The role of dietary unsaturated fat and inflammasome in alcoholic liver disease

 描述（由申请人提供）：酒精性肝病（ALD）是世界上发病率和死亡率的主要原因。它每年影响全世界数百万患者。虽然 尽管在ALD发病机制方面已经取得了实质性进展，但对ALD发展和进展的具体机制仍然知之甚少。重要的是，没有FDA批准的治疗ALD的任何阶段。我们实验室和其他人最近的研究表明，在ALD的实验动物模型中，与膳食饱和脂肪相比，富含亚油酸（LA）的膳食不饱和脂肪加剧了酒精介导的肠通透性和肝损伤。此外，我们的初步数据显示循环氧化LA代谢物（OXLAM）水平升高，特别是9-和13-羟基-十八碳二烯酸（9-和13-HODE），伴随着肝12/15脂氧合酶（12/15-LO）的上调，该酶是LA氧化的关键酶。这些发现提供了初步证据，OXLAMs，这是天然配体的瞬时受体电位香草素1（TRPV 1，亚家族V成员1），有助于ALD的发病机制。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。最近的一些研究表明，细胞内Ca 2+在炎性小体激活中起着关键作用。NLRP 3炎症体激活并释放高度促炎细胞因子白细胞介素-1 β（IL-1β）和白细胞介素-18（IL-18）是ALD中重要的促炎反应。然而，导致ALD中炎性小体引发和激活的分子机制尚未完全确定。 我们的中心假设是，膳食不饱和脂肪（富含亚油酸）通过氧化亚油酸代谢产物促进肝脏炎性小体激活，从而加剧酒精介导的肝脏炎症和损伤。我们认为OXLAM/TRPV 1/Ca 2+信号通路是炎性小体激活的上游机制。为了解决我们的假设，我们提出了以下具体目标。目标1。确定氧化亚油酸代谢物（OXLAMs）和12/15-LO介导的亚油酸氧化途径在ALD发生和/或进展中的作用。 目标二。在ALD动物模型中评估肝脏炎性小体激活是否由OXLAM-TRPV 1-Ca 2+通路介导。 目标3。确定12/15-LO、TRPV 1和OXLAMs在人类酒精性肝炎炎性小体激活中的潜在作用。该提案将提供更好地了解酒精-饮食相互作用和分子机制，有助于酒精诱导的肝脏炎症和损伤的发病机制。这项研究将导致识别新的治疗靶点和治疗ALD的潜在饮食干预， 提供了一个饮食机制来解释为什么只有一些酗酒者发展临床上重要的ALD。 将采用体外、体内动物（功能获得和丧失）和人体研究的组合。

 DESCRIPTION (provided by applicant): Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the world. It affects millions of patients worldwide each year. Although substantial progress has been made in ALD pathogenesis, the specific mechanisms 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 rich in linoleic acid (LA) exacerbated alcohol- mediated intestinal permeability and liver injury as compared with dietary saturated fat in an experimental animal model of ALD. In addition, our preliminary data show elevated levels of circulating oxidized LA metabolites (OXLAMs), specifically 9- and 13-hydroxy-octadecadienoic acids (9- and 13-HODEs), concomitant with the up-regulation of hepatic 12/15 lipoxygenase (12/15-LO), the key enzyme involved in the oxidation of LA. These findings provide initial evidence that OXLAMs, which are natural ligands to the transient receptor potential vanilloid 1 (TRPV1, subfamily V member 1), contribute to the pathogenesis of ALD. TRPV1 is a ligand-gated non-selective cation channel with high permeability for Ca2+. A number of recent studies have shown a critical role for intracellular Ca2+ in inflammasome activation. NLRP3 Inflammasome activation with release of highly pro-inflammatory cytokines interleukin-1β (IL-1β) and interleukin-18 (IL-18) is an important pro-inflammatory response in ALD. However, the molecular mechanisms contributing to the inflammasome priming and activation in ALD are not fully identified. Our central hypothesis is that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol-mediated liver inflammation and injury via oxidized linoleic acid metabolites that facilitate hepatic inflammasome activation. We propose that the OXLAM/TRPV1/Ca2+ signaling pathway is an upstream mechanism of inflammasome activation. To address our hypothesis, we propose the following specific aims. Aim 1. Determine the role of oxidized linoleic acid metabolites (OXLAMs) and the 12/15-LO-mediated pathway of linoleic acid oxidation in the development and/or progression of ALD. Aim 2. Assess whether hepatic inflammasome activation is mediated by an OXLAM-TRPV1-Ca2+ pathway in an animal model of ALD. Aim 3. Determine the potential role of 12/15-LO, TRPV1 and OXLAMs in inflammasome activation in human Alcoholic Hepatitis. The proposal will provide a better understanding of alcohol-diet interactions and molecular mechanisms contributing to the pathogenesis of alcohol-induced liver inflammation and injury. The study will lead to identification of new therapeutic targets and potential dietary interventions for treating ALD, and provide a dietary mechanism to explain why only some heavy drinkers develop clinically important ALD. A combination of in vitro, in-vivo animal (gain and loss of function) and human studies will be employed.