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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2015.10
- 수록면
- 843 - 850 (8page)
- DOI
- dx.doi.org/10.14348/molcells.2015.0072
이용수
초록· 키워드
오류제보하기
The1hepatic 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 allosteric 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 APAPinduced hepatotoxicity in C57BL/6N mice treated with APAP at a dose of 400 mg/kg intraperitoneally. However, mice treated with APAP alone developed massive centrilobular 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 APAPmediated reduction of mitochondrial dysfunction. In contrast, inhibition of glycolysis by 2-deoxy-glucose eliminated the beneficial effects of A769662 on APAPmediated 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 thera-peutic application for APAP overdose.
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참고문헌 (34)
참고문헌 신청
Cohen, S. D. / 1997 / Selective protein arylation and acetaminophen-induced hepatotoxicity / Drug Metab. Rev 29:59~77
Cool, B. / 2006 / Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome / Cell Metab 3:403~416
Dahlin, D. C. / 1984 / Nacetyl-p-benzoquinone imine : a cytochrome P-450-mediated oxidation product of acetaminophen / Proc. Natl. Acad. Sci. USA 81:1327~1331
Dong, G. Z. / 2014 / AMPK activation by isorhamnetin protects hepatocytes against oxidative stress and mitochondrial dysfunction / Eur. J. Pharmacol 740:634~640
Fogarty, S. / 2010 / Development of protein kinase activators : AMPK as a target in metabolic disorders and cancer / Biochim. Biophys. Acta 1804:581~591
Cool, B. / 2006 / Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome / Cell Metab 3:403~416
Dahlin, D. C. / 1984 / Nacetyl-p-benzoquinone imine : a cytochrome P-450-mediated oxidation product of acetaminophen / Proc. Natl. Acad. Sci. USA 81:1327~1331
Dong, G. Z. / 2014 / AMPK activation by isorhamnetin protects hepatocytes against oxidative stress and mitochondrial dysfunction / Eur. J. Pharmacol 740:634~640
Fogarty, S. / 2010 / Development of protein kinase activators : AMPK as a target in metabolic disorders and cancer / Biochim. Biophys. Acta 1804:581~591
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