Role of oxidized linoleic acid metabolites in the pathogenesis of alcoholic liver disease

酒精性肝病(ALD)是世界上发病率和死亡率的主要原因之一， 每年影响全球数百万患者。尽管ALD的发病机制取得了进展，但特异性的 肌萎缩侧索硬化症的发生发展机制(S)仍然知之甚少。重要的是，在那里 FDA是否没有批准对ALD的任何阶段进行治疗。我们实验室和其他实验室最近的研究表明 研究表明，饮食中的不饱和脂肪，特别是富含亚油酸(LA)的脂肪，加剧了酒精介导的 实验性酒精性肝病动物模型的肝脏和肠道损伤。我们的初步数据显示， 循环氧化LA代谢物，特别是9-和13-羟基十八碳二烯酸(9-和13-Hodes) 在肝脏12/15脂氧合酶(12/15-LO)上调的同时，一个关键酶参与了 LA的氧化。这些发现使我们假设特定的氧化LA代谢物(OXLAM)可能 在肌萎缩侧索硬化症中起重要作用。OXLAM是瞬时受体电位香草素1的天然配体 (TRPV1)，一种配体门控的非选择性阳离子通道，对钙离子具有高通透性。最新研究 展示了钙离子释放在炎症体激活中的关键作用，这是 应激源诱导的致病机制，一旦激活，就会触发高度促炎因子的释放 细胞因子白介素1和白介素18。IL-1的释放被认为是一种关键的调节因子 因此，它可作为治疗ALD肝脏炎症的潜在靶点。基座 根据我们自己和其他已发表的研究结果，我们的中心假设是OXLAM在 在ALD的发生发展中的作用。我们假设OXLAM对乙醇有贡献- 通过两种机制诱导肝脏炎症和损伤：1)OXLAMS介导的线粒体 功能障碍和肝细胞死亡；2)OXLAM/TRPV1/Ca~(2+)介导的炎症体激活和 IL-1？释放。拟议的研究将有助于更好地理解导致 酒精性肝脏炎症和损伤的发病机制。这些研究也将帮助我们更好地 了解酒精与饮食的相互作用，这可能有助于确定新的治疗靶点和潜力 饮食干预治疗ALD，以及有助于解释为什么只有一些酗酒的人 发展为临床上重要的ALD。体外、体内动物(基因敲除和嵌合小鼠)的组合 模型)和人体研究将被采用。

Alcoholic liver disease (ALD) ranks among the major causes of morbidity and mortality in the world, and affects millions of patients worldwide each year. Despite the progress made on ALD pathogenesis, the specific mechanism(s) responsible for ALD development and progression remain poorly understood. Importantly, there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others have demonstrated that dietary unsaturated fat, specifically rich in linoleic acid (LA), exacerbated alcohol-mediated liver and intestinal injury in an experimental animal model of ALD. Our preliminary data show elevated levels of circulating oxidized LA metabolites, specifically 9- and 13-hydroxy-octadecadienoic acids (9-and 13-HODEs) in parallel with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO), a key enzyme involved in the oxidation of LA. These findings have led us to postulate that specific oxidized LA metabolites (OXLAMs) may play a significant role in ALD. OXLAMs are natural ligands to the transient receptor potential vanilloid 1 (TRPV1), a ligand-gated non-selective cation channel with high permeability for Ca2+. Recent studies demonstrate a critical role for Ca2+ release in inflammasome activation, which are key signaling platforms for stressor-induced pathogenesis, and which, upon activation, trigger the release of highly pro-inflammatory cytokines interleukin-1¿ (IL-1¿) and interleukin-18 (IL-18). IL-1¿ release is thought to be a critical mediator of inflammation and thus, serves as a potential therapeutic target for treating hepatic inflammation in ALD. Based on our own and other published findings, our CENTRAL HYPOTHESIS is that OXLAMs play a significant role in the development and progression of ALD. We hypothesize that OXLAMs contribute to the EtOH- induced hepatic inflammation and injury via two mechanisms: 1) OXLAMs-mediated mitochondrial dysfunction and hepatocyte death; and 2) OXLAM/TRPV1/Ca2+-mediated inflammasome activation and IL-1¿ release. The proposed studies will lead to better understanding of molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. These studies will also help us to better understand alcohol-diet interactions, which may lead to identification of new therapeutic targets and potential dietary interventions for treating ALD, as well as help to explain why only some people who drink heavily develop clinically important ALD. A combination of in vitro, in-vivo animal (knockouts and chimeric mouse models) and human studies will be employed.