ID | 115105 |
タイトル別表記 | ISR-DEPENDENT METABOLIC REGULATION
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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
Tsugawa, Kazue
The University of Tokushima
Miyamoto, Chinobu
The University of Tokushima
Miura, Naoko
The University of Tokushima
Harding, Heather P.
University of Cambridge
Ron, David
University of Cambridge
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キーワード | ER stress
ATF4
glutathione
obesity
small molecule
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資料タイプ |
学術雑誌論文
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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.
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掲載誌名 |
The FASEB Journal
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ISSN | 15306860
08926638
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cat書誌ID | AA1066874X
AA12037502
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出版者 | Federation of American Societies for Experimental Biology|John Wiley & Sons
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巻 | 30
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号 | 2
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開始ページ | 798
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終了ページ | 812
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発行日 | 2015-10-20
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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.
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出版社版DOI | |
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言語 |
eng
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著者版フラグ |
出版社版
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部局 |
先端酵素学研究所
病院
医学系
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