Analysis of the effects by the regulation of integrative stress response to impaired liver regeneration in NAFLD

• Project/Area Number: 15H05678
• Research Category: Grant-in-Aid for Young Scientists (A)
• Allocation Type: Single-year Grants
• Research Field: Digestive surgery
• Research Institution: Kanazawa University
• Principal Investigator: Inaba Yuka 金沢大学, 新学術創成研究機構, 助教 (20571970)
• Project Period (FY): 2015-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥23,530,000 (Direct Cost: ¥18,100,000、Indirect Cost: ¥5,430,000); Fiscal Year 2018: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2017: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2016: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2015: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000)
• Keywords: 非アルコール性脂肪性肝疾患 / 肝切除 / 肝再生 / 統合的ストレス応答 / 細胞死 / NAFLD

Outline of Final Research Achievements

The liver has robust regenerative potential in response to damage, but hepatic steatosis weakens this potential. That is known the impaired liver regeneration causes complications after surgery, such as liver failure. However the detail of mechanisms was unclear. The enhanced integrated stress response (ISR) is commonly induced by various cellular stress. We found that ISR plays a key role in impaired regeneration of hepatic steatosis. In this study, we revealed that stress induced transcription factor has an important role as the mechanism of liver regeneration disorder in fatty liver disease.

Academic Significance and Societal Importance of the Research Achievements

代表者は、脂肪肝における重篤な再生障害を引き起す誘因として、壊死を伴う細胞死が重要であること、その細胞死の誘導にストレス誘導性転写因子ATF3が重要な役割を担うことを明らかにした。本研究成果は、脂肪肝再生障害における細胞死誘導の新規メカニズムの解明という学術的意義を有する。また、再生障害の重症化の病態理解と新規治療標的に関する新たな知見という社会的意義を有する。

