南方医科大学学报

南方医科大学学报 ›› 2023, Vol. 43 ›› Issue (10): 1689-1696.doi: 10.12122/j.issn.1673-4254.2023.10.06

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甲基转移酶样3抑制剂STM2457通过调节线粒体功能改善代谢相关脂肪性肝病

高毅男，王培君，逯素梅，马万山   

  1. 山东第一医科大学第一附属医院（山东省千佛山医院）检验科//山东省医药卫生临床检验诊断学重点实验室，山东 济南 250014
  • 出版日期:2023-10-20 发布日期:2023-11-02

METTL3 inhibitor STM2457 improves metabolic dysfunction-associated fatty liver disease by regulating mitochondrial function in mice

GAO Yinan, WANG Peijun, LU Sumei, MA Wanshan   

  1. Department of Clinical Laboratory Medicine, First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Shandong Medicine and Health Key Laboratory of Laboratory Medicine, Jinan 250014, China
  • Online:2023-10-20 Published:2023-11-02

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摘要： 目的 探讨甲基转移酶样3（METTL3）特异性抑制剂STM2457在代谢相关脂肪性肝病（MAFLD）中的作用及机制。方法 动物水平：15只SPF级雄性C57BL/6J小鼠随机分为基础组（CD组，n=5，10%低脂饲料喂养16周）、高脂组（HFD组，n=5，60%高脂饲料喂养16周，建模MAFLD）、STM2457组（STM组，n=5，60%高脂饲料建模小鼠MAFLD后，给予STM245750 mg/kg腹腔注射2周）。斑点杂交实验（Dot-blot）检测小鼠肝组织m6A修饰水平，检测各组肝组织匀浆甘油三酯（TG）、谷丙转氨酶（ALT）、谷草转氨酶（AST）含量，HE染色观察小鼠肝组织形态，IPGTT和IPITT检验小鼠胰岛素抵抗程度，代谢笼实验检测代谢方式的改变，透射电镜(TEM)检测线粒体的形态。细胞生物学水平：油酸钠/棕榈酸钠作用48 h诱导建立人肝癌细胞株HepG2脂肪变性模型（FFA）。STM2457组在诱导脂肪变性的同时给予STM2457（1 μmol/L）作用48 h，通过线粒体膜电位荧光探针（JC-1）检测线粒体功能。结果 经高脂饮食诱导建立的MAFLD模型小鼠，其肝组织中m6A修饰水平升高，METT3的mRNA表达上调，与CD组比较，HFD组METT3的mRNA表达上调1.557±0.074倍（P<0.05），而在STM2457作用下，小鼠体质量显著下降且肝脏脂质沉积减少，肝组织m6A修饰水平下降，葡萄糖耐量和胰岛素敏感性升高，肝组织匀浆TG含量减少，（P<0.05），血清ALT、AST含量降低（P<0.05），。HFD组肝细胞线粒体肿胀明显，线粒体膜电位下降，STM2457作用后线粒体形态恢复正常，膜电位上升（P<0.05）。结论 METTL3抑制剂STM2457能够通过减轻高脂饮食诱导的线粒体损伤改善MAFLD。

关键词: m6A甲基化修饰；甲基转移酶样3；STM2457；代谢相关脂肪性肝病；线粒体

Abstract: Objective To investigate the effect of methyltransferase-like 3 (METTL3) inhibitor STM2457 in metabolic dysfunction-associated fatty liver disease (MAFLD). Methods C57BL/6J mouse models of MAFLD induced by high-fat diet feeding for 16 weeks were treated with intraperitoneal injections of STM2457 (50 mg/kg) for 2 weeks. The changes in m6A modification level in the liver tissue of the mice were determined with dot-blot hybridization, and the hepatic levels of triglyceride (TG), alanine aminotransferase (ALT) and glutathione aminotransferase (AST) were detected. The histological changes of the liver and changes in insulin resistance and metabolic profile of the mice were evaluated using HE staining, insulin tolerance tests and metabolic cages; transmission electron microscopy (TEM) was employed to examine the changes in mitochondrial morphology. In a HepG2 cell model of steatosis induced by treatment with sodium oleate/sodium palmitate for 48 h, the protective effect of STM2457 (1 μmol/L) on mitochondrial function was assessed by measuring mitochondrial membrane potential using a fluorescence probe (JC-1). Results The mouse models of MAFLD showed significant elevation of m6A modification level in the liver tissues and obviously upregulated mRNA expression of METT3 (P<0.05). Treatment with STM2457 significantly reduced body weight and liver lipid deposition and m6A modification levels, increased glucose tolerance and insulin sensitivity, lowered hepatic TG and serum ALT and AST levels, and increased respiratory entropy (RQ) in the mouse models (all P<0.05). HepG2 cells with steatosis exhibited obvious mitochondrial swelling with decreased mitochondrial membrane potential, but the STM2457-treated cells maintained a normal mitochondrial morphology with a higher membrane potential (P<0.05). Conclusion The METTL3 inhibitor STM2457 improves MAFLD by reducing high-fat diet-induced mitochondrial damage in mice.

Key words: m6A methylation modification; METTL3; STM2457; metabolic dysfunction-associated fatty liver disease; mitochondria