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: 10201420
• 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/10201420
• 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%的肝炎相关死亡。增加的活性氧 活性氧（ROS）的产生是导致ALD从脂肪变性发展为酒精性肝病的主要致病因素 肝炎（AH）。然而，临床试验测试的化合物，非选择性地抑制ROS或增强 熟悉的抗氧化剂是不成功的。缺乏成功支持ALD干扰内源性 线粒体内的抗氧化系统，线粒体是由两层膜形成的细胞器，限制进入和行动 测试的化合物。我们的提议源于我们对线粒体抗氧化剂和氧化还原的鉴定 酒精性肝脏病导致系统受损，而肝脏此前未知。这个系统是由线粒体内部的 膜ATP结合盒转运蛋白ABCB 10，它通过膜转运蛋白ABCB 10输出一种以前未知的货物。 ATP水解活性（ATP酶）。我们的初步数据支持ABCB 10降低ALD的严重程度， 减少ROS介导的损伤，因为肝脏特异性ABCB 10缺失会加剧肝脏氧化损伤 和小鼠的ALD严重程度。我们假设ABCB 10转运活性通过限制ALD的发生来保护ALD。 乙醇诱导的氧化损伤。值得注意的是，我们的新数据显示，ABCB10含量在晚期减少， ALD阶段，包括患有AH的小鼠和人类。机械地，我们首次表明ABCB 10输出 胆绿素（BV）从线粒体基质转移到胆绿素还原酶（BLVR）所在的细胞质。 输出的BV被胞质BLVR用于再生细胞内胆红素（BR），用于清除ROS。 我们假设ALD患者ABCB10介导的BV输出减少，肝细胞内收缩， 保护免受ROS介导的损伤的BR池。因此，我们的数据显示：i）EtOH和ABCB 10 缺失降低肝细胞内BR水平和ii）ABCB10缺失导致线粒体BV积累， 增加细胞内ROS水平。因此，我们将：1）确定ABCB 10在体内ALD中的作用，以及2） 确定ABCB10调节ALD中氧化应激的机制。