Health Management Center, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; The Sichuan Provincial Key Laboratory for Human Disease Gene Study and Department of Laboratory Medicine, Center for Medical Genetics, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, Sichuan 610072, China; Henan Eye Institute, Henan Eye Hospital, People's Hospital of Zhengzhou University, Henan Provincial People's Hospital, Zhengzhou, Henan 450003, China; School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
Mol Ther. 2022 Jun 1;30(6):2342-2353. doi: 10.1016/j.ymthe.2022.02.021. Epub 2022 Feb 19.
Type 2 diabetes mellitus (DM2) is associated closely with non-alcoholic fatty liver disease (NAFLD) by affecting lipid metabolism, which may lead to non-alcoholic steatohepatitis (NASH), fibrosis, and hepatocellular carcinoma (HCC). N-methyladenosine (m6A) RNA methylation is an important epigenetic regulation for gene expression and is related to HCC development. We developed a new NAFLD model oriented from DM2 mouse, which spontaneously progressed to histological features of NASH, fibrosis, and HCC with high incidence. By RNA sequencing, protein expression and methylated RNA immunoprecipitation (MeRIP)-qPCR analysis, we found that enhanced expression of ACLY and SCD1 in this NAFLD model and human HCC samples was due to excessive m6A modification, but not elevation of mature SREBP1. Moreover, targeting METTL3/14 in vitro increases protein level of ACLY and SCD1 as well as triglyceride and cholesterol production and accumulation of lipid droplets. m6A sequencing analysis revealed that overexpressed METTL14 binds to mRNA of ACLY and SCD1 and alters their expression pattern. Our findings demonstrate a new NAFLD mouse model that provides a study platform for DM2-related NAFLD and reveals a unique epitranscriptional regulating mechanism for lipid metabolism via m6A-modified protein expression of ACLY and SCD1.
2 型糖尿病（DM2）通过影响脂质代谢与非酒精性脂肪性肝病（NAFLD）密切相关，这可能导致非酒精性脂肪性肝炎（NASH）、纤维化和肝细胞癌（HCC）。N6-甲基腺苷（m6A）RNA 甲基化是一种重要的基因表达表观遗传调控，与 HCC 的发生发展有关。我们从 DM2 小鼠中开发了一种新的 NAFLD 模型，该模型自发进展为 NASH、纤维化和 HCC 的组织学特征，发病率较高。通过 RNA 测序、蛋白表达和 m6A RNA 免疫沉淀（MeRIP）-qPCR 分析，我们发现 ACLY 和 SCD1 在该 NAFLD 模型和人 HCC 样本中的高表达是由于 m6A 修饰过度，而不是成熟 SREBP1 的升高。此外，体外靶向 METTL3/14 会增加 ACLY 和 SCD1 的蛋白水平以及甘油三酯和胆固醇的产生和脂质滴的积累。m6A 测序分析显示，过表达的 METTL14 与 ACLY 和 SCD1 的 mRNA 结合，并改变它们的表达模式。我们的研究结果表明，一种新的 NAFLD 小鼠模型为 DM2 相关的 NAFLD 提供了一个研究平台，并揭示了一种通过 m6A 修饰的 ACLY 和 SCD1 蛋白表达来调节脂质代谢的独特转录后调控机制。
