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; Hiroshi Inoue

doi:10.1038/s41467-023-35804-w

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
, Hiroshi Inoue^*

^*Corresponding author for this work

Kanazawa University
Kanazawa University Graduate School of Medical Sciences
Toho University
National Center for Global Health and Medicine
Tokyo Medical and Dental University
Kobe University
Asahi Life Foundation

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Article number	167
Journal	Nature Communications
Volume	14
Issue number	1
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-35804-w
Publication status	Published - Dec 2023

Funding

The authors thank C. Asahi of Kanazawa University for providing technical assistance and ThinkSCIENCE (Tokyo, Japan) for help in preparing the manuscript. This work was supported by KAKENHI Grants (JP20H04943, JP20H04102, and JP22K19545 to H.I. and JP17H06300, JP19K09192, and JP22H03507 to Y.I.) from the Japan Society for the Promotion of Science (JSPS); a Japan Diabetes Foundation grant; a Boehringer and Lilly research grant from the Japan Diabetes Foundation; the MSD Life Science Foundation, Public Interest Incorporated Foundation; the NOVARTIS Foundation (Japan) for the Promotion of Science; the Institute of Medical Science of Asahi Life Foundation; the Uehara Memorial Foundation; the Takeda Science Foundation; the Japan Foundation for Applied Enzymology; the Fuji Foundation; the Hokuriku Bank Research Grant for Young Scientists; the Kanae Foundation; the Mitsubishi Foundation; Taiju Life Social Welfare Foundation; the Naito Foundation; the Japan Agency for Medical Research and Development (AMED) through AMED-CREST (JP20gm1210002 to H.N.) and the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus (JP21ek0210156 to Y.I.); and the Japan Science and Technology Agency (JST), CREST (JPMJCR2123 to Y.I.).

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Inaba, Y., Hashiuchi, E., Watanabe, H., Kimura, K., Oshima, Y., Tsuchiya, K., Murai, S., Takahashi, C., Matsumoto, M., Kitajima, S., Yamamoto, Y., Honda, M., Asahara, S. I., Ravnskjaer, K., Horike, S. I., Kaneko, S., Kasuga, M., Nakano, H., Harada, K., & Inoue, H. (2023). The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice. Nature Communications, 14(1), Article 167. https://doi.org/10.1038/s41467-023-35804-w

@article{f2dc083ecdcd4e92ac9739e63c65e6e8,

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

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.",

author = "Yuka Inaba and Emi Hashiuchi and Hitoshi Watanabe and Kumi Kimura and Yu Oshima and Kohsuke Tsuchiya and Shin Murai and Chiaki Takahashi and Michihiro Matsumoto and Shigetaka Kitajima and Yasuhiko Yamamoto and Masao Honda and Asahara, \{Shun ichiro\} and Kim Ravnskjaer and Horike, \{Shin ichi\} and Shuichi Kaneko and Masato Kasuga and Hiroyasu Nakano and Kenichi Harada and Hiroshi Inoue",

note = "Funding Information: The authors thank C. Asahi of Kanazawa University for providing technical assistance and ThinkSCIENCE (Tokyo, Japan) for help in preparing the manuscript. This work was supported by KAKENHI Grants (JP20H04943, JP20H04102, and JP22K19545 to H.I. and JP17H06300, JP19K09192, and JP22H03507 to Y.I.) from the Japan Society for the Promotion of Science (JSPS); a Japan Diabetes Foundation grant; a Boehringer and Lilly research grant from the Japan Diabetes Foundation; the MSD Life Science Foundation, Public Interest Incorporated Foundation; the NOVARTIS Foundation (Japan) for the Promotion of Science; the Institute of Medical Science of Asahi Life Foundation; the Uehara Memorial Foundation; the Takeda Science Foundation; the Japan Foundation for Applied Enzymology; the Fuji Foundation; the Hokuriku Bank Research Grant for Young Scientists; the Kanae Foundation; the Mitsubishi Foundation; Taiju Life Social Welfare Foundation; the Naito Foundation; the Japan Agency for Medical Research and Development (AMED) through AMED-CREST (JP20gm1210002 to H.N.) and the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus (JP21ek0210156 to Y.I.); and the Japan Science and Technology Agency (JST), CREST (JPMJCR2123 to Y.I.). Publisher Copyright: {\textcopyright} 2023, The Author(s).",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-35804-w",

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Inaba, Y, Hashiuchi, E, Watanabe, H, Kimura, K, Oshima, Y, Tsuchiya, K, Murai, S, Takahashi, C, Matsumoto, M, Kitajima, S, Yamamoto, Y, Honda, M, Asahara, SI, Ravnskjaer, K, Horike, SI, Kaneko, S, Kasuga, M, Nakano, H, Harada, K & Inoue, H 2023, 'The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice', Nature Communications, vol. 14, no. 1, 167. https://doi.org/10.1038/s41467-023-35804-w

TY - JOUR

T1 - The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice

AU - Inaba, Yuka

AU - Hashiuchi, Emi

AU - Watanabe, Hitoshi

AU - Kimura, Kumi

AU - Oshima, Yu

AU - Tsuchiya, Kohsuke

AU - Murai, Shin

AU - Takahashi, Chiaki

AU - Matsumoto, Michihiro

AU - Kitajima, Shigetaka

AU - Yamamoto, Yasuhiko

AU - Honda, Masao

AU - Asahara, Shun ichiro

AU - Ravnskjaer, Kim

AU - Horike, Shin ichi

AU - Kaneko, Shuichi

AU - Kasuga, Masato

AU - Nakano, Hiroyasu

AU - Harada, Kenichi

AU - Inoue, Hiroshi

N1 - Funding Information: The authors thank C. Asahi of Kanazawa University for providing technical assistance and ThinkSCIENCE (Tokyo, Japan) for help in preparing the manuscript. This work was supported by KAKENHI Grants (JP20H04943, JP20H04102, and JP22K19545 to H.I. and JP17H06300, JP19K09192, and JP22H03507 to Y.I.) from the Japan Society for the Promotion of Science (JSPS); a Japan Diabetes Foundation grant; a Boehringer and Lilly research grant from the Japan Diabetes Foundation; the MSD Life Science Foundation, Public Interest Incorporated Foundation; the NOVARTIS Foundation (Japan) for the Promotion of Science; the Institute of Medical Science of Asahi Life Foundation; the Uehara Memorial Foundation; the Takeda Science Foundation; the Japan Foundation for Applied Enzymology; the Fuji Foundation; the Hokuriku Bank Research Grant for Young Scientists; the Kanae Foundation; the Mitsubishi Foundation; Taiju Life Social Welfare Foundation; the Naito Foundation; the Japan Agency for Medical Research and Development (AMED) through AMED-CREST (JP20gm1210002 to H.N.) and the Practical Research Project for Life-Style related Diseases including Cardiovascular Diseases and Diabetes Mellitus (JP21ek0210156 to Y.I.); and the Japan Science and Technology Agency (JST), CREST (JPMJCR2123 to Y.I.). Publisher Copyright: © 2023, The Author(s).

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-023-35804-w

DO - 10.1038/s41467-023-35804-w

M3 - Journal article

C2 - 36690638

AN - SCOPUS:85146789099

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 167

ER -

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

Abstract

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