Microsomal prostaglandin E synthase 2 deficiency is resistant to acetaminophen-induced liver injury.
Acetaminophen (APAP)-induced liver injury is the main cause of acute liver failure. This study investigated the role of microsomal prostaglandin E synthase 2 (mPGES-2), discovered as one of the prostaglandin E2 (PGE2) synthases, in mediating APAP-induced liver injury. Using mPGES-2 wild-type (WT) and knockout (KO) mice, marked resistance to APAP-induced liver damage was found in mPGES-2 KO, as indicated by robust improvement of liver histology, changes in liver enzyme release, and marked decrease in APAP-cysteine adducts (APAP-CYS) and inflammatory markers. Moreover, the results confirmed that increase in liver PGE2 content in KO mice under basal conditions was not critical for the protection from APAP-induced liver injury. Importantly, mPGES-2 deletion inhibited the production of malondialdehyde (MDA), increasing glutathione (GSH) level. Enhanced GSH level may contribute to the inhibition of APAP toxicity in mPGES-2 KO mice. To further elucidate the role of mPGES-2 in the liver injury induced by APAP, adeno-associated viruses (AAV) were used to overexpress mPGES-2 in the liver. The results showed that mPGES-2 overexpression aggravates liver injury associated with an increase in inflammatory markers and chemokines after APAP treatment. Moreover, a lower level of GSH was detected in the mPGES-2 overexpression group compared to the control group. Collectively, our findings indicate that mPGES-2 plays a critical role in regulating APAP-induced liver injury, possibly by regulating GSH and APAP-CYS level, which may provide a potential therapeutic strategy for the prevention and treatment of APAP-induced liver injury.
['Wang|Hu|H|', 'Zhang|Rumeng|R|', 'Zhu|Yangyang|Y|', 'Teng|Tian|T|', 'Cheng|Yujia|Y|', 'Chowdhury|Apu|A|', 'Lu|Jihong|J|', 'Jia|Zhanjun|Z|', 'Song|Jun|J|', 'Yin|Xiaoxing|X|', 'Sun|Ying|Y|']
D000082:Acetaminophen D018712:Analgesics, Non-Narcotic D000818:Animals D056486:Chemical and Drug Induced Liver Injury D003545:Cysteine D015232:Dinoprostone D005978:Glutathione D008297:Male D008315:Malondialdehyde D051379:Mice D008810:Mice, Inbred C57BL D018345:Mice, Knockout D000071876:Prostaglandin-E Synthases
Microsomal prostaglandin E synthase 2 Liver injury Acetaminophen Prostaglandin E2 Glutathione