Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration
Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipi...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2023-12-01
|
| Series: | JHEP Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589555923002379 |
| _version_ | 1797435723970772992 |
|---|---|
| author | Guoqiang Li Lijun Zhu Mingwei Guo Dongmei Wang Meiyao Meng Yinzhao Zhong Zhijian Zhang Yi Lin Caizhi Liu Jiawen Wang Yahui Zhang Yining Gao Yuxiang Cao Zhirui Xia Jin Qiu Yu Li Shuang Liu Haibing Chen Wenyue Liu Yu Han Minghua Zheng Xinran Ma Lingyan Xu |
| author_facet | Guoqiang Li Lijun Zhu Mingwei Guo Dongmei Wang Meiyao Meng Yinzhao Zhong Zhijian Zhang Yi Lin Caizhi Liu Jiawen Wang Yahui Zhang Yining Gao Yuxiang Cao Zhirui Xia Jin Qiu Yu Li Shuang Liu Haibing Chen Wenyue Liu Yu Han Minghua Zheng Xinran Ma Lingyan Xu |
| author_sort | Guoqiang Li |
| collection | DOAJ |
| description | Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. Methods: Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3–Cebpb axis in human liver samples. Results: Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. Conclusions: These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. Impact and Implications: Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury. |
| first_indexed | 2024-03-09T10:52:23Z |
| format | Article |
| id | doaj.art-610a395a4a944b73beda4066a3ff902c |
| institution | Directory Open Access Journal |
| issn | 2589-5559 |
| language | English |
| last_indexed | 2024-03-09T10:52:23Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | JHEP Reports |
| spelling | doaj.art-610a395a4a944b73beda4066a3ff902c2023-12-01T05:02:48ZengElsevierJHEP Reports2589-55592023-12-01512100906Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regenerationGuoqiang Li0Lijun Zhu1Mingwei Guo2Dongmei Wang3Meiyao Meng4Yinzhao Zhong5Zhijian Zhang6Yi Lin7Caizhi Liu8Jiawen Wang9Yahui Zhang10Yining Gao11Yuxiang Cao12Zhirui Xia13Jin Qiu14Yu Li15Shuang Liu16Haibing Chen17Wenyue Liu18Yu Han19Minghua Zheng20Xinran Ma21Lingyan Xu22Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaDepartment of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, ChinaDepartment of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaDepartment of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, ChinaDepartment of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, ChinaDepartment of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China; Department of Endocrinology and Metabolism, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, ChinaDepartment of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaDepartment of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, ChinaMAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China; Corresponding authors. Addresses: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Minhang District, Shanghai, 200241, China. Tel.: +86-021-24206534; Fax: +86-021-24206534 (L. Xu); Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Minhang District, Shanghai, 200241, China. Tel.: +86 021-33503359; Fax: +86 021-33503359 (X. Ma); MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, Zhejiang Province, 325000, China. Tel.: +86 577-55579611; Fax: +86 577-55578522 (M. Zheng)Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Shanghai Frontiers Science Center of Genome Editing and Cell Therapy, Shanghai Key Laboratory of Regulatory Biology and School of Life Sciences, East China Normal University, Shanghai, China; Chongqing Key Laboratory of Precision Optics, Chongqing Institute of East China Normal University, Chongqing, China; Corresponding authors. Addresses: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Minhang District, Shanghai, 200241, China. Tel.: +86-021-24206534; Fax: +86-021-24206534 (L. Xu); Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Minhang District, Shanghai, 200241, China. Tel.: +86 021-33503359; Fax: +86 021-33503359 (X. Ma); MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, Zhejiang Province, 325000, China. Tel.: +86 577-55579611; Fax: +86 577-55578522 (M. Zheng)Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China; Corresponding authors. Addresses: Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Minhang District, Shanghai, 200241, China. Tel.: +86-021-24206534; Fax: +86-021-24206534 (L. Xu); Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, 500 Dongchuan Road, Minhang District, Shanghai, 200241, China. Tel.: +86 021-33503359; Fax: +86 021-33503359 (X. Ma); MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, No. 2 Fuxue Lane, Wenzhou, Zhejiang Province, 325000, China. Tel.: +86 577-55579611; Fax: +86 577-55578522 (M. Zheng)Background & Aims: Liver regeneration is vital for the recovery of liver function after injury, yet the underlying mechanism remains to be elucidated. Forkhead box protein A3 (FOXA3), a member of the forkhead box family, plays important roles in endoplasmic reticulum stress sensing, and lipid and glucose homoeostasis, yet its functions in liver regeneration are unknown. Methods: Here, we explored whether Foxa3 regulates liver regeneration via acute and chronic