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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要酒精性肝病 (ALD) 涵盖一系列损伤，从简单的脂肪变性到严重的肝硬化。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引起肝损伤的主要机制。 CYP2E1 增加并减少 SOD1 活性会导致乙醇喂养条件下超氧化物水平升高。尽管氧化应激似乎是肥胖与酒精性肝病（ALD）之间的一种常见机制，氧化应激的作用是由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，潜在的作用抗氧化剂在调节肥胖中 ALD 进展方面的作用仍然很大程度上未知。我们最近报道了纳米铜/锌超氧化物歧化酶 (nanoSOD) 可减轻脂肪组织炎症以及肥胖引起的非酒精性脂肪肝（NAFLD）。我们的初步数据表明，结合乙醇和亚油酸（LA）（一种饮食中的多不饱和脂肪酸）诱导初级氧化应激肝细胞和 CYP2E1 过表达的 HepG2 细胞。我们的数据还表明，乙醇和 LA 组合引起来自 HF 饮食喂养的脂肪变性肝细胞氧化应激的显着增加大鼠，表明 NAFLD 的存在会加剧乙醇引起的肝损伤。我们还提供有证据表明，长期喂食乙醇的大鼠的原代肝细胞表现出氧化应激增加与被nanoSOD减弱的对照相比。最后，我们提供了证据来证明 AMPK 信号传导介导 nanoSOD 的抗脂肪变性作用。这些数据共同表明，交付 SOD 进入肝细胞可有效改善超氧化物诱导的肝损伤。因为新陈代谢乙醇和FFA会产生超氧自由基，我们假设乙醇在肥胖的情况下增强超氧化物的生成，导致肝损伤加剧，并且以新型纳米-SOD 的形式输送封装形式可减轻肥胖相关的 ALD。本申请中提出的研究将采取生理学、药理学和分子方法研究如何使用还原超氧化物无论是否患有肥胖症，nanoSOD 都会影响 ALD 的发展。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 诱导的过程中的作用肝细胞中的超氧化物。在具体目标 2 中，我们将确定肝细胞 SOD1 缺失对伴有或不伴有肥胖的 ALD 的进展以及 nanoSOD 在改善乙醇方面的有效性和/或肥胖引起的 ALD。这些发现将有助于定义超氧化物在调节肥胖相关 ALD 的发病机制以及纳米配方抗氧化酶的治疗潜力在存在或不存在肥胖的情况下治疗 ALD。