The regulatory mechanism involved in the prostaglandin E2 disposition in carbon tetrachloride-induced liver injury

Abstract

Prostaglandin E₂ (PGE₂) exhibits hepatoprotective effects against various types of liver injury. However, there is little information on the disposition of endogenous PGE₂ during liver injury. In the present study, we attempted to elucidate the mechanism involved in regulating PGE₂ distribution during liver injury. Carbon tetrachloride (CCl₄) was used to establish a liver injury mouse model. PGE₂ was measured by LC-MS/MS. The plasma and hepatic PGE₂ levels were significantly increased at 6 to 48 h after CCl₄ treatment. The ratio of plasma levels of 13,14-dihydro-15-ketoPGE₂ (PGEM), a major PGE₂ metabolite, to PGE₂ decreased significantly after CCl₄ treatment. PGE₂ synthesis and expression of enzymes related to PGE₂ production were not induced, while the activity and mRNA expression of 15-prostaglandin dehydrogenase (15-PGDH/Hpgd), a major enzyme for PGE₂ inactivation, decreased significantly in the liver of CCl₄-treated mice compared to that of vehicle-treated control. The plasma and hepatic PGE₂ 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 PGE₂ transporter, was upregulated, other hepatic OATPs decreased significantly at 24 h after CCl₄ 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 PGE₂ levels due to the CCl₄-induced liver injury.