Exp Mol Med.  2017 Dec;49(12):e407. 10.1038/emm.2017.203.

Lysophosphatidic acid protects against acetaminophen-induced acute liver injury

• Bae GH
• Lee SK
• Kim HS
• Lee M
• Lee HY
• Bae YS

• KMID: 2402944
• DOI: http://doi.org/10.1038/emm.2017.203

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.