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ID 115105
タイトル別表記
ISR-DEPENDENT METABOLIC REGULATION
著者
Nomura, Akitoshi The University of Tokushima
小倉, 淳 The University of Tokushima
Takehana, Kenji Ajinomoto Pharmaceuticals Company
Kitahara, Yoshihiro Ajinomoto Pharmaceuticals Company
高原, 一菜 The University of Tokushima KAKEN研究者をさがす
Tsugawa, Kazue The University of Tokushima
Miyamoto, Chinobu The University of Tokushima
Miura, Naoko The University of Tokushima
佐藤, 亮祐 The University of Tokushima KAKEN研究者をさがす
Harding, Heather P. University of Cambridge
Ron, David University of Cambridge
キーワード
ER stress
ATF4
glutathione
obesity
small molecule
資料タイプ
学術雑誌論文
抄録
The eukaryotic translation initiation factor 2α (eIF2α) phosphorylation‐dependent integrated stress response (ISR), a component of the unfolded protein response, has long been known to regulate intermediary metabolism, but the details are poorly worked out. We report that profiling of mRNAs of transgenic mice harboring a ligand‐activated skeletal muscle–specific derivative of the eIF2α protein kinase R‐like ER kinase revealed the expected up‐regulation of genes involved in amino acid biosynthesis and transport but also uncovered the induced expression and secretion of a myokine, fibroblast growth factor 21 (FGF21), that stimulates energy consumption and prevents obesity. The link between the ISR and FGF21 expression was further reinforced by the identification of a small‐molecule ISR activator that promoted Fgf21 expression in cell‐based screens and by implication of the ISR‐inducible activating transcription factor 4 in the process. Our findings establish that eIF2α phosphorylation regulates not only cell‐autonomous proteostasis and amino acid metabolism, but also affects non‐cell‐autonomous metabolic regulation by induced expression of a potent myokine.—Miyake, M., Nomura, A., Ogura, A., Takehana, K., Kitahara, Y., Takahara, K., Tsugawa, K., Miyamoto, C., Miura, N., Sato, R., Kurahashi, K., Harding, H. P., Oyadomari, M., Ron, D., Oyadomari, S. Skeletal muscle‐specific eukaryotic translation initiation factor 2α phosphorylation controls amino acid metabolism and fibroblast growth factor 21‐mediated non‐cell‐autonomous energy metabolism.
掲載誌名
The FASEB Journal
ISSN
15306860
08926638
cat書誌ID
AA1066874X
AA12037502
出版者
Federation of American Societies for Experimental Biology|John Wiley & Sons
30
2
開始ページ
798
終了ページ
812
発行日
2015-10-20
権利情報
This is an Open Access article distributed under the terms of the Creative Commons Attribution 4.0 International (CC BY 4.0) (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
EDB ID
出版社版DOI
出版社版URL
フルテキストファイル
言語
eng
著者版フラグ
出版社版
部局
先端酵素学研究所
病院
医学系