ナカノ　ヒロヤス   Nakano Hiroyasu   中野　裕康    所属   東邦大学  医学部 医学科    東邦大学  医学部 医学科    職種   教授
論文種別	原著
言語種別	英語
査読の有無	査読あり
表題	The transcription factor ATF3 switches cell death from apoptosis to necroptosis in hepatic steatosis in male mice
掲載誌名	正式名：Nature Communications 略　 称：Nat Commun ISSNコード：2041-1723
掲載区分	国外
巻・号・頁	167
国際共著	国際共著
著者・共著者	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
発行年月	2023/01/23
概要	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.