Enhanced production of adenosine triphosphate by pharmacological activation of adenosine monophosphate-activated protein kinase ameliorates acetaminophen-induced liver injury

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Title
Enhanced production of adenosine triphosphate by pharmacological activation of adenosine monophosphate-activated protein kinase ameliorates acetaminophen-induced liver injury
Author(s)
Jung Hwan HwangYong-Hoon KimJung-Ran NohDong Hee ChoiKyoung Shim KimChul Ho Lee
Bibliographic Citation
Molecules and Cells, vol. 38, no. 10, pp. 843-850
Publication Year
2015
Abstract
The hepatic cell death induced by acetaminophen (APAP) is closely related to cellular adenosine triphosphate (ATP) depletion, which is mainly caused by mitochondrial dysfunction. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is a key sensor of low energy status. AMPK regulates metabolic homeostasis by stimulating catabolic metabolism and suppressing anabolic pathways to increase cellular energy levels. We found that the decrease in active phosphorylation of AMPK in response to APAP correlates with decreased ATP levels, in vivo. Therefore, we hypothesized that the enhanced production of ATP via AMPK stimulation can lead to amelioration of APAP-induced liver failure. A769662, an allo-steric activator of AMPK, produced a strong synergistic effect on AMPK Thr172 phosphorylation with APAP in primary hepatocytes and liver tissue. Interestingly, activation of AMPK by A769662 ameliorated the APAP- induced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centri-lobular necrosis, and APAP increased their serum alanine aminotransferase and aspartate aminotransferase levels. Furthermore, A769662 administration prevented the loss of intracellular ATP without interfering with the APAP- mediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAP- mediated liver injury. In conclusion, A769662 can effectively protect mice against APAP-induced liver injury through ATP synthesis by anaerobic glycolysis. Furthermore, stimulation of AMPK may have potential therapeutic application for APAP overdose.
Keyword
AcetaminophenAMP-activated protein kinase (AMPK)ATPLiver injury
ISSN
1016-8478
Publisher
South Korea
DOI
http://dx.doi.org/10.14348/molcells.2015.0072
Type
Article
Appears in Collections:
Ochang Branch Institute > Division of Bioinfrastructure > Laboratory Animal Resource Center > 1. Journal Articles
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