The m6A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m6A dependent manner.

Meng-Yun Ke, Yi Fang, Hui Cai, Jian-Wen Lu, Lin Yang, Yue Wang, Rong-Qian Wu, Xu-Feng Zhang, Yi Lv, Jian Dong

International journal of biological sciences 2023

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Background and Aims: N6-methyladenosine (m6A) is the most common post-transcriptional modification of RNA in eukaryotes, which has been demonstrated to play important roles in various biological processes. However, its roles in fulminant hepatitis remain largely unknown. In the current study, YTHDF1 expression was found to be significantly downregulated in the livers among patients, as well as murine models with fulminant hepatitis versus normal controls. Thus, we hypothesized that YTHDF1 protects against fulminant hepatitis and investigated the underlying molecular mechanisms. Methods: Fulminant hepatitis was induced by D-GalN/LPS in conventional YTHDF1 knockout (YTHDF1-/-) mice, hepatocyte-specific YTHDF1 overexpression (AAV8- YTHDF1) mice, and corresponding control mice. Primary hepatocytes were cultured and subjected to LPS insult in vitro. Hepatic histology, cell death, oxidative stress and mitochondrial function were examined to assess liver damage. The molecular mechanisms of YTHDF1 function were explored using multi-omics analysis. Results: Ablation of YTHDF1 exacerbated hepatic apoptosis and reactive oxygen species (ROS) production and increased the number of aberrant mitochondria, while YTHDF1 overexpression resulted in the opposite effects. Multiomics analysis identified MFG-E8 as the direct target of YTHDF1. YTHDF1 augmented the translation of MFG-E8 in an m6A-dependent manner without effect on its mRNA expression, thereby restoring mitochondrial function. Additionally, administration of MFG-E8 almost completely reversed the YTHDF1 deficiency-mediated exacerbation of liver injury. Conclusions: The current study suggested that the m6A reader YTHDF1 alleviates cell death, enhances antioxidant capacity and restores mitochondrial function in fulminant hepatitis by promoting MFG-E8 protein translation in an m6A-dependent manner. © The author(s).

Citation

Meng-Yun Ke, Yi Fang, Hui Cai, Jian-Wen Lu, Lin Yang, Yue Wang, Rong-Qian Wu, Xu-Feng Zhang, Yi Lv, Jian Dong. The m6A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m6A dependent manner. International journal of biological sciences. 2023;19(12):3987-4003