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Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen‐induced liver injury in mice
Author(s) -
Furuta Kunimaro,
Yoshida Yuichi,
Ogura Satoshi,
Kurahashi Tomohide,
Kizu Takashi,
Maeda Shinichiro,
Egawa Mayumi,
Chatani Norihiro,
Nishida Keigo,
Nakaoka Yoshikazu,
Kiso Shinichi,
Kamada Yoshihiro,
Takehara Tetsuo
Publication year - 2016
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.28410
Subject(s) - hepatocyte , liver injury , acetaminophen , programmed cell death , signal transducing adaptor protein , cancer research , biology , microbiology and biotechnology , apoptosis , signal transduction , pharmacology , endocrinology , chemistry , medicine , biochemistry , in vitro
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 ( Gab1 CKO) and control mice were treated with 250 mg/kg of APAP. After APAP treatment, Gab1 CKO mice had significantly higher mortality and elevated serum alanine aminotransferase levels compared to control mice. Gab1 CKO mice had increased hepatocyte death and increased serum levels of high mobility group box 1, a marker of hepatocyte necrosis. In addition, Gab1 CKO mice had reduced hepatocyte proliferation. The enhanced hepatotoxicity in Gab1 CKO 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, Gab1 CKO 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. Conclusion: 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. (H epatology 2016;63:1340–1355)