Faculty of Pharmacy, Kindai University, Osaka 577-8502, Japan.
Faculty of Pharmacy, Takasaki University of Health and Welfare, Takasaki 370-0033, Japan.
Prostaglandins Leukot Essent Fatty Acids. 2020 Apr;155:102081. doi: 10.1016/j.plefa.2020.102081. Epub 2020 Feb 21.
Prostaglandin E (PGE) exhibits hepatoprotective effects against various types of liver injury. However, there is little information on the disposition of endogenous PGE during liver injury. In the present study, we attempted to elucidate the mechanism involved in regulating PGE distribution during liver injury. Carbon tetrachloride (CCl) was used to establish a liver injury mouse model. PGE was measured by LC-MS/MS. The plasma and hepatic PGE levels were significantly increased at 6 to 48 h after CCl treatment. The ratio of plasma levels of 13,14-dihydro-15-ketoPGE (PGEM), a major PGE metabolite, to PGE decreased significantly after CCl treatment. PGE synthesis and expression of enzymes related to PGE production were not induced, while the activity and mRNA expression of 15-prostaglandin dehydrogenase (15-PGDH/Hpgd), a major enzyme for PGE inactivation, decreased significantly in the liver of CCl-treated mice compared to that of vehicle-treated control. The plasma and hepatic PGE levels were negatively correlated with the hepatic mRNA expression levels of Hpgd. Although the mRNA expression of organic anion transporting polypeptide 2A1 (OATP2A1/Slco2a1), a major PGE transporter, was upregulated, other hepatic OATPs decreased significantly at 24 h after CCl treatment. Immunohistochemical analysis indicated that 15-PGDH was mainly expressed in endothelial cells and that OATP2A1 was expressed at least in endothelial cells and Kupffer cells in the liver. These results suggest that the decreased 15-PGDH expression in hepatic endothelial cells is the principal mechanism for the increase in hepatic and plasma PGE levels due to the CCl-induced liver injury.
前列腺素 E（PGE）对各种类型的肝损伤具有肝保护作用。然而，关于肝损伤期间内源性 PGE 分布的信息很少。在本研究中，我们试图阐明调节肝损伤期间 PGE 分布的机制。使用四氯化碳（CCl）建立肝损伤小鼠模型。通过 LC-MS/MS 测量 PGE。CCl 处理后 6 至 48 小时，血浆和肝 PGE 水平显着升高。CCl 处理后，PGEM（PGE 的主要代谢物）的血浆水平与 PGE 的比值显着降低。PGE 合成和与 PGE 产生相关的酶的表达没有诱导，而 15-前列腺素脱氢酶（15-PGDH/Hpgd）的活性和 mRNA 表达，一种主要的 PGE 失活酶，在 CCl 处理的小鼠肝脏中显着降低与车辆处理的对照相比。血浆和肝 PGE 水平与肝 Hpgd 的 mRNA 表达水平呈负相关。尽管有机阴离子转运蛋白 2A1（OATP2A1/Slco2a1）的 mRNA 表达上调，一种主要的 PGE 转运蛋白，但 CCl 处理 24 小时后其他肝 OATP 显着降低。免疫组织化学分析表明，15-PGDH 主要在血管内皮细胞中表达，而 OATP2A1 至少在肝内皮细胞和库普弗细胞中表达。这些结果表明，由于 CCl 引起的肝损伤，肝内皮细胞中 15-PGDH 表达的降低是导致肝和血浆 PGE 水平升高的主要机制。
