The elucidation of mechanism of liver ischemia and reperfusion injury by diet restriction

• Project/Area Number: 18K08609
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55010:General surgery and pediatric surgery-related
• Research Institution: The Tazuke Kofukai
• Principal Investigator: Terajima Hiroaki 公益財団法人田附興風会, 医学研究所 第1研究部, 研究主幹 (40314215)
• Co-Investigator(Kenkyū-buntansha): 内田 洋一朗 京都大学, 医学研究科, 助教 (30597745) ; 渡邊 武 公益財団法人田附興風会, 医学研究所 第1研究部, 研究員 (40028684) ; 岡島 英明 京都大学, 医学研究科, 客員研究員 (20308604)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 肝虚血再灌流障害 / 肝臓 / 絶食 / 食事制限 / FOXO1 / アセチル化ヒストン / 肝臓外科 / 肝移植 / メタボローム解析 / βヒドロキシ酪酸 / 肝虚血再還流障害

Outline of Final Research Achievements

Our present research demonstrates that 12 hours fasting remarkably ameliorates liver ischemia and reperfusion injury (IRI) in mice. The 12 hours fasting induces the up-regulation of FOXO1 and HO-1 by raising the level of β-hydroxybutyric acid and acetylated histone, followed by up-regulation of antioxidative enzyme and autophagy activity, and improves liver IRI through the reduction of the inflammation and apoptotic cell death. Finally, these results were reported in Proc.Natl.Acad.Sci.USA (Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury. 116:13533-42,2019) .

Academic Significance and Societal Importance of the Research Achievements

肝切除や移植などの肝臓外科手術においては、肝虚血再灌流障害は回避できない事象である。その肝障害を予防・軽減することは、より良好な術後成績に寄与する。今回、マウスモデルを用いて、短時間（12時間）絶食による著明な障害抑制効果を見出し、その機序に関する解明を行い、PNASへの報告に至った。今後のIRIの予防薬の開発に繋がる社会的な意義の大きい研究である。

Research Products

• [Journal Article] Up-regulation of FOXO1 and reduced inflammation by β-hydroxybutyric acid are essential diet restriction benefits against liver injury (2019)
  • Author(s): Miyauchi Tomoyuki、Uchida Yoichiro、Kadono Kentaro、Hirao Hirofumi、Kawasoe Junya、Watanabe Takeshi、Ueda Shugo、Okajima Hideaki、Terajima Hiroaki、Uemoto Shinji
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 116 Issue: 27 Pages: 13533-13542
  • DOI: 10.1073/pnas.1820282116
  • Peer Reviewed / Open Access
• [Presentation] Current situation in postoperative adjuvant chemotherapy and perioperative nutritional management for the treatment of pancreatic cancer (2020)
  • Author(s): Yoichiro Uchida,Ryo Kamimura,Tomohiro Okamoto,Takayuki Kawai,Kohta Iguchi,Hiroaki Terajima
  • Organizer: 14th World Congress of the International Hepato-Pacreato-Biliary Association
  • Int'l Joint Research
• [Presentation] 肝臓外科手術における短期食事制限の有用性 －基礎的見地からの検討－ (2020)
  • Author(s): 内田 洋一朗,宮内 智之,川添 准矢,嵯峨 謙一,寺嶋 宏明,上本 伸二
  • Organizer: 第57回日本外科代謝栄養学会
• [Presentation] Our trial to develop academic surgeon (2020)
  • Author(s): Yoichiro Uchida,Hiroaki Terajima,Junya Kawasoe,Kenichi Saga,Tomoyuki Miyauchi,Shugo Ueda,Shinji Uemoto
  • Organizer: 第75回日本消化器外科学会総会
• [Presentation] 肝臓外科術後合併症の軽減に対する栄養療法の可能性 (2019)
  • Author(s): 宮内智之、内田洋一朗、海道利実、上本伸二
  • Organizer: 第34回日本静脈経腸栄養学会学術集会