title: Growth arrest and DNA damage-inducible 34 regulates liver regeneration in hepatic steatosis in mice.
abstract: The liver has robust regenerative potential in response to damage, but hepatic steatosis (HS) weakens this potential. We found that the enhanced integrated stress response (ISR) mediated by phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2α) impairs regeneration in HS and that growth arrest and DNA damage-inducible 34 (Gadd34)-dependent suppression of ISR plays a crucial role in fatty liver regeneration. Although mice fed a high-fat diet for 2 weeks developed moderate fatty liver with no increase in eIF2α phosphorylation before 70% hepatectomy, they showed impaired liver regeneration as a result of reduced proliferation and increased death of hepatocytes with increased phosphorylation of eIF2α and ISR. An increased ISR through Gadd34 knockdown induced C/EBP homologous protein (CHOP)-dependent apoptosis and receptor-interacting protein kinase 3-dependent necrosis, resulting in increased hepatocyte death during fatty liver regeneration. Furthermore, Gadd34 knockdown and increased phosphorylation of eIF2α decreased cyclin D1 protein and reduced hepatocyte proliferation. In contrast, enhancement of Gadd34 suppressed phosphorylation of eIF2α and reduced CHOP expression and hepatocyte apoptosis without affecting hepatocyte proliferation, clearly improving fatty liver regeneration. In more severe fatty liver of leptin receptor-deficient db/db mice, forced expression of hepatic Gadd34 also promoted hepatic regeneration after hepatectomy.
  
  
  CONCLUSIONS
  Gadd34-mediated regulation of ISR acts as a physiological defense mechanism against impaired liver regeneration resulting from steatosis and is thus a possible therapeutic target for impaired regeneration in HS.
authors.affiliation: Department of Physiology and Metabolism, Brain/Liver Interface Medicine Research Center, Kanazawa University, Kanazawa, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Inaba
authors.forename: Tomoko
authors.initials: T
authors.lastname: Furutani
authors.forename: Kumi
authors.initials: K
authors.lastname: Kimura
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Watanabe
authors.forename: Sanae
authors.initials: S
authors.lastname: Haga
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kido
authors.forename: Michihiro
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Yamamoto
authors.forename: Kenichi
authors.initials: K
authors.lastname: Harada
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaneko
authors.forename: Seiichi
authors.initials: S
authors.lastname: Oyadomari
authors.forename: Michitaka
authors.initials: M
authors.lastname: Ozaki
authors.forename: Masato
authors.initials: M
authors.lastname: Kasuga
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Inoue
mesh_terms: D000818:Animals; D005234:Fatty Liver; D008115:Liver Regeneration / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D054645:Protein Phosphatase 1 / Q000502:physiology*
chemical_list: C513256:Ppp1r15a protein, mouse; D054645:Protein Phosphatase 1