Abstract
Acetaminophen (APAP) is the leading cause of drug-induced acute liver failure. Sphingosine-1-phosphate (S1P), whose formation is catalyzed by sphingosine kinase (SPHK)-1 or -2, is a bioactive lipid implicated in human health and disease. Here, we show that APAP-treated sphK1-deficient (sphK1−/−) mice exhibited markedly less liver damage and reduced inflammation compared with the wild-type mice. SPHK1 deficiency alleviated APAP-induced endoplasmic reticulum (ER) stress by affecting the phosphorylation of inositol-requiring enzyme 1α (IRE1α) and protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK)-eukaryotic translation initiation factor 2α (eIF2α), levels of activating transcription factor 4 (ATF4), and activation of activating transcription factor 6 (ATF6). SPHK1 deficiency also inhibited mitochondrial permeability transition (MPT), as evidenced by the impaired phosphorylation of JNK, apoptosis signal-regulated kinase 1 (ASK1), and glycogen synthase kinase 3β (GSK3β). In addition, SPHK1 deficiency reduced the levels of histone deacetylase and promoted the acetylation of p65 and STAT1, thereby impairing the transcription of inflammatory genes. Supplementation with exogenous S1P significantly reversed the activation of the PERK-eIF2α-ATF4 pathway and ATF6 during ER stress as well as the activation of GSK3β, ASK1, and JNK during MPT. Both FTY720, a functional S1P receptor antagonist, and PF543, an SPHK1 inhibitor, significantly ameliorated APAP-induced liver injury and improved animal survival. Our study reveals a critical role for SPHK1 in mediating APAP-induced hepatotoxicity by promoting ER stress and MPT.
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Acknowledgements
This work was supported by grants from the National Key Research and Development Program of China (Grant No. 2016YFF0101400), National Natural Science Foundation of China (Grant No. 81571614, 81871241), and Jiangsu Provincial Innovation Team Program Foundation.
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LjL and HZ conceptualized and designed the study; LjL, HW, JZ, YS, and FW performed the experiments; LjL performed the statistical analysis; LjL, HW, and HZ drafted the manuscript; SW, LS, QY, MS, LxL, and HZ revised and approved the final version of the manuscript. All authors read and approved the manuscript.
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Li, L., Wang, H., Zhang, J. et al. SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition. Cell Death Differ 27, 1924–1937 (2020). https://doi.org/10.1038/s41418-019-0471-x
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DOI: https://doi.org/10.1038/s41418-019-0471-x
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