Role of Dietary Fat in Alcoholic Liver Disease

膳食脂肪在酒精性肝病中的作用

基本信息

  • 批准号:
    8978012
  • 负责人:
  • 金额:
    $ 6.82万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-05-15 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

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.
酒精性肝病(ALD)是美国和全世界发病率和死亡率的主要原因。虽然 肌萎缩侧索硬化症发病机制研究取得实质性进展,肌萎缩侧索硬化症具体发病机制S 发展和进步仍然没有完全被理解。重要的是,没有FDA批准的治疗方法 对于ALD的任何阶段。我们实验室和其他实验室最近的研究表明,饮食中的不饱和脂肪 富含亚油酸(LA)增加肠道对肠源性内毒素的通透性并加重肝脏 实验性酒精性肝病动物模型的炎症和损伤。此外,我们的初步数据显示, 循环氧化乳酸代谢产物(OXLAM)水平升高,特别是9-和13-羟基- 十八碳二烯酸(9-和13-Hodes)及其对肝脏12/15脂氧合酶的上调作用 (12/15-LO),参与LA氧化的关键酶。这些发现表明,OXLAM起着 瞬时受体电位香草素1(TRPV1,V亚家族成员1)的天然配体参与 ALD的发病机制。TRPV1是一种配体门控型非选择性阳离子通道,对钙离子有很高的通透性。一个 最近的一些研究表明,细胞内钙离子在炎性小体激活中起着关键作用。NLRP3 白介素1β(IL-1β)和白介素18(IL-18)的释放在炎症小体激活中起重要作用。 ALD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 数据让我们假设,饮食中的不饱和脂肪(富含亚油酸)会加剧酒精-- 氧化亚油酸代谢产物诱导肠道屏障介导的肝脏炎症和损伤 破坏和肝脏炎性小体激活。为了解释我们的假设,我们提出了以下四点 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的开发和/或进展中。目的2.评估肝炎性小体 在ALD动物模型中,激活是由OXLAMS-TRPV1-Ca~(2+)途径介导的。目标3.评估 膳食饱和脂肪减淡和不饱和脂肪加重酒精代谢的分子机制(S) 介导的肠屏障破坏、内毒素血症和肝损伤。目的4.探索OXLAM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 为更好地了解酒精性痴呆发病的分子机制 肝脏炎症和损伤。这些研究还将帮助我们更好地理解酒精与饮食的相互作用, 这也可能导致确定治疗ALD的新药靶点和潜在的饮食干预措施 以帮助解释为什么只有一些酗酒的人会患上临床上重要的ALD。这项建议 它与其他项目、试点和核心广泛互动,并纳入了ULARC的营养主题 以及酒精引起的器官损伤。

项目成果

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CRAIG J. MCCLAIN其他文献

CRAIG J. MCCLAIN的其他文献

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{{ truncateString('CRAIG J. MCCLAIN', 18)}}的其他基金

Inflammation Resolving Lipid Mediators: Novel Therapy for Alcohol AssociatedLiver Disease
消炎脂质介质:酒精相关性肝病的新疗法
  • 批准号:
    10590047
  • 财政年份:
    2023
  • 资助金额:
    $ 6.82万
  • 项目类别:
Administrative Supplement to Hepatobiology and Toxicology COBRE
肝生物学和毒理学 COBRE 行政增刊
  • 批准号:
    10399887
  • 财政年份:
    2021
  • 资助金额:
    $ 6.82万
  • 项目类别:
Alcoholic Hepatitis Network 3/9 University of Louisville
酒精性肝炎网络 3/9 路易斯维尔大学
  • 批准号:
    9752421
  • 财政年份:
    2018
  • 资助金额:
    $ 6.82万
  • 项目类别:
Alcoholic Hepatitis Network 3/9 University of Louisville
酒精性肝炎网络 3/9 路易斯维尔大学
  • 批准号:
    10434741
  • 财政年份:
    2018
  • 资助金额:
    $ 6.82万
  • 项目类别:
Pilot Trial UO1 DUR-928
试点试验 UO1 DUR-928
  • 批准号:
    10201423
  • 财政年份:
    2018
  • 资助金额:
    $ 6.82万
  • 项目类别:
Alcoholic Hepatitis Network 3/9 University of Louisville
酒精性肝炎网络 3/9 路易斯维尔大学
  • 批准号:
    10202391
  • 财政年份:
    2018
  • 资助金额:
    $ 6.82万
  • 项目类别:
Pilot Trial UO1 DUR-928
试点试验 UO1 DUR-928
  • 批准号:
    10441277
  • 财政年份:
    2018
  • 资助金额:
    $ 6.82万
  • 项目类别:
Pilot Trial UO1 DUR-928
试点试验 UO1 DUR-928
  • 批准号:
    9792232
  • 财政年份:
    2018
  • 资助金额:
    $ 6.82万
  • 项目类别:
Hepatobiology and Toxicology COBRE
肝脏生物学和毒理学 COBRE
  • 批准号:
    10377890
  • 财政年份:
    2016
  • 资助金额:
    $ 6.82万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10026251
  • 财政年份:
    2016
  • 资助金额:
    $ 6.82万
  • 项目类别:

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