Characterisation of forkhead box protein A3 as a key transcription factor for hepatocyte regeneration
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
Affiliations
Guoqiang Li
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Lijun Zhu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Mingwei Guo
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Dongmei Wang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Meiyao Meng
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Yinzhao Zhong
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Zhijian Zhang
Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
Yi Lin
Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
Caizhi Liu
Shanghai 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, China
Jiawen Wang
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Yahui Zhang
Department of Endocrinology and Metabolism, Shanghai General Hospital, Shanghai Jiao Tong University of Medicine, Shanghai, China
Yining Gao
Department of Endocrinology and Metabolism, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Yuxiang Cao
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Zhirui Xia
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Jin Qiu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Yu Li
Shanghai 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, China
Shuang Liu
Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, China
Haibing Chen
Department 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, China
Wenyue Liu
Department of Endocrinology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Yu Han
Department of Gastrointestinal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
Minghua Zheng
MAFLD 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)
Xinran Ma
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)
Lingyan Xu
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.
