mPGES-2 deletion remarkably enhances liver injury in streptozotocin-treated mice via induction of GLUT2.
mPGES-2 deletion remarkably enhances liver injury in streptozotocin-treated mice via induction of GLUT2.
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DOI：
10.1016/j.jhep.2014.07.018
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发表时间：
2014-12
影响因子：
25.7
通讯作者：
Yang, Tianxin
中科院分区：
文献类型：
--
作者：
Sun, Ying;Jia, Zhanjun;Yang, Guangrui;Kakizoe, Yutaka;Liu, Mi;Yang, Kevin T.;Liu, Ying;Yang, Baoxue;Yang, Tianxin
微粒体前列腺素E合酶-2（mPGES-2）缺失不影响体内PGE 2的产生，并且这种酶的功能仍然难以捉摸。本研究旨在探讨mPGES-2在链脲佐菌素（STZ）诱导的1型糖尿病和器官损伤中的作用。mPGES-2野生型（WT）和敲除（KO）小鼠通过以120 mg/kg的剂量单次腹膜内注射STZ来处理以诱导1型糖尿病。随后，评价血糖状态和器官损伤。STZ给药4天后，与WT对照小鼠中观察到的正常表型相比，mPGES-2 KO小鼠表现出严重的致死性。在单独的实验中，在STZ处理的第3天进行分析以避免致死性。STZ处理的KO和WT小鼠之间的血糖水平相似。然而，KO小鼠的肝脏呈淡黄色，伴有严重的整体肝脂肪变性，同时伴有肝酶显著升高和胃显著扩张。然而，其他器官的形态基本正常。与WT小鼠相比，STZ处理的KO小鼠显示出广泛的肝细胞凋亡，同时炎症和氧化应激显著增强。更有趣的是，在KO小鼠中发现肝脏特异性GLUT 2上调50%，伴有显著增强的STZ蓄积，这种GLUT 2的诱导可能与胰岛素/SREBP-1c途径相关。原代培养的KO小鼠肝细胞表现出增加的敏感性STZ诱导的损伤和更高的细胞STZ含量，这是显着钝化的选择性GLUT 2抑制剂根皮素。mPGES-2缺失可能通过GLUT 2介导的STZ摄取增强STZ诱导的肝毒性，与糖尿病无关。
Microsomal prostaglandin E synthase-2 (mPGES-2) deletion does not influence in vivo PGE2 production and the function of this enzyme remains elusive. The present study was undertaken to investigate the role of mPGES-2 in streptozotocin (STZ)-induced type-1 diabetes and organ injuries. mPGES-2 wild type (WT) and knockout (KO) mice were treated by a single intraperitoneal injection of STZ at the dose of 120 mg/kg to induce type-1 diabetes. Subsequently, glycemic status and organ injuries were evaluated. Following 4 days of STZ administration, mPGES-2 KO mice exhibited severe lethality in contrast to the normal phenotype observed in WT control mice. In a separate experiment, the analysis was performed at day 3 of the STZ treatment in order to avoid lethality. Blood glucose levels were similar between STZ-treated KO and WT mice. However, the livers of KO mice were yellowish with severe global hepatic steatosis, in parallel with markedly elevated liver enzymes and remarkable stomach expansion. However, the morphology of the other organs was largely normal. The STZ-treated KO mice displayed extensive hepatocyte apoptosis compared with WT mice in parallel with markedly enhanced inflammation and oxidative stress. More interestingly, a liver-specific 50% upregulation of GLUT2 was found in the KO mice accompanied with a markedly enhanced STZ accumulation and this induction of GLUT2 was likely to be associated with the insulin/SREBP-1c pathway. Primary cultured hepatocytes of KO mice exhibited an increased sensitivity to STZ-induced injury and higher cellular STZ content, which was markedly blunted by the selective GLUT2 inhibitor phloretin. mPGES-2 deletion enhanced STZ-induced liver toxicity possibly via GLUT2-mediated STZ uptake, independently of diabetes mellitus.
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DOI：
10.1006/bbrc.2002.6531
发表时间：
2002-03-08
影响因子：
3.1
作者：
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通讯作者：
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影响因子：
7.7
作者：
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影响因子：
2.5
作者：
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影响因子：
8.2
作者：
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通讯作者：
Lenzen, S
DOI：
10.1073/pnas.0404297101
发表时间：
2004-08-03
影响因子：
11.1
作者：
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通讯作者：
Brown, MS