Dongshi Chen1,2, Hong-Min Ni3, Lei Wang1,2, Xiaowen Ma3, Jian Yu1,4, Wen-Xing Ding3, Lin Zhang1,2. 1. UPMC Hillman Cancer Center, Pittsburgh, PA. 2. Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA. 3. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS. 4. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
Abstract
Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical role in APAP-induced liver injury (AILI). However, the mechanisms of APAP-induced necrosis and liver injury are not fully understood. In this study, we found that p53 up-regulated modulator of apoptosis (PUMA), a B-cell lymphoma-2 (Bcl-2) homology domain 3 (BH3)-only Bcl-2 family member, was markedly induced by APAP in mouse livers and in isolated human and mouse hepatocytes. PUMA deficiency suppressed APAP-induced mitochondrial dysfunction and release of cell death factors from mitochondria, and protected against APAP-induced hepatocyte necrosis and liver injury in mice. PUMA induction by APAP was p53 independent, and required receptor-interacting protein kinase 1 (RIP1) and c-Jun N-terminal kinase (JNK) by transcriptional activation. Furthermore, a small-molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP-induced hepatocyte necrosis and liver injury. Conclusion: Our results demonstrate that RIP1/JNK-dependent PUMA induction mediates AILI by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity attributed to APAP overdose.
Acetaminophen (APAP) overdose is one of the leading causes of hepatotoxicity and acute liver failure in the United States. Accumulating evidence suggests that hepatocyte necrosis plays a critical role in APAP-induced liver injury (AILI). However, the mechanisms of APAP-induced necrosis and liver injury are not fully understood. In this study, we found that p53 up-regulated modulator of apoptosis (PUMA), a B-cell lymphoma-2 (Bcl-2) homology domain 3 (BH3)-only Bcl-2 family member, was markedly induced by APAP in mouse livers and in isolated human and mouse hepatocytes. PUMA deficiency suppressed APAP-induced mitochondrial dysfunction and release of cell death factors from mitochondria, and protected against APAP-induced hepatocyte necrosis and liver injury in mice. PUMA induction by APAP was p53 independent, and required receptor-interacting protein kinase 1 (RIP1) and c-Jun N-terminal kinase (JNK) by transcriptional activation. Furthermore, a small-molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP-induced hepatocyte necrosis and liver injury. Conclusion: Our results demonstrate that RIP1/JNK-dependent PUMA induction mediates AILI by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity attributed to APAPoverdose.
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