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

2014 Fiscal Year Final Research Report

• 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
• 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

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.

Free Research Field

肝臓学、代謝学