Ethanol and acetaminophen synergistically induce hepatic aggregation and TCH346-insensitive nuclear translocation of GAPDH

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Abstract

The glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH) signals during cellular stress via several post-translational modifications that change its folding properties, protein-protein interactions and sub-cellular localization. We examined GAPDH properties in acute mouse liver injury due to ethanol and/or acetaminophen (APAP) treatment. Synergistic robust and time-dependent nuclear accumulation and aggregation of GAPDH were observed only in combined, but not individual, ethanol/APAP treatments. The small molecule GAPDH-targeting compound TCH346 partially attenuated liver damage possibly via mitochondrial mechanisms, and independent of nuclear accumulation and aggregation of GAPDH. These findings provide a novel potential mechanism for hepatotoxicity caused by combined alcohol and acetaminophen exposure.

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Snider, N. T., Portney, D. A., Willcockson, H. H., Maitra, D., Martin, H. C., Greenson, J. K., & Omary, M. B. (2016). Ethanol and acetaminophen synergistically induce hepatic aggregation and TCH346-insensitive nuclear translocation of GAPDH. PLoS ONE, 11(8). https://doi.org/10.1371/journal.pone.0160982

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