Nature Communications (Oct 2023)
Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis
- Yuichi Tsuchiya,
- Takao Seki,
- Kenta Kobayashi,
- Sachiko Komazawa-Sakon,
- Shigeyuki Shichino,
- Takashi Nishina,
- Kyoko Fukuhara,
- Kenichi Ikejima,
- Hidenari Nagai,
- Yoshinori Igarashi,
- Satoshi Ueha,
- Akira Oikawa,
- Shinya Tsurusaki,
- Soh Yamazaki,
- Chiharu Nishiyama,
- Tetuo Mikami,
- Hideo Yagita,
- Ko Okumura,
- Taketomo Kido,
- Atsushi Miyajima,
- Kouji Matsushima,
- Mai Imasaka,
- Kimi Araki,
- Toru Imamura,
- Masaki Ohmuraya,
- Minoru Tanaka,
- Hiroyasu Nakano
Affiliations
- Yuichi Tsuchiya
- Department of Biochemistry, Faculty of Medicine, Toho University
- Takao Seki
- Department of Biochemistry, Faculty of Medicine, Toho University
- Kenta Kobayashi
- Department of Biochemistry, Faculty of Medicine, Toho University
- Sachiko Komazawa-Sakon
- Department of Biochemistry, Faculty of Medicine, Toho University
- Shigeyuki Shichino
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science
- Takashi Nishina
- Department of Biochemistry, Faculty of Medicine, Toho University
- Kyoko Fukuhara
- Department of Gastroenterology, Faculty of Medicine and Graduate School of Medicine, Juntendo University
- Kenichi Ikejima
- Department of Gastroenterology, Faculty of Medicine and Graduate School of Medicine, Juntendo University
- Hidenari Nagai
- Department of Gastroenterology, Toho University Omori Medical Center
- Yoshinori Igarashi
- Department of Gastroenterology, Toho University Omori Medical Center
- Satoshi Ueha
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science
- Akira Oikawa
- Laboratory of Quality Analysis and Assessment, Graduate School of Agriculture, Kyoto University
- Shinya Tsurusaki
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine
- Soh Yamazaki
- Department of Biochemistry, Faculty of Medicine, Toho University
- Chiharu Nishiyama
- Department of Biological Science and Technology, Faculty of Advanced Engineering, Tokyo University of Science
- Tetuo Mikami
- Department of Pathology, Faculty of Medicine, Toho University
- Hideo Yagita
- Department of Immunology, Faculty of Medicine and Graduate School of Medicine, Juntendo University
- Ko Okumura
- Atopy Research Center, Faculty of Medicine and Graduate School of Medicine, Juntendo University
- Taketomo Kido
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo
- Atsushi Miyajima
- Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo
- Kouji Matsushima
- Division of Molecular Regulation of Inflammatory and Immune Diseases, Research Institute for Biomedical Sciences, Tokyo University of Science
- Mai Imasaka
- Department of Genetics, Hyogo Medical University
- Kimi Araki
- Center for Animal Resources and Development, Kumamoto University
- Toru Imamura
- Hoshi University School of Pharmacy and Pharmaceutical Sciences
- Masaki Ohmuraya
- Department of Genetics, Hyogo Medical University
- Minoru Tanaka
- Department of Regenerative Medicine, Research Institute, National Center for Global Health and Medicine
- Hiroyasu Nakano
- Department of Biochemistry, Faculty of Medicine, Toho University
- DOI
- https://doi.org/10.1038/s41467-023-42058-z
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 20
Abstract
Abstract Liver fibrosis results from chronic liver injury triggered by factors such as viral infection, excess alcohol intake, and lipid accumulation. However, the mechanisms underlying liver fibrosis are not fully understood. Here, we demonstrate that the expression of fibroblast growth factor 18 (Fgf18) is elevated in mouse livers following the induction of chronic liver fibrosis models. Deletion of Fgf18 in hepatocytes attenuates liver fibrosis; conversely, overexpression of Fgf18 promotes liver fibrosis. Single-cell RNA sequencing reveals that overexpression of Fgf18 in hepatocytes results in an increase in the number of Lrat + hepatic stellate cells (HSCs), thereby inducing fibrosis. Mechanistically, FGF18 stimulates the proliferation of HSCs by inducing the expression of Ccnd1. Moreover, the expression of FGF18 is correlated with the expression of profibrotic genes, such as COL1A1 and ACTA2, in human liver biopsy samples. Thus, FGF18 promotes liver fibrosis and could serve as a therapeutic target to treat liver fibrosis.
