Oxidized Metabolites of Linoleic Acid in Alcohol-induced Liver Injury

酒精性肝损伤中亚油酸的氧化代谢物

• 批准号: 9093663
• 负责人: Ariel Feldstein
• 金额: $ 34.47万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-01 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9093663
• 关键词: Adipose tissue; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Animals; Arachidonate 15-Lipoxygenase; Arts; Attenuated; Biochemical Pathway; Biological Markers; Blood Circulation; Cell Culture Techniques; Cell model; Cessation of life; Chronic; Chronic Disease; Clinical; Clinical Trials; Collaborations; Data; Development; Diet; Disease; Disease Marker; Electrospray Ionization; Endotoxins; Ethanol; Experimental Animal Model; Experimental Models; Extramural Activities; Fatty Acids; Fatty Liver; Fibrosis; Functional disorder; Genus Hippocampus; Goals; Health; Heavy Drinking; Hepatic; Hepatocyte; High Fat Diet; High Pressure Liquid Chromatography; Histopathology; Human; In Vitro; Inflammatory; Inflammatory Response; Injury; Intake; Intestines; Investigation; Knock-in Mouse; Knock-out; Knockout Mice; Linoleic Acids; Liver; Liver diseases; Magnetic Resonance Imaging; Mediating; Mediator of activation protein; Mitochondria; Modeling; Monitor; Mus; Muscle; National Institute on Alcohol Abuse and Alcoholism; Nutritional; Outcome; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Permeability; Plasma; Play; Polyunsaturated Fatty Acids; Population; Production; Randomized Controlled Trials; Resources; Rodent; Role; Sampling; Serum; Severities; Severity of illness; Steatohepatitis; System; Techniques; Technology; Testing; Therapeutic Intervention; Tight Junctions; Time; Tissues; United States National Institutes of Health; Whole Blood; Wild Type Mouse; alcohol research; base; biomarker development; cellular imaging; cytokine; dietary control; drug development; feeding; gain of function; in vitro Model; in vivo; intervention effect; intestinal epithelium; liver inflammation; liver injury; loss of function; monocyte; mortality; mouse model; novel; novel therapeutic intervention; oxidation; programs; randomized trial; tandem mass spectrometry; targeted biomarker; tool

DESCRIPTION (provided by applicant): This is a resubmission of an Extramural/Intramural Alcohol Research Collaboration (U01) Application entitled "Oxidized Metabolites of Linoleic Acid in Alcohol-induced Liver Injury". Alcoholic liver disease (ALD) remains a major cause of chronic illness and death. Despite extensive investigation into ALD pathogenesis, the specific mechanisms responsible for development and progression are incompletely understood. Increased oxidative stress is a core abnormality responsible for liver injury in ALD. Based on our extensive preliminary findings we propose the CENTRAL HYPOTHESIS that oxidized linoleic acid (LA) metabolites (OXLAMs) generated via the 12/15-LO mediated pathway play a critical role in the development and progression of alcohol-mediated hepatic and intestinal injury. We have established a collaborative team with extensive expertise and unique resources that will allow us to accomplish our goals by using in vivo experimental animal models of ALD, in vitro cell culture models, and collaborating with the unique human populations of an ongoing NIAAA Clinical Center randomized trial on dietary linoleic acid (LA) reduction and an NIAAA sponsored U01 clinical trial on alcoholic hepatitis (AH). State-of-the-art technologies including Lipidomics (LC/ESI/MS/MS), Seahorse (to investigate mitochondria dysfunction), Cellomics (the high-throughput technique for cell image-acquisition and analysis) will be utilized in this proposal. FIRST, we will test the hypothesis that OXLAMs are specific mediators of liver damage and intestinal barrier disruption in ALD. We will establish the role of dietary LA and OXLAMs in the induction of hepatic steatosis/injury and intestinal hyper-permeability in murine models of ALD. SECOND, we will evaluate in in vitro systems potential mechanisms by which OXLAMs enhance ethanol-mediated liver damage and disruption of intestinal barrier integrity. We will determine the effect of OXLAMs and their interactions with alcohol on mitochondrial function in hepatocytes and integrity of tight junctions in intestinal epithelium. THIRD, we will evaluate the ability of controlled dietary lowering of LA in humans to reduce circulating OXLAMs, endotoxin/gut permeability, and liver steatosis/injury (NIAAA intramural RCT). We will test the hypothesis that, compared to a control diet containing 8 % of energy as LA, lowering LA to 1% of energy for 12 weeks will result in significant reductions in: liver steatosis assessed by 3T-MRI; OXLAM and LA content of plasma, circulating endotoxin, and serum CK-18 (total and fragmented) levels (two robust markers of hepatocyte injury). FINALLY, we will establish levels of OXLAMs in human Alcoholic Hepatitis and their relation to disease severity and mortality (NIAAA U01 program). This study will help to elucidate a novel biochemical pathway involved in the pathogenesis of ALD. The findings could provide novel targets for biomarkers and drug development, and could identify a potential nutritional strategy for ameliorating liver disease.

描述（由申请人提供）：这是一个重新提交的校外/校内酒精研究合作（U 01）申请，题为“氧化代谢的亚油酸在酒精诱导的肝损伤”。酒精性肝病（ALD）仍然是慢性疾病和死亡的主要原因。尽管对ALD的发病机制进行了广泛的研究，但对发展和进展的具体机制仍不完全了解。氧化应激增加是导致ALD肝损伤的核心异常。基于我们广泛的初步研究结果，我们提出了中心假说，即通过12/15-LO介导的途径产生的氧化亚油酸（LA）代谢产物（OXLAMs）在酒精介导的肝和肠损伤的发生和进展中起关键作用。我们已经建立了一个具有广泛专业知识和独特资源的合作团队，这将使我们能够通过使用ALD的体内实验动物模型，体外细胞培养模型，并与正在进行的NIAAA临床中心关于饮食亚油酸（LA）减少的随机试验和NIAAA赞助的U 01酒精性肝炎（AH）临床试验的独特人群合作来实现我们的目标。本提案将利用最先进的技术，包括脂质组学（LC/ESI/MS/MS），Seahorse（研究线粒体功能障碍），Cellomics（用于细胞图像采集和分析的高通量技术）。首先，我们将测试假设OXLAM是ALD中肝损伤和肠屏障破坏的特异性介质。我们将在ALD小鼠模型中确定饮食LA和OXLAM在诱导肝脂肪变性/损伤和肠通透性过高中的作用。第二，我们将在体外系统中评估OXLAM增强乙醇介导的肝损伤和肠屏障完整性破坏的潜在机制。我们将确定OXLAM及其与酒精的相互作用对肝细胞线粒体功能和肠上皮细胞紧密连接完整性的影响。第三，我们将评估在人类中控制饮食降低LA以减少循环OXLAM、内毒素/肠渗透性和肝脂肪变性/损伤的能力（NIAAA壁内RCT）。我们将检验以下假设：与含有8%能量作为LA的对照饮食相比，将LA降低至1%能量持续12周将导致以下方面的显著降低：通过3 T-MRI评估的肝脏脂肪变性;血浆中OXLAM和LA含量、循环内毒素和血清CK-18（总和片段）水平（肝细胞损伤的两种稳健标志物）。最后，我们将确定人类酒精性肝炎中OXLAM的水平及其与疾病严重程度和死亡率的关系（NIAAA U 01计划）。这项研究将有助于阐明一种新的生化途径参与ALD的发病机制。这些发现可以为生物标志物和药物开发提供新的靶点，并可以确定改善肝脏疾病的潜在营养策略。