Role of the heme-related mitochondrial antioxidant ABCB10 in alcoholic liver disease

血红素相关线粒体抗氧化剂 ABCB10 在酒精性肝病中的作用

基本信息

  • 批准号:
    10201420
  • 负责人:
  • 金额:
    $ 35.1万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-09-01 至 2023-06-30
  • 项目状态:
    已结题

项目摘要

Project Summary Alcoholic liver disease (ALD) causes 48% of cirrhotic deaths derived from hepatitis. Increased reactive oxygen species (ROS) production is a major pathogenic factor leading the progression of ALD from steatosis to alcoholic hepatitis (AH). However, clinical trials testing compounds that unselectively scavenge ROS or enhance acquainted antioxidants were unsuccessful. This lack of success supports that ALD disrupts endogenous antioxidant systems inside mitochondria, an organelle formed by two membranes that limit the entry and action of the compounds tested. Our proposal stems from our identification of a mitochondrial antioxidant and redox system impaired in ALD and previously unknown in liver. This system is constituted by the mitochondrial inner membrane ATP binding cassette transporter ABCB10, which exports a previously unknown cargo through its ATP hydrolysis activity (ATPase). Our preliminary data supports that ABCB10 decreases ALD severity by decreasing ROS-mediated damage, as liver-specific deletion of ABCB10 exacerbates hepatic oxidative damage and ALD severity in mice. We hypothesize that ABCB10 transport activity protects from ALD by limiting EtOH-induced oxidative damage. Remarkably, our new data shows that ABCB10 content is decreased in late- stage ALD, including mice and humans with AH. Mechanistically, we show for the first time that ABCB10 exports Biliverdin (BV) from the mitochondrial matrix to the cytosol, where biliverdin reductase (BLVR) is located. Exported BV is used by cytosolic BLVR to regenerate intracellular Bilirubin (BR) destined for ROS scavenging. We hypothesize that ABCB10-mediated BV export is decreased in ALD, shrinking the intrahepatocyte BR pool that protects from ROS-mediated damage. Accordingly, our data show that: i) EtOH and ABCB10 deletion reduce intrahepatocyte BR levels and ii) ABCB10 deletion causes mitochondrial BV accumulation and increases intracellular ROS levels. Thus, we will: 1) Determine the role of ABCB10 in ALD in vivo and 2) Determine the mechanism by which ABCB10 modulates oxidative stress in ALD.
项目总结

项目成果

期刊论文数量(0)
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Orian S Shirihai其他文献

Cardiac-Specific Fatty Acid Transport Protein 1 (FATP1) Overexpression Causes Decreased Mitochondrial Respiration, Increased Oxidative Stress and Activation of AMPK
  • DOI:
    10.1016/j.freeradbiomed.2012.10.434
  • 发表时间:
    2012-11-01
  • 期刊:
  • 影响因子:
  • 作者:
    Aly Elezaby;Edward J Miller;Fuzhong Qin;Marc Liesa;Orian S Shirihai;Wilson S Colucci
  • 通讯作者:
    Wilson S Colucci

Orian S Shirihai的其他文献

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{{ truncateString('Orian S Shirihai', 18)}}的其他基金

MITOCHONDRIAL RESPIROMETRY IN FROZEN BIOLOGICAL SAMPLES
冷冻生物样品中的线粒体呼吸测定
  • 批准号:
    10251412
  • 财政年份:
    2021
  • 资助金额:
    $ 35.1万
  • 项目类别:
MITOCHONDRIAL RESPIROMETRY IN FROZEN BIOLOGICAL SAMPLES
冷冻生物样品中的线粒体呼吸测定
  • 批准号:
    10011475
  • 财政年份:
    2020
  • 资助金额:
    $ 35.1万
  • 项目类别:
Role of the heme-related mitochondrial antioxidant ABCB10 in alcoholic liver disease
血红素相关线粒体抗氧化剂 ABCB10 在酒精性肝病中的作用
  • 批准号:
    10443585
  • 财政年份:
    2019
  • 资助金额:
    $ 35.1万
  • 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
  • 批准号:
    7645363
  • 财政年份:
    2007
  • 资助金额:
    $ 35.1万
  • 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
  • 批准号:
    8012816
  • 财政年份:
    2007
  • 资助金额:
    $ 35.1万
  • 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
  • 批准号:
    7346916
  • 财政年份:
    2007
  • 资助金额:
    $ 35.1万
  • 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
  • 批准号:
    7535553
  • 财政年份:
    2007
  • 资助金额:
    $ 35.1万
  • 项目类别:
Mitochondrial dynamics in beta cell function and dysfunction
β细胞功能和功能障碍的线粒体动力学
  • 批准号:
    7212876
  • 财政年份:
    2007
  • 资助金额:
    $ 35.1万
  • 项目类别:
FUNCTIONAL HETEROGENEITY OF MITOCHONDRIA IN AN INDIVIDUAL PANCREATIC BETA CELL
单个胰腺β细胞中线粒体的功能异质性
  • 批准号:
    7357321
  • 财政年份:
    2005
  • 资助金额:
    $ 35.1万
  • 项目类别:
Metabolic Profiling of Pancreatic Beta Cells
胰腺β细胞的代谢分析
  • 批准号:
    6879325
  • 财政年份:
    2004
  • 资助金额:
    $ 35.1万
  • 项目类别:
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