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.
Highlights
Induced liver injury involves the formation of reactive intermediates, including electrophiles and oxygen free radicals, which can damage cellular structures and organelles and promote hepatocyte death [1, 2]
We previously demonstrated that glyceraldehyde-3-phosphate dehydrogenase (GAPDH) undergoes nuclear translocation in isolated hepatocytes and in vivo during chronic mouse liver injury induced by the porphyrinogenic drug 3,5-diethoxycarbonyl-1,4-dihydrocollidine, which is associated with oxidative liver damage [11]
We tested the effect of short-term (6 day) ethanol pre-treatment on nuclear GAPDH accumulation in response to APAP (500mg/kg; 4h)
Summary
Induced liver injury involves the formation of reactive intermediates, including electrophiles and oxygen free radicals, which can damage cellular structures and organelles and promote hepatocyte death [1, 2]. Alterations in protein post-translational modifications and formation of various types of oligomeric and misfolded protein species are common cellular responses to oxidative injury [3,4,5]. Some protein alterations carry functional consequences for cell fate and may provide opportunities to devise protective strategies against stressinduced cellular damage. The metabolic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which has homeostasis-related glycolytic roles as well as multiple stress- and toxicity-related functions [6,7,8,9,10], represents a potential target for pharmacological modulation in mitigating chemically induced liver injury [11].
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