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

项目摘要 酒精性肝病(ALD)导致48%的肝炎所致的肝硬变死亡。增加了活性氧 物种(ROS)的产生是导致ALD从脂肪变性发展为酒精中毒的主要致病因素 肝炎(AH)。然而，测试化合物的临床试验不加选择地清除ROS或增强 我们熟知的抗氧化剂都不成功。这种缺乏成功支持了ALD扰乱内源性 线粒体内的抗氧化剂系统，线粒体是由两层膜形成的细胞器，限制了线粒体的进入和作用 在测试的化合物中。我们的建议源于我们对线粒体抗氧化剂和氧化还原的鉴定 ALD患者的系统受损，以前在肝脏中未知。该系统由线粒体内部构成。 膜ATP结合盒运输器ABCB10，它通过其 ATP水解活性(ATPase)。我们的初步数据支持ABCB10通过以下方式降低ALD的严重性 减少ROS介导的损伤，因为肝脏特异性的ABCB10缺失加剧了肝脏的氧化损伤 以及小鼠ALD的严重程度。我们假设ABCB10转运活动通过限制 乙醇引起的氧化损伤。值得注意的是，我们的新数据显示，ABCB10的含量在晚期有所下降。 ALD分期，包括小鼠和人的AH。从机制上讲，我们第一次表明ABCB10出口 胆绿素(BV)从线粒体基质到胞浆，胆绿素还原酶(BLVR)位于胞浆中。 输出的BV被胞质BLVR用来再生细胞内的胆红素(BR)，用于清除ROS。 我们假设ABCB10介导的BV输出在ALD时减少，使肝内细胞收缩 BR保护池不受ROS介导的损害。因此，我们的数据表明：i)Etoh和ABCB10 缺失降低肝细胞内BR水平和ii)ABCB10缺失导致线粒体BV聚集和 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；2) 确定ABCB10调节ALD氧化应激的机制。

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.