已知非酒精性脂肪性肝炎 (NASH) 在某些患者中会进展为肝硬化和肝细胞癌。尽管NASH与脂质代谢相关的线粒体功能异常有关，但其发生机制和有效治疗仍不清楚。因此，需要新的方法来阐明病理生理学。在之前的研究中，我们从 NASH 模型小鼠的不同阶段生成了肝脏类器官，可以重现 NASH 病理学的一部分。在本研究中，我们通过比较 NASH 肝类器官（NLO）和对照肝类器官（CLO）来研究线粒体功能与 NASH 疾病之间的关系。与 CLO 相比，NLO 中线粒体和类器官形态异常，线粒体有丝分裂原蛋白、DRP1 表达增加，线粒体源性活性氧 (ROS) 产生增加。用 DPR1 抑制剂 Mdivi-1 治疗 NLO 可改善形态并减少纤维化相关标志物 Col1a1 和 Acta2 的表达。此外，用Mdivi-1治疗NASH模型小鼠显示脂肪肝减少。 Mdivi-1 治疗还可以防止肝脏纤维化和 ROS 产生。这些结果表明，与 CLO 相比，NLO 的代谢增强，线粒体形态异常。还有人建议，Mdivi-1 可用作改善 NASH 病理学的治疗剂。版权所有 © 2023 Elbadawy、Tanabe、Yamamoto、Ishihara、Mochizuki、Abugomaa、Yamawaki、Kaneda、Usui 和 Sasaki。

Non-alcoholic steatohepatitis (NASH) is known to progress to cirrhosis and hepatocellular carcinoma in some patients. Although NASH is associated with abnormal mitochondrial function related to lipid metabolism, mechanisms for the development and effective treatments are still unclear. Therefore, new approaches to elucidate the pathophysiology are needed. In the previous study, we generated liver organoids from different stages of NASH model mice that could recapitulate the part of NASH pathology. In the present study, we investigated the relationship between mitochondrial function and NASH disease by comparing NASH liver organoids (NLO) and control liver organoids (CLO). Compared with CLO, mitochondrial and organoid morphology was abnormal in NLO, with increased expression of mitochondrial mitogen protein, DRP1, and mitochondria-derived reactive oxygen species (ROS) production. Treatment of NLO with a DPR1 inhibitor, Mdivi-1 resulted in the improvement of morphology and the decreased expression of fibrosis-related markers, Col1a1 and Acta2. In addition, treatment of NASH model mice with Mdivi-1 showed a decrease in fatty liver. Mdivi-1 treatment also prevented fibrosis and ROS production in the liver. These results indicate that NLO undergoes enhanced metabolism and abnormal mitochondrial morphology compared with CLO. It was also suggested that Mdivi-1 may be useful as a therapeutic agent to ameliorate NASH pathology.Copyright © 2023 Elbadawy, Tanabe, Yamamoto, Ishihara, Mochizuki, Abugomaa, Yamawaki, Kaneda, Usui and Sasaki.