The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice

Yuka Inaba, Emi Hashiuchi, Hitoshi Watanabe, Kumi Kimura, Yu Oshima, Kohsuke Tsuchiya, Shin Murai, Chiaki Takahashi, Michihiro Matsumoto, Shigetaka Kitajima, Yasuhiko Yamamoto, Masao Honda, Shun-ichiro Asahara, Kim Ravnskjaer, Shin-ichi Horike, Shuichi Kaneko, Masato Kasuga, Hiroyasu Nakano, Kenichi Harada and Hiroshi Inoue ()
Additional contact information
Yuka Inaba: Kanazawa University
Emi Hashiuchi: Kanazawa University
Hitoshi Watanabe: Kanazawa University
Kumi Kimura: Kanazawa University
Yu Oshima: Kanazawa University
Kohsuke Tsuchiya: Kanazawa University
Shin Murai: Toho University School of Medicine
Chiaki Takahashi: Kanazawa University
Michihiro Matsumoto: National Center for Global Health and Medicine
Shigetaka Kitajima: Tokyo Medical and Dental University
Yasuhiko Yamamoto: Kanazawa University
Masao Honda: Kanazawa University
Shun-ichiro Asahara: Kobe University Graduate School of Medicine
Kim Ravnskjaer: University of Southern Denmark
Shin-ichi Horike: Kanazawa University
Shuichi Kaneko: Kanazawa University
Masato Kasuga: Asahi Life Foundation
Hiroyasu Nakano: Toho University School of Medicine
Kenichi Harada: Kanazawa University
Hiroshi Inoue: Kanazawa University

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract Hepatocellular death increases with hepatic steatosis aggravation, although its regulation remains unclear. Here we show that hepatic steatosis aggravation shifts the hepatocellular death mode from apoptosis to necroptosis, causing increased hepatocellular death. Our results reveal that the transcription factor ATF3 acts as a master regulator in this shift by inducing expression of RIPK3, a regulator of necroptosis. In severe hepatic steatosis, after partial hepatectomy, hepatic ATF3-deficient or -overexpressing mice display decreased or increased RIPK3 expression and necroptosis, respectively. In cultured hepatocytes, ATF3 changes TNFα-dependent cell death mode from apoptosis to necroptosis, as revealed by live-cell imaging. In non-alcoholic steatohepatitis (NASH) mice, hepatic ATF3 deficiency suppresses RIPK3 expression and hepatocellular death. In human NASH, hepatocellular damage is correlated with the frequency of hepatocytes expressing ATF3 or RIPK3, which overlap frequently. ATF3-dependent RIPK3 induction, causing a modal shift of hepatocellular death, can be a therapeutic target for steatosis-induced liver damage, including NASH.

Date: 2023
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DOI: 10.1038/s41467-023-35804-w

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