Lysophosphatidic acid protects against acetaminophen-induced acute liver injury

Abstract

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 APAP-induced 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. Boosting levels of a particular signalling molecule helps repair the damage caused by drug-induced acute liver injury. The popular pain reliever paracetamol can cause severe damage to the liver in the case of overdose. The drug impairs the function of glutathione, an antioxidant found in most tissues that helps prevent cellular damage. Yoe-Sik Bae at Sungkyunkwan University in Korea and co-workers used mice to examine the effect of increasing levels of lysophosphatidic acid (LPA), a signalling molecule involved in maintaining cell health, on paracetamol-induced acute liver injury. They found that LPA enhances glutathione recovery in the liver after drug overdose, thus rescuing liver cells from further damage and cell death. LPA also reduces inflammatory protein levels in the liver, and so could be used in future therapies.