Research Products

• [Journal Article] Nicotinic alpha‐7 acetylcholine receptor deficiency exacerbates hepatic inflammation and fibrosis in a mouse model of non‐alcoholic steatohepatitis (2019)
  • Author(s): Kimura Kumi、Inaba Yuka、Watanabe Hitoshi、Matsukawa Toshiya、Matsumoto Michihiro、Inoue Hiroshi
  • Journal Title: Journal of Diabetes Investigation Volume: 10 Issue: 3 Pages: 659-666
  • DOI: 10.1111/jdi.12964
  • Peer Reviewed / Open Access
• [Journal Article] PHD3 regulates glucose metabolism by suppressing stress-induced signalling and optimising gluconeogenesis and insulin signalling in hepatocytes. (2018)
  • Author(s): Yano H, Sakai M, Matsukawa T, Yagi T, Naganuma T, Mitsushima M, Iida S, Inaba Y, Inoue H, Unoki-Kubota H, Kaburagi Y, Asahara S, Kido Y, Minami S, Kasuga M, Matsumoto M.
  • Journal Title: Sci Rep. Volume: 8 Issue: 1 Pages: 14290-14290
  • DOI: 10.1038/s41598-018-32575-z
  • NAID: 120006529679
  • Peer Reviewed / Open Access
• [Journal Article] Dietary soybean protein ameliorates high-fat diet-induced obesity by modifying the gut microbiota-dependent biotransformation of bile acids. (2018)
  • Author(s): Watanabe K, Igarashi M, Li X, Nakatani A, Miyamoto J, Inaba Y, Sutou A, Saito T, Sato T, Tachibana N, Inoue H, Kimura I.
  • Journal Title: PLoS One. Volume: 13 Issue: 8 Pages: e0202083-e0202083
  • DOI: 10.1371/journal.pone.0202083
  • Peer Reviewed / Open Access
• [Journal Article] Sirt2 facilitates hepatic glucose uptake by deacetylating glucokinase regulatory protein (2018)
  • Author(s): Watanabe Hitoshi、Inaba Yuka、Kimura Kumi、Matsumoto Michihiro、Kaneko Shuichi、Kasuga Masato、Inoue Hiroshi
  • Journal Title: Nat Commun. Volume: 9 Issue: 1 Pages: 30-30
  • DOI: 10.1038/s41467-017-02537-6
  • Peer Reviewed / Open Access
• [Journal Article] PDGFRβ Regulates Adipose Tissue Expansion and Glucose Metabolism via Vascular Remodeling in Diet-Induced Obesity (2017)
  • Author(s): Y. Onogi, T. Wada, C. Kamiya, K. Inata, T. Matsuzawa, Y. Inaba, K. Kimura, H. Inoue, S. Yamamoto, Y. Ishii, D. Koya, H. Tsuneki, M. Sasahara, T. Sasaoka
  • Journal Title: Diabetes Volume: 4 Issue: 4 Pages: 1008-1021
  • DOI: 10.2337/db16-0881
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Dietary Mung Bean Protein Reduces Hepatic Steatosis, Fibrosis, and Inflammation in Male Mice with Diet-Induced, Nonalcoholic Fatty Liver Disease. (2017)
  • Author(s): Watanabe H, Inaba Y, Kimura K, Asahara SI, Kido Y, Matsumoto M, Motoyama T, Tachibana N, Kaneko S, Kohno M, Inoue H*.
  • Journal Title: J Nutr. Volume: 147 Issue: 1 Pages: 52-60
  • DOI: 10.3945/jn.116.231662
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Eicosapentaenoic acid ameliorates hyperglycemia in high-fat diet-sensitive diabetes mice in conjunction with restoration of hypoadiponectinemia. (2016)
  • Author(s): Morimoto M, Lee EY, Zhang X, Inaba Y, Inoue H, Ogawa M, Shirasawa T, Yokosuka O, Miki T
  • Journal Title: Nutr Diabetes Volume: 27 Issue: 6 Pages: e213-e213
  • DOI: 10.1038/nutd.2016.21
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Centra insulin-action activates Kupffer cells by suppressing hepatic vagal activation through nicotinic alpha 7 acetylcholine receptor. (2016)
  • Author(s): Kimura K, Tanida M, Nagata N, Inaba Y, Watanabe H, Nagashimada M, Ota T, Asahara S, Kido Y, Matsumoto M, Toshinai K, Nakazato M, Shibamoto T, Kaneko S, Kasuga M, Inoue H
  • Journal Title: Cell reports Volume: 14 Issue: 10 Pages: 2362-2374
  • DOI: 10.1016/j.celrep.2016.02.032
  • Peer Reviewed / Open Access
• [Journal Article] Gadd34 regulates liver regeneration in hepatic steatosis. (2015)
  • Author(s): Inaba Y, Furutani T, Kimura K, Watanabe H, Haga S, Kido Y, Yamamoto Y, Harada K, Kaneko S, Oyadomari S, Ozaki M, Kasuga M, Inoue H.
  • Journal Title: Hepatology Volume: 61(4) Issue: 4 Pages: 1343-1356
  • DOI: 10.1002/hep.27619
  • Peer Reviewed / Open Access
• [Journal Article] Chronic activation of FXR in transgenic mice caused perinatal toxicity and cholesterol toxicity (2015)
