Nrf2 signaling and autophagy are complementary in protecting lipopolysaccharide/d-galactosamine-induced acute liver injury by licochalcone A.
Cell Death Dis. 2019 04 5 ;10(4):313. Epub 2019 Apr 5. PMID: 30952839
Licochalcone A (Lico A), isolated from Xinjiang licorice Glycyrrhiza inflate, has been shown to have antioxidative potential via the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, which is involved in the prevention of acetaminophen-induced hepatotoxicity. The purpose of the current study was to further explore the protective effect of Lico A against lipopolysaccharide/d-galactosamine (LPS/GalN)-induced acute liver injury (ALI) and its underlying molecular mechanisms. Our results found that treatment with Lico A significantly reduced in LPS/GalN-induced hepatotoxicity by lessening lethality, alleviating histopathological liver changes, decreasing the alanine transaminase, and aspartate aminotransferase levels, attenuating the secretion of inflammatory cytokines, and regulating oxidative markers. Furthermore, Lico A efficiently alleviated LPS-induced inflammatory response by inhibiting TLR4-MAPK and -NF-κB, as well as the Txnip-NLRP3 signaling pathway. Meanwhile, Lico A induced the activation of Nrf2 and QSTM1 (P62) signaling and promoted autophagy involved in AMP-activated protein kinase (AMPK)-the transcription factor EB (TFEB) signaling, which may contribute to its hepatoprotective activity. Additional mechanistic investigations to evaluate the dependence of the hepatoprotective role of Lico A on Nrf2 revealed that a lack of Nrf2 promoted Lico A-induced autophagy, which contributed to the hepatoprotective effect of Lico A in Nrf2mice. In addition, cotreatment with autophagy inhibitor (3-methyladenine, 3-MA) alleviated but did not abrogate the hepatoprotective effect of Lico A, which may be attributed to its ability to activate Nrf2. Our study firstly suggests that Lico A has protective potential against LPS/GalN-induced hepatotoxicity, which may be strongly associated with activation of Nrf2 and autophagy.