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

膳食不饱和脂肪和炎症小体在酒精性肝病中的作用

• 批准号: 9104742
• 负责人: IRINA A. KIRPICH
• 金额: $ 34.65万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9104742
• 关键词: Address; Affect; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic beverage heavy drinker; Alcohols; Animal Model; Animals; Arachidonate 15-Lipoxygenase; Attenuated; Binding; Cations; Data; Development; Diet; Dietary Fats; Dietary Intervention; Enzymes; Experimental Animal Model; FDA approved; Fatty Acids; Genetic; Hepatic; Hepatocyte; Human; In Vitro; Inflammatory; Inflammatory Response; Interleukin-1 beta; Interleukin-18; Intestines; Knock-in; Knockout Mice; Kupffer Cells; Laboratories; Lead; Ligands; Linoleic Acids; Mediating; Molecular; Morbidity - disease rate; Mus; Pathogenesis; Pathway interactions; Patients; Permeability; Research; Role; Sampling; Severities; Signal Pathway; Staging; TRPV1 gene; Testing; Transgenic Organisms; United States National Institutes of Health; Unsaturated Fats; Up-Regulation; Vanilloid; Whole Blood; cytokine; in vivo; liver inflammation; liver injury; loss of function; macrophage; member; monocyte; mortality; new therapeutic target; octadecadienoic acid; overexpression; oxidation; peripheral blood; public health relevance; receptor; saturated fat; translational study

 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.

 描述（由申请人提供）：酒精性肝病（ALD）是世界范围内发病和死亡的主要原因。它每年影响全世界数百万患者。虽然 ALD 发病机制已取得实质性进展，但 ALD 发生和进展的具体机制仍知之甚少。重要的是，FDA 还没有批准针对 ALD 任何阶段的治疗方法。我们实验室和其他实验室的最新研究表明，在 ALD 实验动物模型中，与膳食饱和脂肪相比，富含亚油酸 (LA) 的膳食不饱和脂肪会加剧酒精介导的肠道通透性和肝损伤。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），同时肝脏12/15脂氧合酶（12/15-LO）（参与LA氧化的关键酶）上调。这些发现提供了初步证据，证明 OXLAM 是瞬时受体电位香草酸 1（TRPV1，亚科 V 成员 1）的天然配体，有助于 ALD 的发病机制。 TRPV1 是一种配体门控的非选择性阳离子通道，对 Ca2+ 具有高渗透性。最近的许多研究表明细胞内 Ca2+ 在炎症小体激活中发挥着关键作用。 NLRP3 炎症小体激活并释放高度促炎细胞因子白细胞介素 1β (IL-1β) 和白细胞介素 18 (IL-18)，是 ALD 中重要的促炎反应。然而，ALD 中炎症小体启动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物促进肝脏炎症小体激活，从而加剧酒精介导的肝脏炎症和损伤。我们认为OXLAM/TRPV1/Ca2+信号通路是炎症小体激活的上游机制。为了解决我们的假设，我们提出以下具体目标。目标 1. 确定氧化亚油酸代谢物 (OXLAM) 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 2. 在 ALD 动物模型中评估肝脏炎症小体激活是否由 OXLAM-TRPV1-Ca2+ 通路介导。 目标 3. 确定 12/15-LO、TRPV1 和 OXLAM 在人类酒精性肝炎炎症小体激活中的潜在作用。该提案将有助于更好地了解酒精与饮食的相互作用以及导致酒精引起的肝脏炎症和损伤发病机制的分子机制。该研究将确定治疗 ALD 的新治疗靶点和潜在的饮食干预措施，以及 提供了一种饮食机制来解释为什么只有一些酗酒者才会出现临床上重要的酒精性肝病。 将结合体外、体内动物（功能的获得和丧失）和人体研究。