Lysophosphatidic acid protects against acetaminophen-induced acute liver injury

  • Exp Mol Med. 2017 Dec 8;49(12):e407. doi: 10.1038/emm.2017.203.
Geon Ho Bae  1 ,  Sung Kyun Lee  1 ,  Hyung Sik Kim  1 ,  Mingyu Lee  2 ,  Ha Young Lee  1 ,  Yoe-Sik Bae  1  2
Affiliations
  • 1. Department of Biological Sciences, Sungkyunkwan University, Suwon, Republic of Korea.
  • 2. Department of Health Sciences and Technology, Samsung Advanced Institute for Health Sciences and Technology, Seoul, Republic of Korea.
PMID: 29217823 DOI: 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.

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