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The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner

Background and Aims: N6-methyladenosine (m(6)A) 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, YTHD...

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Autores principales: Ke, Meng-Yun, Fang, Yi, Cai, Hui, Lu, Jian-Wen, Yang, Lin, Wang, Yue, Wu, Rong-Qian, Zhang, Xu-Feng, Lv, Yi, Dong, Jian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Ivyspring International Publisher 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411475/
https://www.ncbi.nlm.nih.gov/pubmed/37564203
http://dx.doi.org/10.7150/ijbs.84768
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author Ke, Meng-Yun
Fang, Yi
Cai, Hui
Lu, Jian-Wen
Yang, Lin
Wang, Yue
Wu, Rong-Qian
Zhang, Xu-Feng
Lv, Yi
Dong, Jian
author_facet Ke, Meng-Yun
Fang, Yi
Cai, Hui
Lu, Jian-Wen
Yang, Lin
Wang, Yue
Wu, Rong-Qian
Zhang, Xu-Feng
Lv, Yi
Dong, Jian
author_sort Ke, Meng-Yun
collection PubMed
description Background and Aims: N6-methyladenosine (m(6)A) 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 m(6)A-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 m(6)A reader YTHDF1 alleviates cell death, enhances antioxidant capacity and restores mitochondrial function in fulminant hepatitis by promoting MFG-E8 protein translation in an m(6)A-dependent manner.
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spelling pubmed-104114752023-08-10 The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner Ke, Meng-Yun Fang, Yi Cai, Hui Lu, Jian-Wen Yang, Lin Wang, Yue Wu, Rong-Qian Zhang, Xu-Feng Lv, Yi Dong, Jian Int J Biol Sci Research Paper Background and Aims: N6-methyladenosine (m(6)A) 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 m(6)A-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 m(6)A reader YTHDF1 alleviates cell death, enhances antioxidant capacity and restores mitochondrial function in fulminant hepatitis by promoting MFG-E8 protein translation in an m(6)A-dependent manner. Ivyspring International Publisher 2023-07-31 /pmc/articles/PMC10411475/ /pubmed/37564203 http://dx.doi.org/10.7150/ijbs.84768 Text en © The author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/). See http://ivyspring.com/terms for full terms and conditions.
spellingShingle Research Paper
Ke, Meng-Yun
Fang, Yi
Cai, Hui
Lu, Jian-Wen
Yang, Lin
Wang, Yue
Wu, Rong-Qian
Zhang, Xu-Feng
Lv, Yi
Dong, Jian
The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner
title The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner
title_full The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner
title_fullStr The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner
title_full_unstemmed The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner
title_short The m(6)A reader YTHDF1 attenuates fulminant hepatitis via MFG-E8 translation in an m(6)A dependent manner
title_sort m(6)a reader ythdf1 attenuates fulminant hepatitis via mfg-e8 translation in an m(6)a dependent manner
topic Research Paper
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10411475/
https://www.ncbi.nlm.nih.gov/pubmed/37564203
http://dx.doi.org/10.7150/ijbs.84768
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