SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition
SPHK1 deficiency protects mice from acetaminophen-induced ER stress and mitochondrial permeability transition
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SPHK1 缺陷可保护小鼠免受对乙酰氨基酚诱导的 ER 应激和线粒体通透性转变
DOI：
10.1038/s41418-019-0471-x
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发表时间：
2020-06-01
影响因子：
12.4
通讯作者：
Zhou, Hong
中科院分区：
文献类型：
--
作者：
Li, Longjun;Wang, Haitao;Zhou, Hong
对乙酰氨基酚（APAP）是药物性急性肝衰竭的主要原因。鞘氨醇-1-磷酸（S1 P）是一种与人类健康和疾病有关的生物活性脂质，其形成由鞘氨醇激酶（SPHK）-1或-2催化。在这里，我们发现APAP治疗的JNK 1缺陷（JNK 1 −/−）小鼠与野生型小鼠相比，肝损伤明显减轻，炎症减少。SPHK 1缺陷通过影响肌醇需要酶1α（IRE 1 α）和蛋白激酶R（PKR）样内质网激酶（PERK）-真核翻译起始因子2α（eIF 2 α）的磷酸化、转录激活因子4（ATF 4）的水平和转录激活因子6（ATF 6）的激活来减轻APAP诱导的内质网（ER）应激。SPHK 1缺陷还抑制线粒体通透性转换（MPT），如JNK、凋亡信号调节激酶1（ASK 1）和糖原合成酶激酶3β（GSK 3 β）磷酸化受损所证明。此外，SPHK 1缺陷降低了组蛋白去乙酰化酶的水平，促进了p65和STAT 1的乙酰化，从而损害了炎症基因的转录。补充外源性S1 P可显著逆转ER应激期间PERK-eIF 2 α-ATF 4通路和ATF 6的激活以及MPT期间GSK 3 β、ASK 1和JNK的激活。功能性S1 P受体拮抗剂FTY 720和SPHK 1抑制剂PF 543均显著改善APAP诱导的肝损伤并提高动物存活率。我们的研究揭示了SPHK 1通过促进ER应激和MPT在介导APAP诱导的肝毒性中的关键作用。
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-treatedsphK1-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.