Autophagy and Drug-Induced Liver Injury

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DESCRIPTION (provided by applicant): Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure in the US and many other countries. APAP produces liver cell death by a sequence of events that requires the early formation of a reactive metabolite, N-acetyl-p-benzoquinone imine (NAPQI), a subsequent phase where adducts of cellular and mitochondrial proteins are formed, and a final phase where these adducts trigger mitochondrial dysfunction and necrotic cell death. Administration of N-acetyl cysteine (NAC) at the early phase can efficiently increase intracellular glutathione levels and scavenge NAPQI and protect against liver injury. However, patients frequently present only after this phase is over and there are no treatments available to prevent liver injury in the subsequent phases of pathogenesis. Our recent work has shown that cell survival in the later injury phases is dependent on the autophagy pathway, presumably because of the autophagic removal of damaged mitochondria. Our preliminary data show that p62/SQSTM1 (hereafter referred to as p62) is recruited both to APAP-AD and damaged mitochondria and it induces their selective removal by autophagy. Our published data also show that liver-specific Atg5 knockout mice are resistant to APAP-induced liver injury even though they have defective autophagy. In this case, resistance results from the accumulation of p62 which results in persistent activation of the antioxidant transcription factor Nrf2. These data suggest that both autophagic and non-autophagic roles of p62 are involved in protecting against APAP-induced liver injury. The central hypothesis of this proposal is that selective p62-mediated autophagic removal of APAP-AD and damaged mitochondria and non-autophagic activation of Nrf2 are crucial to protect against the later phase of APAP-induced liver injury. To examine our hypothesis, three specific aims are proposed: 1) determine the central role of p62 in autophagic removal of APAP-AD and damaged mitochondria in vivo and in primary mouse and human hepatocytes, 2) determine the autophagic and non-autophagic role of p62 in protection against APAP-induced liver injury, and 3) determine the induction of p62-mediated autophagy and non- autophagic activation of Nrf2 can promote the recovery from APAP-induced liver injury in a post-APAP treatment mouse model. Results from this study will lead to the in-depth understanding of p62-mediated autophagy and non-autophagic mechanisms in protecting against cell injury in the late phase of APAP-induced pathogenesis, which no treatment is available and NAC treatment is no longer effective. Ultimately, such knowledge has the potential of identifying novel therapeutic approaches for treating the late phase of APAP- induced liver injury and liver failure.