Oxidized Linoleic Acid metabolites (OXLAMs) play a critical role in the development and progression of alcohol-mediated hepatic injury

氧化亚油酸代谢物（OXLAM）在酒精介导的肝损伤的发生和进展中发挥着关键作用

• 批准号: 299295825
• 负责人: Dr. Susanne Gaul
• 金额: --
• 依托单位: Division of Gastroenterology
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/299295825?language=en
• 关键词: Oxidized; Linoleic; Acid; metabolites; OXLAMs

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 thought to be a core abnormality responsible for liver injury in ALD. It is hypothesized that specific oxidation products of linoleic acid (LA), the most abundant polyunsaturated fatty acid in human diets, play a direct causal role in ALD. Oxidation products of LA, called OXLAMs, are formed enzymatically via the action of 12/15-lipoxygenase (12/15-LO). It has been shown that OXLAMs are elevated in the circulation of rodents fed an ethanol diet (Lieber-DeCarli diet) as well as in patients with steatohepatitis and that they lead to mitochondrial dysfunction and Nlrp3 inflammasome activation in WT mice. This project proposes the central hypothesis that OXLAMs generated via the 12/15-LO-mediated pathway play a critical role in the development and progression of alcohol-mediated hepatic injury. Therefore, gain and loss of function approaches will be used (12/15- LO knockout, 12/15- LO knockin, wild-type mice). In vitro studies on primary cells will be performed to determine the effects of OXLAMs and their interactions with alcohol on mitochondrial function and Nlrp3 inflammasome activation. This project will help to elucidate a novel biochemical pathway involved in the pathogenesis of ALD. If successful, the findings could provide novel targets for both biomarker and drug development, and could identify a potential nutritional strategy for ameliorating liver disease.

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。氧化应激增加被认为是导致ALD肝损伤的核心异常。据推测，亚油酸（LA），在人类饮食中最丰富的多不饱和脂肪酸的特定氧化产物，在ALD中发挥直接的因果作用。LA的氧化产物，称为OXLAM，通过12/15-脂氧合酶（12/15-LO）的作用酶促形成。已经表明，OXLAM在喂食乙醇饮食（Lieber-DeCarli饮食）的啮齿动物的循环中以及在患有脂肪性肝炎的患者中升高，并且它们导致WT小鼠中的线粒体功能障碍和Nlrp 3炎性小体激活。该项目提出了一个中心假设，即通过12/15-LO介导的途径产生的OXLAMs在酒精介导的肝损伤的发生和进展中起关键作用。因此，将使用功能获得和丧失方法（12/15- LO敲除、12/15- LO敲入、野生型小鼠）。对原代细胞进行体外研究以确定OXLAM及其与醇的相互作用对线粒体功能和Nlrp 3炎性小体活化的影响。该项目将有助于阐明ALD发病机制中的一种新的生化途径。如果成功，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。

项目成果

Effects of diets enriched in linoleic acid and its peroxidation products on brain fatty acids, oxylipins, and aldehydes in mice.

• DOI: 10.1016/j.bbalip.2018.07.007
• 发表时间: 2018-10
• 期刊: Biochimica et biophysica acta. Molecular and cell biology of lipids
• 作者: Ramsden CE;Hennebelle M;Schuster S;Keyes GS;Johnson CD;Kirpich IA;Dahlen JE;Horowitz MS;Zamora D;Feldstein AE;McClain CJ;Muhlhausler BS;Makrides M;Gibson RA;Taha AY
• 通讯作者: Taha AY

Dietary Linoleic Acid and Its Oxidized Metabolites Exacerbate Liver Injury Caused by Ethanol via Induction of Hepatic Proinflammatory Response in Mice.

• DOI: 10.1016/j.ajpath.2017.06.008
• 发表时间: 2017-10
• 期刊: The American journal of pathology
• 作者: D. Warner;Huilin Liu;M. Miller;C. Ramsden;B. Gao;A. Feldstein;Susanne Schuster;C. McClain;I. Kirpich