Oxidized phospholipids (OxPLs), which arise due to oxidative stress, are proinflammatory and proatherogenic, but their roles in non-alcoholic steatohepatitis (NASH) are unknown. Here, we show that OxPLs accumulate in human and mouse NASH. Using a transgenic mouse that expresses a functional single-chain variable fragment of E06, a natural antibody that neutralizes OxPLs, we demonstrate the causal role of OxPLs in NASH. Targeting OxPLs in hyperlipidemic Ldlr-/- mice improved multiple aspects of NASH, including steatosis, inflammation, fibrosis, hepatocyte death, and progression to hepatocellular carcinoma. Mechanistically, we found that OxPLs promote ROS accumulation to induce mitochondrial dysfunction in hepatocytes. Neutralizing OxPLs in AMLN-diet-fed Ldlr-/- mice reduced oxidative stress, improved hepatic and adipose-tissue mitochondrial function, and fatty-acid oxidation. These results suggest targeting OxPLs may be an effective therapeutic strategy for NASH.

中文翻译：

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氧化磷脂的中和可改善非酒精性脂肪性肝炎。

由于氧化应激而产生的氧化磷脂 (OxPLs) 具有促炎和促动脉粥样硬化的作用，但它们在非酒精性脂肪性肝炎 (NASH) 中的作用尚不清楚。在这里，我们表明 OxPLs 在人和小鼠 NASH 中积累。我们使用表达 E06 的功能性单链可变片段（一种中和 OxPLs 的天然抗体）的转基因小鼠，证明了 OxPLs 在 NASH 中的因果作用。在高脂血症 Ldlr-/- 小鼠中靶向 OxPLs 改善了 NASH 的多个方面，包括脂肪变性、炎症、纤维化、肝细胞死亡和进展为肝细胞癌。从机制上讲，我们发现 OxPLs 促进 ROS 积累以诱导肝细胞中的线粒体功能障碍。中和 AMLN 饮食喂养的 Ldlr-/- 小鼠中的 OxPLs 可减少氧化应激，改善肝脏和脂肪组织线粒体功能以及脂肪酸氧化。这些结果表明靶向 OxPLs 可能是 NASH 的有效治疗策略。