Neutralization of Oxidized Phospholipids Restrains Nonalcoholic Steatohepatitis

Oxidized phospholipids (OxPL) are pro-inflammatory and pro-atherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPL accumulate in human and murine NASH. Using a transgenic mouse that expresses a functional single chain variable fragment of E06, a natural antibody that neutralizes OxPL, we demonstrate the casual role of OxPL in NASH. Targeting OxPL in hyperlipidemic Ldlr-/- mice decreased multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death and progression to hepatocellular carcinoma. Mechanistically, we found that OxPL promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. Neutralizing OxPL in AMLN diet-fed Ldlr-/- mice reduced oxidative stress, improved hepatic and adipose tissue mitochondrial function and fatty acid oxidation. Since neutralizing OxPL also protects against atherogenesis, targeting OxPL may be an effective therapeutic strategy for both NASH and atherosclerosis. Bulk RNA-Seq of RNA isolated from Ldlr-/- or E06-scFvLdlr-/- mice fed AMLN diet.

氧化磷脂（Oxidized phospholipids, OxPL）兼具促炎与致动脉粥样硬化活性，但其在非酒精性脂肪性肝炎（NASH）中的功能作用尚未明确。本研究证实，OxPL可在人类及小鼠NASH模型组织中蓄积。通过构建表达可中和OxPL的天然抗体E06的功能性单链可变片段的转基因小鼠，我们验证了OxPL在NASH发生发展中的因果作用。在高脂血症性Ldlr-/-小鼠中靶向干预OxPL，可显著改善NASH的多项病理特征，包括脂肪变性、炎症反应、纤维化、肝细胞死亡及肝细胞癌进展。机制研究显示，OxPL可促进活性氧（Reactive Oxygen Species, ROS）蓄积，进而诱导肝细胞线粒体功能障碍。在经AMLN饮食喂养的Ldlr-/-或E06-scFvLdlr-/-小鼠中中和OxPL，可减轻氧化应激，改善肝脏与脂肪组织的线粒体功能及脂肪酸氧化过程。鉴于中和OxPL同时可抑制动脉粥样硬化发生，靶向OxPL或可成为同时针对NASH与动脉粥样硬化的有效治疗策略。本数据集包含经AMLN饮食喂养的Ldlr-/-或E06-scFvLdlr-/-小鼠的分离RNA的批量RNA测序（Bulk RNA-Seq）数据。