PUMA induction mediates acetaminophen‐induced necrosis and liver injury

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. 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 BH3‐only Bcl‐2 family member, was markedly induced by APAP in the 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 RIP1 and JNK via transcriptional activation. Furthermore, a small‐molecule PUMA inhibitor, administered after APAP treatment, mitigated APAP‐induced hepatocyte necrosis and liver injury. Conclusions: Our results demonstrate that RIP1/JNK‐dependent PUMA induction mediates APAP‐induced liver injury by promoting hepatocyte mitochondrial dysfunction and necrosis, and suggest that PUMA inhibition is useful for alleviating acute hepatotoxicity due to APAP overdose.

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