Mdivi1 ameliorates mitochondrial dysfunction in non‐alcoholic steatohepatitis by inhibiting JNK/MFF signaling

作者：Ying Quan, Diwen Shou, Siqi Yang, Jiemin Cheng, Yongqiang Li, Chen Huang, Huiting Chen, Yongjian Zhou · 发表于：Journal of Gastroenterology and Hepatology · 年份：2023 · DOI：10.1111/jgh.16372 · 被引用次数：16 · 研究领域：Liver Disease Diagnosis and Treatment、Mitochondrial Function and Pathology、Liver physiology and pathology

BACKGROUND AND AIMS: Mitochondrial dysfunction plays a crucial role in the progression of non-alcoholic steatohepatitis (NASH). Mitochondrial division inhibitor 1 (Mdivi1) is a potential inhibitor of dynamin-related protein (Drp1) and mitochondrial fission. However, the therapeutic effect of Mdivi1 against NASH and its underlying molecular mechanisms remain unclear. METHODS: In this study, we established mouse models of NASH by inducing high-fat/high-cholesterol (HFHC) or methionine- and choline-deficient (MCD) diets and treated the animals with 5 mg/kg/day Mdivi1 or placebo. RESULTS: Treatment with Mdivi1 significantly alleviated diet-induced fatty liver phenotypes, including increased liver weight/body weight ratio, insulin resistance, hepatic lipid accumulation, steatohepatitis, and liver injury. Furthermore, Mdivi1 treatment suppressed HFHC or MCD diet-induced changes in the expression of genes related to lipid metabolism and inflammatory cytokines. Additionally, Mdivi1 reduced macrophage infiltration in the injured liver and promoted polarization of macrophages towards the M1 phenotype. At the molecular level, Mdivi1 attenuated mitochondrial fission by reducing Drp1 activation and expression, thereby decreasing mitochondrial reactive oxygen species accumulation and mitochondrial DNA damage. Moreover, Mdivi1-treated mice exhibited elevated levels of phosphorylated-c-Jun N-terminal kinase (p-JNK), mitochondrial fission factor (MFF), cleaved caspase 3 protein, and TUNEL-pos...