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

doi:10.1038/s41467-023-42058-z

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 MiyajimaKouji Matsushima, Mai Imasaka, Kimi Araki, Toru Imamura, Masaki Ohmuraya, Minoru Tanaka, Hiroyasu Nakano

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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.

Original language	English
Article number	6304
Journal	Nature communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-42058-z
Publication status	Published - Dec 2023

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Tsuchiya, Y., Seki, T., Kobayashi, K., Komazawa-Sakon, S., Shichino, S., Nishina, T., Fukuhara, K., Ikejima, K., Nagai, H., Igarashi, Y., Ueha, S., Oikawa, A., Tsurusaki, S., Yamazaki, S., Nishiyama, C., Mikami, T., Yagita, H., Okumura, K., Kido, T., ... Nakano, H. (2023). Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis. Nature communications, 14(1), Article 6304. https://doi.org/10.1038/s41467-023-42058-z

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title = "Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis",

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.",

author = "Yuichi Tsuchiya and Takao Seki and Kenta Kobayashi and Sachiko Komazawa-Sakon and Shigeyuki Shichino and Takashi Nishina and Kyoko Fukuhara and Kenichi Ikejima and Hidenari Nagai and Yoshinori Igarashi and Satoshi Ueha and Akira Oikawa and Shinya Tsurusaki and Soh Yamazaki and Chiharu Nishiyama and Tetuo Mikami and Hideo Yagita and Ko Okumura and Taketomo Kido and Atsushi Miyajima and Kouji Matsushima and Mai Imasaka and Kimi Araki and Toru Imamura and Masaki Ohmuraya and Minoru Tanaka and Hiroyasu Nakano",

note = "Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-42058-z",

language = "English",

volume = "14",

journal = "Nature communications",

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Tsuchiya, Y, Seki, T, Kobayashi, K, Komazawa-Sakon, S, Shichino, S, Nishina, T, Fukuhara, K, Ikejima, K, Nagai, H, Igarashi, Y, Ueha, S, Oikawa, A, Tsurusaki, S, Yamazaki, S, Nishiyama, C, Mikami, T, Yagita, H, Okumura, K, Kido, T, Miyajima, A, Matsushima, K, Imasaka, M, Araki, K, Imamura, T, Ohmuraya, M, Tanaka, M & Nakano, H 2023, 'Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis', Nature communications, vol. 14, no. 1, 6304. https://doi.org/10.1038/s41467-023-42058-z

TY - JOUR

T1 - Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis

AU - Tsuchiya, Yuichi

AU - Seki, Takao

AU - Kobayashi, Kenta

AU - Komazawa-Sakon, Sachiko

AU - Shichino, Shigeyuki

AU - Nishina, Takashi

AU - Fukuhara, Kyoko

AU - Ikejima, Kenichi

AU - Nagai, Hidenari

AU - Igarashi, Yoshinori

AU - Ueha, Satoshi

AU - Oikawa, Akira

AU - Tsurusaki, Shinya

AU - Yamazaki, Soh

AU - Nishiyama, Chiharu

AU - Mikami, Tetuo

AU - Yagita, Hideo

AU - Okumura, Ko

AU - Kido, Taketomo

AU - Miyajima, Atsushi

AU - Matsushima, Kouji

AU - Imasaka, Mai

AU - Araki, Kimi

AU - Imamura, Toru

AU - Ohmuraya, Masaki

AU - Tanaka, Minoru

AU - Nakano, Hiroyasu

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85173717253&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-42058-z

DO - 10.1038/s41467-023-42058-z

M3 - Article

C2 - 37813881

AN - SCOPUS:85173717253

SN - 2041-1723

VL - 14

JO - Nature communications

JF - Nature communications

IS - 1

M1 - 6304

ER -

Fibroblast growth factor 18 stimulates the proliferation of hepatic stellate cells, thereby inducing liver fibrosis

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