- •Plasma PGE2 increased before elevation of plasma AST and ALT in CCl4 liver injury.
- •Hepatic 15-PGDH-mediated PGE2 degradation decreased in CCl4 liver injury.
- •Plasma PGE2 level was negatively correlated with hepatic 15-PGDH expression level.
- •15-PGDH is mainly expressed in the hepatic endothelial cells.
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.
Abbreviations:CCl4 (carbon tetrachloride), PGE2 (prostaglandin E2), PGEM (13,14-dihydro-15-ketoPGE2), 15-PGDH (15-prostaglandin dehydrogenase), COX (cyclooxygenase), PGES (prostaglandin E synthase), OATP (organic anion transporting polypeptide), AST (aspartate aminotransferase), ALT (alanine aminotransferase)
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- Prostaglandin E2 and rat liver regeneration.Gastroenterology. 1993; 105: 495-499
- Significance and therapeutic potential of prostaglandin E2 receptor in hepatic ischemia/reperfusion injury in mice.Hepatology. 2005; 42: 608-617
- A protective role for cyclooxygenase-2 in drug-induced liver injury in mice.Chem. Res. Toxicol. 2001; 14: 1620-1628
- The role of prostaglandin E2 in acute acetaminophen hepatotoxicity in mice.Histol. Histopathol. 2010; 25: 819-830
- Prostaglandin uptake and metabolism by the perfused rat liver.Br. J. Pharmacol. 1970; 39: 585-598
- Beta-oxidation of the carboxyl side chain of prostaglandin E2 in rat liver peroxisomes and mitochondria.J. Biol. Chem. 1988; 263: 2724-2731
- Identification of CYP4F8 in human seminal vesicles as a prominent 19-hydroxylase of prostaglandin endoperoxides.J. Biol. Chem. 2000; 275: 21844-21849
- TISSUE REGENERATION. Inhibition of the prostaglandin-degrading enzyme 15-PGDH potentiates tissue regeneration.Science. 2015; 348 (aaa2340)
- Cloning and expression of the cDNA for mouse NAD(+)-dependent 15-hydroxyprostaglandin dehydrogenase.Biochim. Biophys. Acta. 1996; 1309: 21-24
- OATP2A1/SLCO2A1-mediated prostaglandin E2 loading into intracellular acidic compartments of macrophages contributes to exocytotic secretion.Biochem. Pharmacol. 2015; 98: 629-638
- A novel role for OATP2A1/SLCO2A1 in a murine model of colon cancer.Sci. Rep. 2017; 7: 16567
- Prostaglandin transporter (PGT/SLCO2A1) protects the lung from bleomycin-induced fibrosis.PLoS One. 2015; 10e0123895
- Prostaglandin transporter OATP2A1/.J. Neurosci. 2018; 38: 5584-5595
- Molecular identification and characterization of novel members of the human organic anion transporter (OATP) family.Biochem. Biophys. Res. Commun. 2000; 273: 251-260
- Prostaglandin protection of carbon tetrachloride-induced liver cell necrosis in the rat.Gastroenterology. 1981; 81: 211-217
- Cyclooxygenase-1 serves a vital hepato-protective function in chemically induced acute liver injury.Toxicol. Sci. 2015; 143: 430-440
- Celecoxib, a selective cyclooxygenase-2 inhibitor, lowers plasma cholesterol and attenuates hepatic lipid peroxidation during carbon-tetrachloride-associated hepatotoxicity in rats.Drug Chem. Toxicol. 2013; 36: 1-8
- Immunosuppression in acutely decompensated cirrhosis is mediated by prostaglandin E2.Nat. Med. 2014; 20: 518-523
- Prostaglandin transporter (OATP2A1/SLCO2A1) contributes to local disposition of eicosapentaenoic acid-derived PGE3.Prostaglandins Other Lipid Mediat. 2016; 122: 10-17
- Plasma PGE-2 levels and altered cytokine profiles in adherent peripheral blood mononuclear cells in non-small cell lung cancer (NSCLC).Mol. Cancer. 2002; 1: 5
- Inactivation of prostaglandins by the lungs.Nature. 1970; 225: 600-604
- Colon tumour cells increase PGE(2) by regulating COX-2 and 15-PGDH to promote survival during the microenvironmental stress of glucose deprivation.Carcinogenesis. 2011; 32: 1741-1747
- NAD+-dependent 15-hydroxyprostaglandin dehydrogenase regulates levels of bioactive lipids in non-small cell lung cancer.Cancer Prev. Res. (Phila.). 2008; 1: 241-249
- 15-hydroxyprostaglandin dehydrogenase is down-regulated in gastric cancer.Clin. Cancer Res. 2009; 15: 4572-4580
- Cyclooxygenase in normal human tissues–is COX-1 really a constitutive isoform, and COX-2 an inducible isoform?.J. Cell. Mol. Med. 2009; 13: 3753-3763
- Stimulation of prostaglandin synthesis in cultured liver cells by CCl4.Hepatology. 1996; 24: 677-684
- Prostanoid secretion by rat hepatic sinusoidal endothelial cells and its regulation by exogenous adenosine triphosphate.Hepatology. 1995; 21: 1713-1718
- Expression cloning and characterization of a novel multispecific organic anion transporter.J. Biol. Chem. 1997; 272: 18526-18529
- The human multidrug resistance protein MRP4 functions as a prostaglandin efflux transporter and is inhibited by nonsteroidal antiinflammatory drugs.Proc. Natl. Acad. Sci. U. S. A. 2003; 100: 9244-9249
- Identification and characterization of a prostaglandin transporter.Science. 1995; 268: 866-869
- Differential expression of mouse hepatic transporter genes in response to acetaminophen and carbon tetrachloride.Toxicol. Sci. 2005; 83: 44-52
- Limited effect of anti-rheumatic treatment on 15-prostaglandin dehydrogenase in rheumatoid arthritis synovial tissue.Arthritis Res. Ther. 2012; 14: R121
Published online: February 21, 2020
Accepted: February 18, 2020
Received in revised form: February 13, 2020
Received: October 17, 2019
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