Targeting ferroptosis alleviates methionine-choline deficient (MCD)-diet induced NASH by suppressing liver lipotoxicity
Targeting ferroptosis alleviates methionine-choline deficient (MCD)-diet induced NASH by suppressing liver lipotoxicity
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DOI：
10.1111/liv.14428
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发表时间：
2020-03-20
影响因子：
6.7
通讯作者：
Yuan, Hai-Xin
中科院分区：
文献类型：
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作者：
Li, Xiaoya;Wang, Tian-Xiang;Yuan, Hai-Xin
NASH是发展最快的肝脏疾病之一，可导致严重的脂肪变性、炎症和最终的肝损伤。然而，NASH的病理生理机制仍不清楚，目前尚无针对该疾病的药物治疗。铁凋亡是由铁依赖性脂质过氧化诱导的非凋亡形式的细胞死亡。由于NASH进展伴随着大量的脂质积累，这产生脂毒性物质，我们研究了铁凋亡在NASH进展中的作用。方法用MCD饮食喂养小鼠以模拟NASH进展，并通过RNA-seq分析肝脏中的基因表达。通过脂质ROS水平、电镜和体内PI染色检测肝脏铁凋亡的发生。通过肝脏病理学分析评估铁凋亡抑制剂对NASH的有益作用。结果RNA-seq分析表明，花生四烯酸代谢水平的升高促进了MCD小鼠肝脏的铁凋亡，并进一步通过脂质ROS的积累、线粒体的形态学改变和细胞死亡的增加来证实。铁的积累，检测到在肝脏和血清中的MCD喂养小鼠。清除铁中毒相关的脂质过氧化物减少体内和体外的脂质蓄积。重要的是，铁凋亡抑制剂减轻了MCD饮食诱导的炎症、纤维化和肝损伤。最后，脂质活性氧促进肝脏脂肪变性，通过促进脂滴formation.Conclusion我们的研究结果表明，在MCD饮食诱导的NASH的进展中的重要作用，并建议，ferroptosis可以作为NASH治疗的治疗靶点。
Background NASH is one of the fastest growing liver diseases that leads to severe steatosis, inflammation and ultimately liver injury. However, the pathophysiological mechanisms of NASH remain unclear and pharmacological treatment against the disease is unavailable currently. Ferroptosis is a non-apoptotic form of cell death induced by iron-dependent lipid peroxidation. Since NASH progression is accompanied by massive lipid accumulation, which generates lipotoxic species, we investigated the role of ferroptosis in NASH progression.Method Mice were fed on MCD-diet to mimic NASH progression and gene expression in liver was analysed by RNA-seq. The occurrence of hepatic ferroptosis was measured by lipid ROS level, electron microscopy and in vivo PI staining. The beneficial effects of ferroptosis inhibitors on NASH was evaluated by liver pathology analysis. The mechanism of lipid ROS induced lipid droplets accumulation was investigated by in vitro cell culture.Results RNA-seq analysis suggested that elevated arachidonic acid metabolism promotes ferroptosis in MCD-diet fed mouse livers, which was further demonstrated by lipid ROS accumulation, morphological change of mitochondria and increased cell death. Iron accumulation was detected in the liver and the serum of MCD-fed mice. Scavenging of ferroptosis-linked lipid peroxides reduced lipid accumulation both in vivo and in vitro. Importantly, ferroptosis inhibitors alleviated MCD-diet induced inflammation, fibrogenesis and liver injury. Finally, lipid ROS promotes liver steatosis by boosting lipid droplets formation.Conclusion Our results demonstrate an important role of ferroptosis in the progression of MCD-diet induced NASH and suggest that ferroptosis may serve as a therapeutic target for NASH treatment.