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
• 负责人: Orian S Shirihai
• 金额: $ 35.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/10443585
• 关键词: ATP Hydrolysis; ATP phosphohydrolase; ATP-Binding Cassette Transporters; Alcoholic Hepatitis; Alcoholic Liver Diseases; Antioxidants; Bilirubin; Biliverdin reductase; Biliverdine; Cessation of life; Cirrhosis; Clinical Trials; Cysteine; Cytosol; Data; Defect; Dependence; Disease Progression; Effectiveness; Engineering; Equilibrium; Ethanol; Glutathione; Heme; Hepatic; Hepatitis; Hepatocyte; Human; Hydrogen Peroxide; Impairment; Inner mitochondrial membrane; Knockout Mice; Liver; Liver Mitochondria; Measures; Mediating; Membrane; Mitochondria; Mitochondrial Matrix; Molecular; Mus; Natural regeneration; Organelles; Oxidation-Reduction; Oxidative Stress; Patients; Post-Translational Regulation; Process; Production; Proteins; Public Health; Reactive Oxygen Species; Role; Severity of illness; Sulfinic Acids; Sulfonic Acids; System; Testing; Time; Virulence Factors; fluorescence imaging; gain of function; heme oxygenase-1; hydrophilicity; in vivo; live cell imaging; liver biopsy; liver function; mitochondrial dysfunction; mouse model; mutant; overexpression; oxidation; oxidative damage; prevent; stem; success

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.

项目摘要 酒精性肝病（ALD）导致48％来自肝炎的肝硬化死亡。活性氧增加 物种（ROS）生产是主要的致病因素，导致ALD从脂肪变性到酒精 肝炎（AH）。但是，临床试验测试化合物，可非选择地清除ROS或增强 熟悉的抗氧化剂没有成功。缺乏成功支持破坏内源性的 线粒体内部的抗氧化剂系统，这是一个由两个膜形成的细胞器，限制了进入和动作 测试的化合物。我们的建议源于我们对线粒体抗氧化剂和氧化还原的识别 系统受损害的ALD损害，以前在肝脏中未知。该系统由线粒体内部构成 膜ATP绑定盒式转运蛋白ABCB10，它通过其以前未知的货物出口 ATP水解活性（ATPase）。我们的初步数据支持ABCB10通过 减少ROS介导的损伤，因为ABCB10的肝脏特异性缺失加剧了肝氧化损伤 和小鼠的ALD严重程度。我们假设ABCB10运输活动可以通过限制来保护ALD EtOH诱导的氧化损伤。值得注意的是，我们的新数据表明，后期ABCB10含量减少 舞台ALD，包括老鼠和与AH的人类。从机械上讲，我们首次表明ABCB10出口 Biliverdin（BV）从线粒体基质到细胞质，其中Biliverdin还原酶（BLVR）位于其中。 胞质BLVR使用导出的BV用于再生的细胞内胆红素（BR），以进行ROS清除。 我们假设ABCB10介导的BV导出在ALD中降低，缩小了epatocyte 可保护ROS介导的损伤的BR池。因此，我们的数据表明：i）etoh和abcb10 删除降低epatocyte BR水平和II）ABCB10缺失会导致线粒体BV的积累和 增加细胞内ROS水平。因此，我们将：1）确定ABCB10在体内ALD中的作用和2） 确定ABCB10调节ALD中氧化应激的机制。