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We investigated the effect of lysophosphatidic acid (LPA) in experimental acetaminophen (APAP)-induced acute liver injury. LPA administration significantly reduced APAP-challenged acute liver injury, showing attenuated liver damage, liver cell death and aspartate aminotransferase and alanine aminotransferase levels. APAP overdose-induced mortality was also significantly decreased by LPA administration. Regarding the mechanism involved in LPA-induced protection against acute liver injury, LPA administration significantly increased the glutathione level, which was markedly decreased in APAP challenge-induced acute liver injury. LPA administration also strongly blocked the APAP challenge-elicited phosphorylation of JNK, ERK and GSK3β, which are involved in the pathogenesis of acute liver injury. Furthermore, LPA administration decreased the production of TNF-α and IL-1β in an experimental drug-induced liver injury animal model. Mouse primary hepatocytes express LPA1,3–6, and injection of the LPA receptor antagonist KI16425 (an LPA1,3-selective inhibitor) or H2L 5765834 (an LPA1,3,5-selective inhibitor) did not reverse the LPA-induced protective effects against acute liver injury. The therapeutic administration of LPA also blocked APAPinduced liver damage, leading to an increased survival rate. Collectively, these results indicate that the well-known bioactive lipid LPA can block the pathogenesis of APAP-induced acute liver injury by increasing the glutathione level but decreasing inflammatory cytokines in an LPA1,3,5-independent manner. Our results suggest that LPA might be an important therapeutic agent for drug-induced liver injury.
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참고문헌 (23)
참고문헌 신청
Bernal W / 2010 / Acute liver failure / Lancet 376 : 190 ~ 201
Choi JW / 2010 / LPA receptors : subtypes and biological actions / Annu Rev Pharmacol Toxicol 50 : 157 ~ 186
Chou C-H / 2015 / Lysophosphatidic acid alters the expression profiles of angiogenic factors, cytokines, and chemokines in mouse liver sinusoidal endothelial cells / PLoS ON
Cohen SD / 1997 / Selective protein arylation and acetaminopheninduced hepatotoxicity / Drug Metab Rev 29 : 59 ~ 77
David M / 2014 / Lysophosphatidic acid receptor type 1(LPA1)plays a functional role in osteoclast differentiation and bone resorption activity / J Biol Chem 289 : 6551 ~ 656
Choi JW / 2010 / LPA receptors : subtypes and biological actions / Annu Rev Pharmacol Toxicol 50 : 157 ~ 186
Chou C-H / 2015 / Lysophosphatidic acid alters the expression profiles of angiogenic factors, cytokines, and chemokines in mouse liver sinusoidal endothelial cells / PLoS ON
Cohen SD / 1997 / Selective protein arylation and acetaminopheninduced hepatotoxicity / Drug Metab Rev 29 : 59 ~ 77
David M / 2014 / Lysophosphatidic acid receptor type 1(LPA1)plays a functional role in osteoclast differentiation and bone resorption activity / J Biol Chem 289 : 6551 ~ 656
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