Gab1 adaptor protein acts as a gatekeeper to balance hepatocyte death and proliferation during acetaminophen-induced liver injury in mice
| Autor: | Kunimaro Furuta, Yoshihiro Kamada, Keigo Nishida, Norihiro Chatani, Mayumi Egawa, Tetsuo Takehara, Shinichiro Maeda, Shinichi Kiso, Yuichi Yoshida, Takashi Kizu, Tomohide Kurahashi, Satoshi Ogura, Yoshikazu Nakaoka |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
Male Programmed cell death medicine.medical_treatment Mitochondria Liver Mitochondrion Pharmacology Biology 03 medical and health sciences Mice Random Allocation Reference Values Risk Factors Conditional gene knockout medicine Animals Protein kinase B Cells Cultured Acetaminophen Adaptor Proteins Signal Transducing Cell Proliferation Liver injury Mice Knockout Hepatology Cell Death Growth factor digestive oral and skin physiology Biopsy Needle medicine.disease Phosphoproteins Immunohistochemistry Liver regeneration Mice Inbred C57BL Disease Models Animal 030104 developmental biology medicine.anatomical_structure Hepatocyte Immunology Hepatocytes Chemical and Drug Induced Liver Injury |
| Zdroj: | Hepatology (Baltimore, Md.). 63(4) |
| ISSN: | 1527-3350 |
| Popis: | 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. 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) |
| Databáze: | OpenAIRE |
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