title: Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice.
abstract: Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. In APAP-induced acute liver failure, hepatocyte death and subsequent liver regeneration determines the prognosis of patients, making it necessary to identify suitable therapeutic targets based on detailed molecular mechanisms. Grb2-associated binder 1 (Gab1) adaptor protein plays a crucial role in transmitting signals from growth factor and cytokine receptors to downstream effectors. In this study, we hypothesized that Gab1 is involved in APAP-induced acute liver failure. Hepatocyte-specific Gab1 conditional knockout (Gab1CKO) and control mice were treated with 250 mg/kg of APAP. After APAP treatment, Gab1CKO mice had significantly higher mortality and elevated serum alanine aminotransferase levels compared to control mice. Gab1CKO mice had increased hepatocyte death and increased serum levels of high mobility group box 1, a marker of hepatocyte necrosis. In addition, Gab1CKO mice had reduced hepatocyte proliferation. The enhanced hepatotoxicity in Gab1CKO mice was associated with increased activation of stress-related c-Jun N-terminal kinase (JNK) and reduced activation of extracellular signal-regulated kinase and AKT. Furthermore, Gab1CKO mice showed enhanced mitochondrial translocation of JNK accompanied by an increase in the release of mitochondrial enzymes into the cytosol, which is indicative of increased mitochondrial dysfunction and subsequent nuclear DNA fragmentation. Finally, in vitro experiments showed that Gab1-deficient hepatocytes were more susceptible to APAP-induced mitochondrial dysfunction and cell death, suggesting that hepatocyte Gab1 is a direct target of APAP-induced hepatotoxicity.
  
  
  CONCLUSIONS
  Our current data demonstrate that hepatocyte Gab1 plays a critical role in controlling the balance between hepatocyte death and compensatory hepatocyte proliferation during APAP-induced liver injury.
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kunimaro
authors.initials: K
authors.lastname: Furuta
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tomohide
authors.initials: T
authors.lastname: Kurahashi
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Kizu
authors.affiliation: Department of Pharmacy, Osaka University Hospital, Suita, Osaka, Japan.
authors.forename: Shinichiro
authors.initials: S
authors.lastname: Maeda
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Egawa
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Chatani
authors.affiliation: Laboratory of Immune Regulation, Faculty of Pharmaceutical Sciences, Suzuka University of Medical Science, Suzuka, Mie, Japan.
authors.forename: Keigo
authors.initials: K
authors.lastname: Nishida
authors.affiliation: Department of Cardiovascular Medicine, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.|Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science Technology Agency, Kawaguchi, Saitama, Japan.
authors.forename: Yoshikazu
authors.initials: Y
authors.lastname: Nakaoka
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Kiso
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.|Departments of Molecular Biochemistry and Clinical Investigation, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Kamada
authors.affiliation: Department of Gastroenterology and Hepatology, Osaka University, Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Takehara
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects* / Q000494:pharmacology; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001707:Biopsy, Needle; D016923:Cell Death / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects*; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008930:Mitochondria, Liver / Q000187:drug effects*; D010750:Phosphoproteins / Q000187:drug effects / Q000378:metabolism*; D011897:Random Allocation; D012016:Reference Values; D012307:Risk Factors
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C490897:Gab1 protein, mouse; D010750:Phosphoproteins; D000082:Acetaminophen