Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA; Molecular and Cellular Integrative Physiology, Interdepartmental Program, University of California, Los Angeles, CA, USA.
Department of Medicine, Division of Endocrinology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Redox Biol. 2024 Apr;70:103052. doi: 10.1016/j.redox.2024.103052. Epub 2024 Jan 24.
Acute liver failure caused by alcoholic hepatitis (AH) is only effectively treated with liver transplantation. Livers of patients with AH show a unique molecular signature characterized by defective hepatocellular redox metabolism, concurrent to hepatic infiltration of neutrophils that express myeloperoxidase (MPO) and form neutrophil extracellular traps (NETs). Exacerbated NET formation and MPO activity contribute to liver damage in mice with AH and predicts poor prognosis in AH patients. The identification of pathways that maladaptively exacerbate neutrophilic activity in liver could inform of novel therapeutic approaches to treat AH. Whether the redox defects of hepatocytes in AH directly exacerbate neutrophilic inflammation and NET formation is unclear. Here we identify that the protein content of the mitochondrial biliverdin exporter ABCB10, which increases hepatocyte-autonomous synthesis of the ROS-scavenger bilirubin, is decreased in livers from humans and mice with AH. Increasing ABCB10 expression selectively in hepatocytes of mice with AH is sufficient to decrease MPO gene expression and histone H3 citrullination, a specific marker of NET formation. These anti-inflammatory effects can be explained by ABCB10 function reducing ROS-mediated actions in liver. Accordingly, ABCB10 gain-of-function selectively increased the mitochondrial GSH/GSSG ratio and decreased hepatic 4-HNE protein adducts, without elevating mitochondrial fat expenditure capacity, nor mitigating steatosis and hepatocyte death. Thus, our study supports that ABCB10 function regulating ROS-mediated actions within surviving hepatocytes mitigates the maladaptive activation of infiltrated neutrophils in AH. Consequently, ABCB10 gain-of-function in human hepatocytes could potentially decrease acute liver failure by decreasing the inflammatory flare caused by excessive neutrophil activity.
由酒精性肝炎 (AH) 引起的急性肝衰竭仅可通过肝移植有效治疗。AH 患者的肝脏表现出独特的分子特征，其特征为肝细胞氧化还原代谢功能缺陷，同时伴有中性粒细胞浸润，这些中性粒细胞表达髓过氧化物酶 (MPO) 并形成中性粒细胞胞外诱捕网 (NETs)。NET 形成和 MPO 活性的加剧导致 AH 小鼠的肝损伤，并预测 AH 患者的预后不良。确定适应性地加剧肝脏中性粒细胞活性的途径可以为治疗 AH 提供新的治疗方法。AH 肝细胞的氧化还原缺陷是否直接加剧中性粒细胞炎症和 NET 形成尚不清楚。在这里，我们发现 ABCB10（一种增加肝细胞自主合成 ROS 清除剂胆红素的线粒体胆绿素外排蛋白）的蛋白含量在 AH 患者和小鼠的肝脏中降低。在 AH 小鼠的肝细胞中选择性增加 ABCB10 的表达足以降低 MPO 基因表达和组蛋白 H3 瓜氨酸化，这是 NET 形成的特异性标志物。这些抗炎作用可以通过 ABCB10 功能减少肝脏中的 ROS 介导作用来解释。相应地，ABCB10 功能获得性选择性增加了线粒体 GSH/GSSG 比，减少了肝 4-HNE 蛋白加合物，而不增加线粒体脂肪消耗能力，也不减轻脂肪变性和肝细胞死亡。因此，我们的研究支持 ABCB10 功能调节存活肝细胞中的 ROS 介导作用可减轻 AH 中浸润中性粒细胞的适应性激活。因此，ABCB10 在人类肝细胞中的功能获得性可能通过减少过度中性粒细胞活性引起的炎症爆发来降低急性肝衰竭的风险。
