Pleiotropic Role of p53 in Injury and Liver Regeneration after Acetaminophen Overdose

Abstract

p53 is the major cellular gatekeeper involved in proliferation, cell death, migration, and homeostasis. The role of p53 in pathogenesis of drug-induced liver injury is unknown. We investigated the role of p53 in liver injury and regeneration after acetaminophen (APAP) overdose, the most common cause of acute liver failure in the Western world. Eight-week-old male wild-type (WT) and p53 knockout (p53KO) mice were treated with 300 mg/kg APAP, and the dynamics of liver injury and regeneration were studied over a time course of 0 to 96 hours. Deletion of p53 resulted in a threefold higher liver injury than in WT mice. Interestingly, despite higher liver injury, p53KO mice recovered similarly as the WT mice because of faster liver regeneration. Deletion of p53 did not affect APAP bioactivation and initiation of injury. Microarray analysis revealed that p53KO mice had disrupted metabolic homeostasis and induced inflammatory and proliferative signaling. p53KO mice showed prolonged steatosis correlating with prolonged liver injury. Initiation of liver regeneration in p53KO mice was delayed, but once initiated, cell cycle was significantly faster than WT mice because of sustained AKT, extracellular signal-regulated kinase, and mammalian target of rapamycin signaling. These studies show that p53 plays a pleotropic role after APAP overdose, where it prevents progression of liver injury by maintaining metabolic homeostasis and also regulates initiation of liver regeneration through proliferative signaling.