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

基本信息

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
项目类别：
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

项目摘要

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）：这是题为“酒精性肝损伤中亚油酸氧化代谢物”的校外/校内酒精研究合作 (U01) 申请的重新提交。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 发病机制进行了广泛的研究，但其发生和进展的具体机制尚不完全清楚。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，我们提出中心假设，即通过 12/15-LO 介导途径产生的氧化亚油酸 (LA) 代谢物 (OXLAM) 在酒精介导的肝和肠道损伤的发生和进展中发挥着关键作用。我们建立了一支拥有丰富专业知识和独特资源的协作团队，这将使我们能够通过使用 ALD 体内实验动物模型、体外细胞培养模型以及与正在进行的 NIAAA 临床中心随机化的独特人群合作来实现我们的目标减少膳食亚油酸 (LA) 的试验和 NIAAA 赞助的一项关于酒精性肝炎 (AH) 的 U01 临床试验。该提案将采用最先进的技术，包括脂质组学 (LC/ESI/MS/MS)、Seahorse（用于研究线粒体功能障碍）、细胞组学（用于细胞图像采集和分析的高通量技术）。首先，我们将检验这样的假设：OXLAM 是 ALD 中肝损伤和肠道屏障破坏的特异性介质。我们将确定膳食 LA 和 OXLAM 在 ALD 小鼠模型中诱导肝脂肪变性/损伤和肠道通透性过高中的作用。其次，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紧密连接完整性的影响。第三，我们将评估控制饮食降低人类 LA 减少循环 OXLAM、内毒素/肠道通透性和肝脏脂肪变性/损伤的能力（NIAAA 壁内随机对照试验）。我们将测试以下假设：与含有 8% LA 能量的对照饮食相比，将 LA 降低至 1% 能量持续 12 周将导致以下方面显着减少：通过 3T-MRI 评估的肝脏脂肪变性；血浆中的 OXLAM 和 LA 含量、循环内毒素和血清 CK-18（总和片段）水平（肝细胞损伤的两个强有力的标志物）。最后，我们将确定人类酒精性肝炎中的 OXLAM 水平及其与疾病严重程度和死亡率的关系（NIAAA U01 计划）。这项研究将有助于阐明 ALD 发病机制中的一条新的生化途径。这些发现可以为生物标志物和药物开发提供新的靶标，并可以确定改善肝病的潜在营养策略。