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， 每年影响全世界数百万患者。尽管在ALD发病机制方面取得了进展，但特定的 对ALD发展和进展的机制仍然知之甚少。重要的是 没有FDA批准的治疗ALD的任何阶段。我们实验室和其他机构最近的研究表明， 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， ALD实验动物模型中肝脏和肠道损伤。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-HODE）， 与肝12/15脂氧合酶（12/15-LO）的上调平行，12/15-LO是参与肝硬化的关键酶。 氧化LA。这些发现使我们假设特定的氧化LA代谢物（OXLAM）可能 在ALD中发挥重要作用。OXLAM是瞬时受体电位香草酸1的天然配体 TRPV 1是一种配体门控的非选择性阳离子通道，对Ca 2+具有高渗透性。最近的研究 证明了Ca 2+释放在炎性小体激活中的关键作用，这是炎性小体激活的关键信号平台。 应激诱导的发病机制，并在激活后，触发释放高度促炎性 细胞因子白细胞介素-1 <$（IL-1 <$）和白细胞介素-18（IL-18）。IL-1的释放被认为是一个关键的调解人， 因此，它是治疗ALD中肝脏炎症的潜在治疗靶点。基于 根据我们自己的和其他已发表的研究结果，我们的中心假设是，奥克斯拉姆发挥了重要的作用。 在ALD的发展和进展中的作用。我们假设OXLAM有助于EtOH- 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;和2）OXLAM/TRPV 1/Ca 2+介导的炎性小体活化和 IL-1释放。拟议的研究将有助于更好地理解有助于 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，这可能导致识别新的治疗靶点和潜在的 饮食干预治疗ALD，以及帮助解释为什么只有一些人谁喝得很多， 出现临床上重要的ALD。体外、体内动物（敲除和嵌合小鼠）的组合 模型）和人类研究将被采用。

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.