Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges
As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1...
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eLife Sciences Publications Ltd
2025-01-01
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| Online Access: | https://elifesciences.org/articles/96798 |
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| author | Weigao Zhang Hu Liu Danyang Zhang Yuguo Yi Liang Tao Yunfeng Zhu Shuxian Huang Xunan Zhao Qianchao Shao Peiqi Li Yiwen Weng Wei Lu Jianfa Zhang Haibing Zhang Yuxin Chen Dan Weng |
| author_facet | Weigao Zhang Hu Liu Danyang Zhang Yuguo Yi Liang Tao Yunfeng Zhu Shuxian Huang Xunan Zhao Qianchao Shao Peiqi Li Yiwen Weng Wei Lu Jianfa Zhang Haibing Zhang Yuxin Chen Dan Weng |
| author_sort | Weigao Zhang |
| collection | DOAJ |
| description | As a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1-hepKO) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1-hepKO mice, with up-regulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1-hepKO mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1-hepKO mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism. |
| format | Article |
| id | doaj-art-914ce9bf0b9e4147bdc5a66572fe240c |
| institution | Kabale University |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-914ce9bf0b9e4147bdc5a66572fe240c2025-01-31T11:44:03ZengeLife Sciences Publications LtdeLife2050-084X2025-01-011310.7554/eLife.96798Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challengesWeigao Zhang0Hu Liu1Danyang Zhang2Yuguo Yi3Liang Tao4Yunfeng Zhu5Shuxian Huang6Xunan Zhao7Qianchao Shao8Peiqi Li9Yiwen Weng10Wei Lu11Jianfa Zhang12https://orcid.org/0000-0002-8814-9103Haibing Zhang13Yuxin Chen14Dan Weng15https://orcid.org/0000-0001-8078-6864School of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, China; Department of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaSchool of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, ChinaThe First Affiliated Hospital, Basic Medical Sciences, University of South China, Hengyang, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaInternal Medicine Department, Chengdu Jinniu District People's Hospital, Chengdu, ChinaAffiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Shanghai, ChinaDepartment of Laboratory Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, ChinaSchool of Environmental and Biological Engineering, Key Laboratory of Metabolic Engineering and Biosynthesis Technology, Ministry of Industry and Information Technology, Nanjing University of Science and Technology, Nanjing, ChinaAs a central hub for metabolism, the liver exhibits strong adaptability to maintain homeostasis in response to food fluctuations throughout evolution. However, the mechanisms governing this resilience remain incompletely understood. In this study, we identified Receptor interacting protein kinase 1 (RIPK1) in hepatocytes as a critical regulator in preserving hepatic homeostasis during metabolic challenges, such as short-term fasting or high-fat dieting. Our results demonstrated that hepatocyte-specific deficiency of RIPK1 sensitized the liver to short-term fasting-induced liver injury and hepatocyte apoptosis in both male and female mice. Despite being a common physiological stressor that typically does not induce liver inflammation, short-term fasting triggered hepatic inflammation and compensatory proliferation in hepatocyte-specific RIPK1-deficient (Ripk1-hepKO) mice. Transcriptomic analysis revealed that short-term fasting oriented the hepatic microenvironment into an inflammatory state in Ripk1-hepKO mice, with up-regulated expression of inflammation and immune cell recruitment-associated genes. Single-cell RNA sequencing further confirmed the altered cellular composition in the liver of Ripk1-hepKO mice during fasting, highlighting the increased recruitment of macrophages to the liver. Mechanically, our results indicated that ER stress was involved in fasting-induced liver injury in Ripk1-hepKO mice. Overall, our findings revealed the role of RIPK1 in maintaining liver homeostasis during metabolic fluctuations and shed light on the intricate interplay between cell death, inflammation, and metabolism.https://elifesciences.org/articles/96798fastingRIPK1liver homeostasisinflammationER stress |
| spellingShingle | Weigao Zhang Hu Liu Danyang Zhang Yuguo Yi Liang Tao Yunfeng Zhu Shuxian Huang Xunan Zhao Qianchao Shao Peiqi Li Yiwen Weng Wei Lu Jianfa Zhang Haibing Zhang Yuxin Chen Dan Weng Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges eLife fasting RIPK1 liver homeostasis inflammation ER stress |
| title | Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges |
| title_full | Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges |
| title_fullStr | Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges |
| title_full_unstemmed | Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges |
| title_short | Role of hepatocyte RIPK1 in maintaining liver homeostasis during metabolic challenges |
| title_sort | role of hepatocyte ripk1 in maintaining liver homeostasis during metabolic challenges |
| topic | fasting RIPK1 liver homeostasis inflammation ER stress |
| url | https://elifesciences.org/articles/96798 |
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