Elbadawy Mohamed, Tanabe Kiwamu, Yamamoto Haru, Ishihara Yusuke, Mochizuki Maria, Abugomaa Amira, Yamawaki Hideyuki, Kaneda Masahiro, Usui Tatsuya, Sasaki Kazuaki
Laboratory of Veterinary Pharmacology, Department of Veterinary Medicine, Faculty of Agriculture, Tokyo University of Agriculture and Technology, Tokyo, Japan.
Department of Pharmacology, Faculty of Veterinary Medicine, Benha University, Benha, Egypt.
Front Pharmacol. 2023 Oct 12;14:1243258. doi: 10.3389/fphar.2023.1243258. eCollection 2023.
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, and . 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.
已知非酒精性脂肪性肝炎（NASH）在一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，但其发病机制和有效治疗方法仍不清楚。因此，需要新的方法来阐明其病理生理学。在先前的研究中，我们从NASH模型小鼠的不同阶段生成了肝类器官，其可以重现部分NASH病理。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），研究了线粒体功能与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，线粒体促分裂原蛋白DRP1的表达增加，且线粒体衍生的活性氧（ROS）生成增加。用DRP1抑制剂Mdivi-1处理NLO可改善形态，并降低纤维化相关标志物的表达。此外，用Mdivi-1处理NASH模型小鼠可使脂肪肝减轻。Mdivi-1处理还可预防肝脏纤维化和ROS生成。这些结果表明，与CLO相比，NLO经历了增强的代谢和异常的线粒体形态。还表明Mdivi-1可能作为改善NASH病理的治疗剂。
