SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition
Autor: | Hong Zhou, Shuang Wen, Yeqin Sha, Qiang You, Haitao Wang, Liang Sheng, Lixin Liu, Lianping He, Fengjiao Wu, Jun Zhang, Longjun Li, Meiqing Shi |
---|---|
Jazyk: | angličtina |
Rok vydání: | 2019 |
Předmět: |
0301 basic medicine
Pyrrolidines Sphingosine kinase Article Mitochondrial Transmembrane Permeability-Driven Necrosis 03 medical and health sciences Mice 0302 clinical medicine GSK-3 Animals ASK1 Sulfones Enzyme Inhibitors Molecular Biology Sphingosine-1-Phosphate Receptors Acetaminophen Mice Knockout Chemistry ATF6 Fingolimod Hydrochloride Endoplasmic reticulum Methanol ATF4 Cell Biology Endoplasmic Reticulum Stress Protein kinase R Cell biology Mice Inbred C57BL Phosphotransferases (Alcohol Group Acceptor) 030104 developmental biology 030220 oncology & carcinogenesis Unfolded protein response |
Zdroj: | Cell Death Differ |
Popis: | 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. |
Databáze: | OpenAIRE |
Externí odkaz: |