  • Author(s): Cheng Q#, Inaba Y#, Xu M, Lu P, He J, Guo GL, Kuruba R, De La Vega R, Evans RW, Li S, Xie W
  • Journal Title: Mol Endocrinol Volume: 29 Issue: 4 Pages: 571-582
  • DOI: 10.1210/me.2014-1337
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Presentation] The role of cell death induced by integrated stress response in fatty liver regeneration (2018)
  • Author(s): Inaba Yuka, Inoue Hiroshi
  • Organizer: Australia-Japan Meeting on Cell Death
  • Int'l Joint Research
• [Presentation] 脂肪肝再生障害における肝細胞死様式の役割とその選択メカニズム (2018)
  • Author(s): 稲葉有香、松本道宏、春日雅人、井上啓
  • Organizer: 第30回分子糖尿病学シンポジウム
• [Presentation] 脂肪肝再生過程におけるATF3の役割 (2018)
  • Author(s): 稲葉有香
  • Organizer: 自然科学研究機構生理学研究所研究会
• [Presentation] 脂肪肝再生過程で生じる肝細胞死様式誘導メカニズム (2018)
  • Author(s): 稲葉有香、春日雅人、井上啓
  • Organizer: 第5回肝臓と糖尿病・代謝研究会
• [Presentation] 肪肝における肝再生障害誘導メカニズムの解明 (2017)
  • Author(s): 稲葉有香
  • Organizer: 金沢大学 第2回新学術創成研究機構シンポジウム
  • Place of Presentation: 金沢大学 金沢
  • Year and Date: 2017-01-26
• [Presentation] Role of nicotinic acetylcholine receptor and gut microbiota in central-insulin mediated regulation of hepatic glucose production (2017)
  • Author(s): Yuka Inaba, Kumi Kimura, Mamoru Tanida, Hitoshi Watanabe, Yoshiaki Kido, Michihiro Matsumoto, Masato Kasuga, Hiroshi Inoue
  • Organizer: 13th International Symposium on Insulin Receptor and Insulin Action
  • Int'l Joint Research
• [Presentation] 肝再生過程における統合的ストレス応答による細胞死誘導メカニズムの解明 (2017)
  • Author(s): 稲葉有香、春日雅人、井上啓
  • Organizer: 第35回内分泌代謝学サマーセミナー
  • Invited
• [Presentation] NAD+による肝糖取り込み調節機構の解析 (2017)
  • Author(s): 渡邉一史、稲葉有香、木村久美、松本道宏、金子周一、春日雅人、井上啓
  • Organizer: 第35回内分泌代謝学サマーセミナー
• [Presentation] 脂肪肝再生障害における統合的ストレス応答による細胞死誘導のメカニズムの検討 (2017)
  • Author(s): 稲葉有香、渡辺一史、木村久美、井上啓
  • Organizer: 第38回日本肥満学会
• [Presentation] 非アルコール性脂肪性肝疾患の予防における緑豆タンパクの有用性 (2017)
  • Author(s): 井上啓、渡邉一史、稲葉有香、木村久美、橘伸彦、本山貴康、河野光登
  • Organizer: 第38回日本肥満学会
• [Presentation] 脂肪肝における肝再生障害誘導メカニズムの解明 (2016)
  • Author(s): 稲葉有香
  • Organizer: 平成28年度HWRNシンポジウム
  • Place of Presentation: 金沢大学 金沢
  • Year and Date: 2016-12-19
• [Presentation] 脂肪肝と統合的ストレス応答による細胞死 (2016)
  • Author(s): 稲葉有香
  • Organizer: 第27回日本レチノイド研究会
  • Place of Presentation: 昭和薬科大学 東京
  • Year and Date: 2016-10-22
  • Invited
• [Presentation] 脂肪肝再生過程での細胞傷害関連転写因子の役割 (2016)
  • Author(s): 稲葉有香、春日雅人、井上啓
  • Organizer: 第37回日本肥満学会
  • Place of Presentation: 東京ファッションタウンビル 東京
  • Year and Date: 2016-10-07
• [Presentation] 脂肪肝における肝再生障害のメカニズムの解明 (2016)
  • Author(s): 稲葉有香
  • Organizer: 平成28年度 自然科学研究機構生理学研究所研究会 臓器相関による生体制御システムとその変容の仕組み
  • Place of Presentation: 生理学研究所 岡崎
  • Year and Date: 2016-09-10
• [Presentation] 脂肪肝再生過程での細胞傷害関連転写因子の役割 (2016)
  • Author(s): 稲葉有香，北嶋繁孝，春日雅人，井上啓
  • Organizer: 第21回アディポサイエンスシンポジウム
  • Place of Presentation: 千里ライフサイエンスセンター 大阪
  • Year and Date: 2016-08-20
• [Presentation] 脂肪肝再生過程での肝細胞障害関連転写因子の役割 (2016)
  • Author(s): 稲葉有香，渡辺一史，木村久美，井上啓
  • Organizer: 第34回内分泌代謝学サマーセミナー
  • Place of Presentation: 久山温泉ホテル夢家 福岡
  • Year and Date: 2016-07-14
• [Presentation] 脂肪肝再生障害に対する統合的ストレス応答に伴う肝細胞死の分子メカニズムの解明 (2016)
  • Author(s): 稲葉有香
  • Organizer: 成人病の病因・病態の解明に関する研究助成（TMFC）第22回研究発表会
  • Place of Presentation: セントレジスホテル大阪 大阪
  • Year and Date: 2016-07-02
• [Presentation] 脂肪肝での肝再生障害における肝細胞死誘導メカニズムの解明 (2016)
  • Author(s): 稲葉有香，春日雅人，井上啓
  • Organizer: 第89回日本内分泌学会学術総会
  • Place of Presentation: 国立京都国際会館 京都
  • Year and Date: 2016-04-21
• [Presentation] 脂肪肝再生における統合的ストレス応答による肝細胞死誘導メカニズムの解明 (2015)
  • Author(s): 稲葉有香、春日雅人、井上啓
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-02
• [Presentation] 脂肪肝再生過程における肝細胞死制御に対する統合的ストレス応答の重要性 (2015)
  • Author(s): 稲葉有香、春日雅人、井上啓
  • Organizer: 第20回アディポサイエンスシンポジウム
  • Place of Presentation: 大阪
  • Year and Date: 2015-08-22
• [Presentation] 統合的ストレス応答による脂肪肝再生障害の分子メカニズムの解明 (2015)
  • Author(s): 稲葉有香、芳香早苗、尾崎倫孝、春日雅人、井上啓
  • Organizer: 第33回内分泌代謝学サマーセミナー
  • Place of Presentation: 九州
  • Year and Date: 2015-07-09
• [Presentation] 統合的ストレス応答による脂肪肝再生障害の分子メカニズムの解明 (2015)
  • Author(s): 稲葉有香、芳香早苗、尾崎倫孝、春日雅人、井上啓
  • Organizer: 第22回肝細胞研究会
  • Place of Presentation: 鳥取
  • Year and Date: 2015-06-04