E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis
Abstract Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction‐associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macr...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410880 |
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| author | Zheng Liu Hao Wang Yuan Liang Mu Liu Qiyuan Huang Mingming Wang Jinren Zhou Qingfa Bu Haoming Zhou Ling Lu |
| author_facet | Zheng Liu Hao Wang Yuan Liang Mu Liu Qiyuan Huang Mingming Wang Jinren Zhou Qingfa Bu Haoming Zhou Ling Lu |
| author_sort | Zheng Liu |
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| description | Abstract Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction‐associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macrophage E2F2 is dramatically downregulated in MASH livers from mice and humans, and that this expression is adversely correlated with the severity of the disease. Myeloid‐specific E2F2 depletion aggravates intrahepatic inflammation, hepatic stellate cell activation, and hepatocyte lipid accumulation during MASH progression. Mechanistically, E2F2 can inhibit the SLC7A5 transcription directly. E2F2 deficiency upregulates the expression of SLC7A5 to mediate amino acids flux, resulting in enhanced glycolysis, impaired mitochondrial function, and increased macrophages proinflammatory response in a Leu‐mTORC1‐dependent manner. Moreover, bioinformatics analysis and CUT &Tag assay identify the direct binding of Nrf2 to E2F2 promoter to promote its transcription and nuclear translocation. Genetic or pharmacological activation of Nrf2 effectively activates E2F2 to attenuate the MASH progression. Finally, patients treated with CDK4/6 inhibitors demonstrate reduced E2F2 activity but increased SLC7A5 activity in PBMCs. These findings indicated macrophage E2F2 suppresses MASH progression by reprogramming amino acid metabolism via SLC7A5‐ Leu‐mTORC1 signaling pathway. Activating E2F2 holds promise as a therapeutic strategy for MASH. |
| format | Article |
| id | doaj-art-64477c1964ae451787fad05c22e5d44a |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-64477c1964ae451787fad05c22e5d44a2025-08-20T02:43:28ZengWileyAdvanced Science2198-38442024-12-011148n/an/a10.1002/advs.202410880E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated SteatohepatitisZheng Liu0Hao Wang1Yuan Liang2Mu Liu3Qiyuan Huang4Mingming Wang5Jinren Zhou6Qingfa Bu7Haoming Zhou8Ling Lu9Department of General Surgery the First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of Liver Surgery State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 ChinaHepatobiliary Center The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology Chinese Academy of Medical Sciences Nanjing 210029 ChinaHepatobiliary Center The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology Chinese Academy of Medical Sciences Nanjing 210029 ChinaHepatobiliary Center The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology Chinese Academy of Medical Sciences Nanjing 210029 ChinaDepartment of Liver Surgery State Key Laboratory of Complex Severe and Rare Diseases Peking Union Medical College Hospital Chinese Academy of Medical Sciences and Peking Union Medical College Beijing 100730 ChinaHepatobiliary Center The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology Chinese Academy of Medical Sciences Nanjing 210029 ChinaHepatobiliary Center The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology Chinese Academy of Medical Sciences Nanjing 210029 ChinaHepatobiliary Center The First Affiliated Hospital of Nanjing Medical University & Research Unit of Liver Transplantation and Transplant Immunology Chinese Academy of Medical Sciences Nanjing 210029 ChinaAffiliated Hospital of Xuzhou Medical University Xuzhou 220005 ChinaAbstract Macrophages are essential for the development of steatosis, hepatic inflammation, and fibrosis in metabolic dysfunction‐associated steatohepatitis(MASH). However, the roles of macrophage E2F2 in the progression of MASH have not been elucidated. This study reveals that the expression of macrophage E2F2 is dramatically downregulated in MASH livers from mice and humans, and that this expression is adversely correlated with the severity of the disease. Myeloid‐specific E2F2 depletion aggravates intrahepatic inflammation, hepatic stellate cell activation, and hepatocyte lipid accumulation during MASH progression. Mechanistically, E2F2 can inhibit the SLC7A5 transcription directly. E2F2 deficiency upregulates the expression of SLC7A5 to mediate amino acids flux, resulting in enhanced glycolysis, impaired mitochondrial function, and increased macrophages proinflammatory response in a Leu‐mTORC1‐dependent manner. Moreover, bioinformatics analysis and CUT &Tag assay identify the direct binding of Nrf2 to E2F2 promoter to promote its transcription and nuclear translocation. Genetic or pharmacological activation of Nrf2 effectively activates E2F2 to attenuate the MASH progression. Finally, patients treated with CDK4/6 inhibitors demonstrate reduced E2F2 activity but increased SLC7A5 activity in PBMCs. These findings indicated macrophage E2F2 suppresses MASH progression by reprogramming amino acid metabolism via SLC7A5‐ Leu‐mTORC1 signaling pathway. Activating E2F2 holds promise as a therapeutic strategy for MASH.https://doi.org/10.1002/advs.202410880amino acid transportationglycolysismacrophagemetabolic dysfunction‐associated steatohepatitisslc7a5 |
| spellingShingle | Zheng Liu Hao Wang Yuan Liang Mu Liu Qiyuan Huang Mingming Wang Jinren Zhou Qingfa Bu Haoming Zhou Ling Lu E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis Advanced Science amino acid transportation glycolysis macrophage metabolic dysfunction‐associated steatohepatitis slc7a5 |
| title | E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis |
| title_full | E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis |
| title_fullStr | E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis |
| title_full_unstemmed | E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis |
| title_short | E2F2 Reprograms Macrophage Function By Modulating Material and Energy Metabolism in the Progression of Metabolic Dysfunction‐Associated Steatohepatitis |
| title_sort | e2f2 reprograms macrophage function by modulating material and energy metabolism in the progression of metabolic dysfunction associated steatohepatitis |
| topic | amino acid transportation glycolysis macrophage metabolic dysfunction‐associated steatohepatitis slc7a5 |
| url | https://doi.org/10.1002/advs.202410880 |
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