Alcohol metabolism in liver sinusoidal endothelial cells

肝窦内皮细胞的酒精代谢

基本信息

  • 批准号:
    9116749
  • 负责人:
  • 金额:
    $ 19.77万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-08-01 至 2018-07-31
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Liver sinusoidal endothelial cells (LSECs) protect the liver, acting as the first barrier against insults coming from the sinusoidal blood. LSEC dysfunction is associated with the development of a wide range of liver diseases including alcohol liver disease. Cytochrome P450 2E1 (CYP2E1) is a key enzyme in alcohol and drug metabolism. Induction of CYP2E1 by alcohol generates metabolic products, such as reactive oxygen species (ROS), which cause tissue injury. The study of CYP2E1 in the liver has largely focused on hepatocytes. The presence and function of CYP2E1 in LSECs remains unknown. We recently found that CYP2E1 is expressed in LSECs. This finding is important, since it implies that LSEC-mediated metabolism of alcohol may generate metabolites that impair normal endothelial cell function. The goal of this study is to understand the role of CYP2E1 in LSECs in ethanol-induced liver injury. Dysfunctional LSECs are characterized by loss of fenestrae and decreased nitric oxide (NO) production. NO is a key regulator of intrahepatic vascular tone. NO is also essential for the maintenance of LSEC's fenestrae structure, which allows bi-directional movement of proteins and other substances between blood vessels and hepatocytes. Chronic alcohol consumption decreases endothelial NO synthase (eNOS)-derived NO production. Further, blocking NO production enhances ethanol-induced liver injury, suggesting NO's protective role. The mechanisms by which alcohol consumption diminishes eNOS activity and NO production are unknown. We hypothesize that ethanol induces CYP2E1 expression in LSECs and that induced CYP2E1 in turn decreases eNOS-derived NO production. To test these hypotheses, we will propose the following two aims: 1) Define the role of CYP2E1 in LSEC function in response to ethanol, and 2) Define CYP2E1-dependent regulation of NO production in LSECs in response to ethanol. Given that CYP2E1 metabolizes a wide range of drugs and chemicals besides alcohol, this study will also open the door to reveal LSEC's role in metabolizing those substances, which has most commonly been attributed to hepatocytes.
 描述(由申请人提供):肝窦内皮细胞(LSEC)保护肝脏,作为第一道屏障抵御来自窦血的损伤。LSEC功能障碍与包括酒精性肝病在内的多种肝病的发展相关。细胞色素P450 2E1(CYP 2E1)是酒精和药物代谢的关键酶。酒精诱导CYP2E1产生代谢产物,如活性氧(ROS),导致组织损伤。肝脏中CYP2E1的研究主要集中在肝细胞。CYP2E1在LSEC中的存在和功能仍然未知。我们最近发现CYP2E1在LSEC中表达。这一发现很重要,因为它意味着LSEC介导的酒精代谢可能产生损害正常内皮细胞功能的代谢产物。本研究的目的是了解CYP2E1在乙醇诱导的肝损伤中的作用。功能障碍性LSEC的特征在于窗孔丧失和一氧化氮(NO)产生减少。NO是肝内血管张力的关键调节因子。NO对于维持LSEC的窗孔结构也是必不可少的,该结构允许蛋白质和其他物质在血管和肝细胞之间双向移动。长期饮酒减少内皮NO合酶(eNOS)衍生的NO产生。此外,阻断NO的产生增强了乙醇诱导的肝损伤,表明NO的保护作用。饮酒减少eNOS活性和NO产生的机制尚不清楚。我们假设乙醇诱导CYP2E1在LSEC中的表达,并且诱导的CYP2E1反过来降低eNOS衍生的NO产生。为了验证这些假设,我们将提出以下两个目标:1)确定CYP2E1在响应乙醇的LSEC功能中的作用,以及2)确定响应乙醇的LSEC中NO产生的CYP2E1依赖性调节。鉴于CYP2E1代谢除酒精外的多种药物和化学物质,这项研究也将揭示LSEC在代谢这些物质中的作用,这通常归因于肝细胞。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Biology of portal hypertension.
门户高血压的生物学。
  • DOI:
    10.1007/s12072-017-9826-x
  • 发表时间:
    2018-03
  • 期刊:
  • 影响因子:
    6.6
  • 作者:
    McConnell M;Iwakiri Y
  • 通讯作者:
    Iwakiri Y
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YASUKO IWAKIRI其他文献

YASUKO IWAKIRI的其他文献

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{{ truncateString('YASUKO IWAKIRI', 18)}}的其他基金

Hepatic lymphatics in alcohol-associated liver disease
酒精相关性肝病中的肝淋巴管
  • 批准号:
    10824029
  • 财政年份:
    2023
  • 资助金额:
    $ 19.77万
  • 项目类别:
Lymphatics in the liver
肝脏中的淋巴管
  • 批准号:
    10391056
  • 财政年份:
    2022
  • 资助金额:
    $ 19.77万
  • 项目类别:
Lymphatics in the liver
肝脏中的淋巴管
  • 批准号:
    10657334
  • 财政年份:
    2022
  • 资助金额:
    $ 19.77万
  • 项目类别:
Endotheliopathy and liver injury in COVID-19
COVID-19 中的内皮病和肝损伤
  • 批准号:
    10468220
  • 财政年份:
    2021
  • 资助金额:
    $ 19.77万
  • 项目类别:
Endotheliopathy and liver injury in COVID-19
COVID-19 中的内皮病和肝损伤
  • 批准号:
    10662455
  • 财政年份:
    2021
  • 资助金额:
    $ 19.77万
  • 项目类别:
Endotheliopathy and liver injury in COVID-19
COVID-19 中的内皮病和肝损伤
  • 批准号:
    10319358
  • 财政年份:
    2021
  • 资助金额:
    $ 19.77万
  • 项目类别:
Hemodynamics and hepatic remodeling
血流动力学和肝脏重塑
  • 批准号:
    9920142
  • 财政年份:
    2018
  • 资助金额:
    $ 19.77万
  • 项目类别:
Hemodynamics and hepatic remodeling
血流动力学和肝脏重塑
  • 批准号:
    9542958
  • 财政年份:
    2018
  • 资助金额:
    $ 19.77万
  • 项目类别:
The role of Kupffer cells in alcohol-induced liver disease
库普弗细胞在酒精性肝病中的作用
  • 批准号:
    9761401
  • 财政年份:
    2017
  • 资助金额:
    $ 19.77万
  • 项目类别:
Mechanisms of Alcohol-Induced Hepatic Osteodystrophy
酒精性肝性骨营养不良的机制
  • 批准号:
    8969937
  • 财政年份:
    2016
  • 资助金额:
    $ 19.77万
  • 项目类别:

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