Acetaminophen (APAP) hepatotoxicity is the most frequent cause of acute liver failure of any etiology in the United States. However, no effective therapeutic strategies for APAP-induced liver injury are currently available, especially for late presenting patients. It is well known that after APAP overdose, N-acetyl-p- benzoquinone imine (NAPQI), the reactive metabolite of APAP, binds to cellular and mitochondrial proteins to form APAP-protein adducts (APAP-AD) following the depletion of cellular glutathione, which triggers mitochondrial dysfunction, oxidant stress and subsequent necrosis. In our previous funding cycle, we demonstrated that activation of autophagy, a cellular adaptive response of lysosomal degradation pathway, protects against APAP-induced liver injury by removing APAP-AD and damaged mitochondria. Liver is a very dynamic organ that has the capacity to repair and regenerate after injury. We also demonstrated that increased mitochondrial biogenesis can improve liver regeneration and recovery from APAP-induced liver injury. Importantly, our preliminary data showed that the transcription factor EB (TFEB), a master regulator that governs both the biogenesis of lysosomes for autophagy and mitochondria for regeneration, was impaired during the course of APAP-induced liver injury. Therefore, the major goal of this competitive R01 renewal is to understand the molecular mechanisms by which APAP impairs TFEB signaling in the liver. Our central hypothesize is that activation of TFEB will lead to increased biogenesis of both lysosomes and mitochondria that inhibits the progression of APAP-induced liver injury and promotes the liver regeneration.
Two specific aims are proposed: 1) determine the mechanisms by which APAP impairs TFEB-mediated biogenesis of lysosomes and mitochondria in hepatocytes; and 2) determine the mechanism(s) by which TFEB promotes the recovery from APAP-induced liver injury by increased biogenesis of lysosomes and mitochondria. The proposed research is innovative in the concept that a transcription program that governs both the autophagy-lysosomal pathway and mitochondrial biogenesis is impaired in APAP-induced liver injury. We will utilize novel genetic animal models such as liver-specific TFEB KO mice, and adeno-associated virus- mediated overexpression of TFEB and PGC-1? approaches to specifically investigate the role of TFEB and PGC-1? in autophagic removal of damaged mitochondrial and enhancing new mitochondria biogenesis in reversal of APAP-induced liver injury. Moreover, we will also utilize the newly developed new molecular tools to accurately monitor and quantify the zonated changes of mitophagy and mitochondrial biogenesis in mouse livers after APAP. Results from our proposed study will lead to the in-depth understanding of the TFEB- mediated cellular adaptive response in promoting autophagic degradation of damaged mitochondria and mitochondrial biogenesis in the reversal of APAP-induced liver injury. Ultimately, such knowledge has the potential of identifying novel therapeutic targets for treating APAP-induced liver injury and acute liver failure.

Public Health Relevance

Acetaminophen (APAP)-induced liver injury is the most frequent cause of acute liver failure of any etiology in the United States. The only currently available treatment for APAP-induced acute liver injury, N-acetylcysteine (NAC), has a limited window of efficacy. Based on the findings of our previous funding cycle and the preliminary data, we propose to study a transcription program that governs the autophagy-lysosomal degradation and mitochondria biogenesis in mice and human hepatocytes to identify TFEB as a novel therapeutic target to attenuate cell death and promote liver regeneration in the late stage of APAP overdose, which would prevent liver failure and promote recovery of the patient.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Serrano, Jose
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University of Kansas
Schools of Medicine
Kansas City
United States
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