Role of Dietary Fat in Alcoholic Liver Disease

酒精性肝病（ALD）是美国和世界范围内发病率和死亡率的主要原因。虽然 在ALD发病机制方面已经取得了实质性进展，ALD的具体机制是 发展和进步仍然不完全清楚。重要的是，没有FDA批准的治疗方法 对于任何阶段的ALD。我们实验室和其他机构最近的研究表明，膳食不饱和脂肪 富含亚油酸（LA）增加了肠道对肠源性内毒素的渗透性， 在ALD实验动物模型中的炎症和损伤。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），以及伴随的肝12/15脂氧合酶上调 (12/15-LO），是参与LA氧化的关键酶。这些研究结果表明，作为 瞬时受体电位香草素1（TRPV 1，亚家族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。一 近年来的研究表明，细胞内Ca~（2+）在炎性小体活化中起着重要作用。NLRP3 炎症体激活并释放白细胞介素-1 β（IL-1 β）和白细胞介素-18（IL-18）是一个重要的促进因素 ALD中的炎症反应。炎性小体启动和激活网络涉及多种因素， 包括肠源性内毒素脂多糖（LPS）。这些发现与我们初步的 数据使我们假设饮食中的不饱和脂肪（富含亚油酸）会加重酒精， 通过氧化亚油酸代谢物介导的肝脏炎症和损伤，诱导肠道屏障 破坏和肝脏炎性小体激活。为了解决我们的假设，我们提出以下四个问题 具体目标：目标1。确定饮食中不饱和脂肪的作用，特别是亚油酸及其氧化 产品，在ALD的发展和/或进展。目标2.评估肝脏炎性小体是否 在ALD的动物模型中，OXLAMs-TRPV1-Ca2+通路介导激活。目标3：评价 饮食饱和脂肪减少酒精和不饱和脂肪加剧酒精的分子机制， 介导的肠道屏障破坏、内毒素血症和肝损伤。目标4。探索OXLAMs的作用，12/15-LO 和TRPV1在人酒精性肝炎单核细胞炎性小体激活中的作用。拟议的研究将导致 为了更好地理解酒精诱导的糖尿病发病机制的分子机制， 肝脏炎症和损伤。这些研究还将帮助我们更好地了解酒精与饮食的相互作用， 这可能会导致识别新的药物靶点和潜在的饮食干预治疗ALD，以及 这有助于解释为什么只有一些酗酒的人会患上临床上重要的酒精性肝病。这项建议 与其他项目、试点项目和核心项目广泛互动，并将ULARC的营养主题纳入其中 以及酒精引起的器官损伤

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality in the US and worldwide. Although substantial progress has been made in ALD pathogenesis, the specific mechanism(s) responsible for ALD development and progression remain incompletely understood. Importantly, there is no FDA approved therapy for any stage of ALD. Recent studies from our laboratory and others demonstrated that dietary unsaturated fat rich in linoleic acid (LA) increased intestinal permeability to gut-derived endotoxins and exacerbated liver inflammation and injury 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), and concomitant up-regulation of hepatic 12/15 lipoxygenase (12/15-LO), the key enzyme involved in the oxidation of LA. These findings suggest that OXLAMs, which act as 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 interleukin-1β (IL-1β) and interleukin-18 (IL-18) is an important pro- inflammatory response in ALD. Many factors are involved in inflammasome priming and activation network, including gut-derived endotoxin lipopolysaccharide (LPS). These findings in conjunction with our preliminary data have led us to hypothesize that dietary unsaturated fat (linoleic acid enriched) exacerbates alcohol- mediated liver inflammation and injury via oxidized linoleic acid metabolites that induce gut barrier disruption and hepatic inflammasome activation. To address our hypothesis, we propose the following four specific aims: Aim 1. Determine the role of dietary unsaturated fat, specifically linoleic acid and its oxidation products, in the development and/or progression of ALD. Aim 2. Assess whether hepatic inflammasome activation is mediated by OXLAMs-TRPV1-Ca2+ pathway in an animal model of ALD. Aim 3. Evaluate the molecular mechanism(s) by which dietary saturated fat attenuates and unsaturated fat exacerbates alcohol- mediated gut barrier disruption, endotoxemia and liver injury. Aim 4. Explore the role of OXLAMs, 12/15-LO and TRPV1 in monocyte inflammasome activation in human alcoholic hepatitis. The proposed studies will lead to a better understanding of the 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 drug 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. This proposal extensively interacts with other projects, pilots, and cores, and it incorporates the ULARC theme of nutrition and alcohol-induced organ injury.