Analysis of the effects of Gadd34 inhibition to impaired liver regeneration in NAFLD

• Project/Area Number: 25861179
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kanazawa University
• Principal Investigator: INABA YUKA 金沢大学, 脳・肝インターフェースメディシン研究センター, 特任助教 (20571970)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: NAFLD / 肝切除 / 肝再生 / 統合的ストレス応答 / Gadd34 / eIF2a / アデノ随伴ウィルス / eIF2α / 小胞体ストレス

Outline of Final Research Achievements

The liver has robust regenerative potential in response to damage, but hepatic steatosis weakens this potential. We found that the enhanced integrated stress response (ISR) mediated by phosphorylation of eIF2α impairs regeneration in hepatic steatosis. Gadd34 is known to regulate ISR by dephosphorylation of eIF2α. Gadd34 knockdown enhanced ISR, reduced hepatocyte proliferation, increased cell death, and increased plasma ALT levels. In contrast, Gadd34 overexpression suppressed ISR, hepatocyte apoptosis without affecting hepatocyte proliferation, and decreased plasma ALT levels, clearly improving fatty liver regeneration. These data suggest that Gadd34-mediated regulation of ISR acts as a physiological defense mechanism against impaired liver regeneration due to steatosis.

Research Products

• [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] Histidine augments the suppression of hepatic glucose production by central insulin action. (2013)
  • Author(s): Kimura K, Nakamura Y, Inaba Y, Matsumoto M, Kido Y, Asahara S, Matsuda T, Watanabe H, Maeda A, Inagaki F, Mukai C, Takeda K, Akira S, Ota T, Nakabayashi H, Kaneko S, Kasuga M, Inoue H.
  • Journal Title: Diabetes Volume: 62 Issue: 7 Pages: 2266-77
  • DOI: 10.2337/db12-1701
  • Peer Reviewed
• [Presentation] NALFDに伴う肝再生障害におけるGadd34の役割の解明 (2014)
  • Author(s): 稲葉有香、尾崎倫孝、親泊政一、春日雅人、井上 啓
  • Organizer: 第26回分子糖尿病学シンポジウム
  • Place of Presentation: 高知
  • Year and Date: 2014-12-06
• [Presentation] Gadd34は脂肪肝での肝再生障害を改善する (2014)
  • Author(s): 稲葉有香、松本道宏、春日雅人、井上啓
  • Organizer: 第35回日本肥満学会
  • Place of Presentation: 宮崎
  • Year and Date: 2014-10-24 – 2014-10-25
• [Presentation] 脂肪肝に伴う切除後肝再生障害に対するeIF2αリン酸化制御の重要性 (2014)
  • Author(s): 稲葉有香、芳賀早苗、尾崎倫孝、春日雅人、井上啓
  • Organizer: 第21回肝細胞研究会
  • Place of Presentation: 東京
  • Year and Date: 2014-06-27 – 2014-06-28
• [Presentation] 肥満による肝切除後肝再生障害におけるeIF2aリン酸化制御の重要性 (2014)
  • Author(s): 稲葉有香、松本道宏、尾崎倫孝、春日雅人、井上啓
  • Organizer: 第51回日本臨床分子医学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-11 – 2014-04-12
• [Remarks] 金沢大学 脳・肝インターフェースメディシン研究センター
  • URL: http://inoue.w3.kanazawa-u.ac.jp/