Li Qunhua, Xiang Junying
Department of Gastroenterology, Affiliated Hospital of Chengdu University, 2nd N Section of 2nd Ring Rd, Chengdu, 610036, Sichuan, China.
Sci Rep. 2025 Feb 20;15(1):6162. doi: 10.1038/s41598-025-90419-z.
N6-methyladenosine (m6A) is involved in the development of non-alcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the effect of m6A methyltransferase METTL3 on liver damage in high-fat diet (HFD)-induced mouse model and hepatocyte damage treated with free fatty acid (FFA). Plasma lipid, lipogenesis, viability, and apoptosis were measured to assess injury. m6A methylation was evaluated using m6A dot blot, methylated RNA immunoprecipitation, dual-luciferase reporter assay, and RNA decay assay. The results indicated that METTL3 was highly expressed in the liver of HFD mice, which knockdown improved plasma lipid and reduced liver lipids. Additionally, silencing of METTL3 promoted cell viability, inhibited apoptosis, reduced lipid concentrations, and downregulated lipogenesis-related marker levels. Moreover, METTL3 promoted the m6A methylation of FAS and enhanced its stability. In conclusion, silencing of METTL3 attenuates the progression of NAFLD by FAS m6A methylation, suggesting that METTL3 may be a promising target for treating NAFLD.
N6-甲基腺苷（m6A）参与非酒精性脂肪性肝病（NAFLD）的发展。在此，我们旨在研究m6A甲基转移酶METTL3在高脂饮食（HFD）诱导的小鼠模型中的肝损伤以及游离脂肪酸（FFA）处理的肝细胞损伤中的作用。通过检测血浆脂质、脂肪生成、细胞活力和细胞凋亡来评估损伤情况。使用m6A斑点印迹、甲基化RNA免疫沉淀、双荧光素酶报告基因检测和RNA降解检测来评估m6A甲基化。结果表明，METTL3在HFD小鼠肝脏中高表达，敲低该基因可改善血浆脂质并降低肝脏脂质。此外，沉默METTL3可促进细胞活力、抑制细胞凋亡、降低脂质浓度并下调脂肪生成相关标志物水平。而且，METTL3促进脂肪酸合酶（FAS）的m6A甲基化并增强其稳定性。总之，沉默METTL3通过FAS的m6A甲基化减弱NAFLD的进展，提示METTL3可能是治疗NAFLD的一个有前景的靶点。
