Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice.

Acetaminophen (APAP) overdose is the leading cause of drug-induced acute liver failure. In APAP-induced acute liver failure, hepatocytedeath and subsequent liver regenerationdetermines 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 receptorsto downstream effectors. In this study, we hypothesized that Gab1is involved in APAP-induced acute liver failure. Hepatocyte-specific Gab1conditional 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 hepatocytedeath and increased serum levels of high mobility groupbox 1, a marker of hepatocytenecrosis. In addition, Gab1CKO mice had reduced hepatocyteproliferation. 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 hepatocyteswere more susceptible to APAP-induced mitochondrial dysfunction and cell death, suggesting that hepatocyte Gab1is a direct target of APAP-induced hepatotoxicity. Conclusion: Our current data demonstrate that hepatocyte Gab1plays a critical role in controlling the balance between hepatocytedeath and compensatory hepatocyteproliferation during APAP-induced liver injury. ( Hepatology2016;63:1340–1355)