liver injury mice models. We further characterised the molecular mechanism by chromatin immunoprecipitation sequencing and rescue experiments in vivo and in vitro. Then, we assessed the impact of Foxa3 pharmacological activation on progression and termination of liver regeneration. Finally, we confirmed the Foxa3–Cebpb axis in human liver samples. Results: Foxa3 is dominantly expressed in hepatocytes and cholangiocytes and is induced upon partial hepatectomy (PH) or carbon tetrachloride (CCl4) administration. Foxa3 deficiency in mice decreased cyclin gene levels and delayed liver regeneration after PH, or acute or chronic i.p. CCl4 injection. Conversely, hepatocyte-specific Foxa3 overexpression accelerated hepatocytes proliferation and attenuated liver damage in an CCl4-induced acute model. Mechanistically, Foxa3 directly regulates Cebpb transcription, which is involved in hepatocyte division and apoptosis both in vivo and in vitro. Of note, Cebpb overexpression in livers of Foxa3-deficient mice rescued their defects in cell proliferation and regeneration upon CCl4 treatment. In addition, pharmacological induction of Foxa3 via cardamonin speeded up hepatocyte proliferation after PH, without interfering with liver regeneration termination. Finally, Cebpb and Ki67 levels had a positive correlation with Foxa3 expression in human chronic disease livers. Conclusions: These data characterise Foxa3 as a vital regulator of liver regeneration, which may represent an essential factor to maintain liver mass after liver injury by governing Cebpb transcription. Impact and Implications: Liver regeneration is vital for the recovery of liver function after chemical insults or hepatectomy, yet the underlying mechanism remains to be elucidated. Herein, via in vitro and in vivo models and analysis, we demonstrated that Forkhead box protein A3 (FOXA3), a Forkhead box family member, maintained normal liver regeneration progression by governing Cebpb transcription and proposed cardamonin as a lead compound to induce Foxa3 and accelerate liver repair, which signified that FOXA3 may be a potential therapeutic target for further preclinical study on treating liver injury.http://www.sciencedirect.com/science/article/pii/S2589555923002379Liver regenerationPartial hepatectomyCarbon tetrachlorideProliferationForkhead box A |
| spellingShingle | Guoqiang Li Lijun Zhu Mingwei Guo Dongmei Wang Meiyao Meng Yinzhao Zhong Zhijian Zhang Yi Lin Caizhi Liu Jiawen Wang Yahui Zhang Yining Gao Yuxiang Cao Zhirui Xia Jin Qiu Yu Li Shuang Liu Haibing Chen Wenyue Liu Yu Han Minghua Zheng Xinran Ma Lingyan Xu Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration JHEP Reports Liver regeneration Partial hepatectomy Carbon tetrachloride Proliferation Forkhead box A |
| title | Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration |
| title_full | Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration |
| title_fullStr | Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration |
| title_full_unstemmed | Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration |
| title_short | Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration |
| title_sort | characterisation of forkhead box protein a3 as a key transcription factor for hepatocyte regeneration |
| topic | Liver regeneration Partial hepatectomy Carbon tetrachloride Proliferation Forkhead box A |
| url | http://www.sciencedirect.com/science/article/pii/S2589555923002379 |
| work_keys_str_mv | AT guoqiangli characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT lijunzhu characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT mingweiguo characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT dongmeiwang characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT meiyaomeng characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT yinzhaozhong characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT zhijianzhang characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT yilin characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT caizhiliu characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT jiawenwang characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT yahuizhang characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT yininggao characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT yuxiangcao characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT zhiruixia characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT jinqiu characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT yuli characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT shuangliu characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT haibingchen characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT wenyueliu characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT yuhan characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT minghuazheng characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT xinranma characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration AT lingyanxu characterisationofforkheadboxproteina3asakeytranscriptionfactorforhepatocyteregeneration |