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 -