Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen‐induced liver injury in mice. Issue 4 (22nd January 2016)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Hepatology. Volume 63:Issue 4(2016:Apr.)
• Page Start: 1340
• Page End: 1355
• Publication Date: 2016-01-22
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.28410
• Languages: English
• ISSNs: 0270-9139

Abstract

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 ( 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. (Hepatology 2016;63:1340–1355)