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 and Hiroyasu Nakano ()
Additional contact information
Yuichi Tsuchiya: Toho University
Takao Seki: Toho University
Kenta Kobayashi: Toho University
Sachiko Komazawa-Sakon: Toho University
Shigeyuki Shichino: Tokyo University of Science
Takashi Nishina: Toho University
Kyoko Fukuhara: Juntendo University
Kenichi Ikejima: Juntendo University
Hidenari Nagai: Toho University Omori Medical Center
Yoshinori Igarashi: Toho University Omori Medical Center
Satoshi Ueha: Tokyo University of Science
Akira Oikawa: Kyoto University
Shinya Tsurusaki: National Center for Global Health and Medicine
Soh Yamazaki: Toho University
Chiharu Nishiyama: Tokyo University of Science
Tetuo Mikami: Toho University
Hideo Yagita: Juntendo University
Ko Okumura: Juntendo University
Taketomo Kido: The University of Tokyo
Atsushi Miyajima: The University of Tokyo
Kouji Matsushima: Tokyo University of Science
Mai Imasaka: Hyogo Medical University
Kimi Araki: Kumamoto University
Toru Imamura: Hoshi University School of Pharmacy and Pharmaceutical Sciences
Masaki Ohmuraya: Hyogo Medical University
Minoru Tanaka: National Center for Global Health and Medicine
Hiroyasu Nakano: Toho University

Nature Communications, 2023, vol. 14, issue 1, 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.

Date: 2023
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DOI: 10.1038/s41467-023-42058-z

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