肝损伤。因为新陈代谢 乙醇和游离脂肪酸产生超氧自由基，我们假设，在肥胖的存在， 增强超氧化物的产生，导致增强的肝损伤，并在一种新的纳米- 包封形式减弱肥胖相关的ALD。本申请中提出的研究将采取 生理学、药理学和分子学方法来研究如何使用 nanoSOD将影响ALD的发展，无论是否肥胖。在具体目标1中，我们将确定 nanoSOD在向肝细胞递送活性SOD以及清除乙醇和LA诱导的作用 肝细胞超氧化物。在具体目标2中，我们将确定肝细胞SOD 1缺失对 伴有或不伴有肥胖的ALD的进展以及nanoSOD改善乙醇的有效性 和/或肥胖诱导的ALD。这些发现将有助于确定超氧化物在调节细胞凋亡中的作用。 肥胖相关ALD的发病机制和纳米抗氧化酶在肥胖相关ALD中的治疗潜力 在存在或不存在肥胖的情况下治疗ALD。