Protective effect of SRT1720 on acute liver injury induced by acetaminophen in mice and its mechanism
Objective To evaluate the protective effect of the activator of silent information regulator 2-related enzymes 1(SIRT1),SRT1720,on liver injury induced by acetaminophen(APAP)in mice and explore its mechanism.Methods Forty male C57BL/6J mice were randomly divided into normal control group,SRT1720 treatment group,APAP treatment group,and APAP+SRT1720 treatment group,with 10 mice in each group.Mice in SRT1720 and APAP+SRT1720 groups were given SRT1720(30 mg/kg body mass)by intragastric administration,while normal saline of equal volume was given by intragastric administration in control and APAP groups,once a day for 5 days;On the 6th day,mice in APAP and APAP+SRT1720 groups were injected i.p.with APAP(325 mg/kg body mass),while those in control and SRT1720 groups with equal volume of normal saline.After 24 hours,the peripheral blood was taken and the serum was separated,which were detected for the levels of alanine aminotransferase(ALT)and aspartate aminotransferase(AST)by the corresponding kits;The liver tissue of mice was taken aseptically,observed for the pathological changes by HE staining,detected for the mRNA transcription levels of GRP78,PERK,eIF2 α,ATF4 and CHOP genes related to PERK-eIF2α-CHOP signaling pathway by RT-qPCR and detected for the relative expression levels of these corresponding proteins and Caspase 12 protein by Western blot.Results Compared with normal control group,the serum ALT and AST levels of mice in APAP group significantly increased(t=55.21 and 34.29 respectively,each P＜0.01);significant necrosis of hepatocytes was observed in liver tissue,the structure of hepatic lobules changed significantly,and the swelling and deformation of hepatocytes in some areas were serious;the mRNA transcription and relative protein expression levels of GRP78,PERK,eIFα,ATF4 and CHOP genes increased significantly(t=9.85～33.89,each P＜0.05)and the relative expression level of Caspase 12 protein increased significantly(t=11.78,P＜0.01).Compared with APAP group,the serum ALT and AST levels of mice in APAP+SRT1720 group decreased significantly(t=42.92 and 18.02 respectively,each P＜0.01);the degree of hepatocyte injury was obviously reduced and the number of swollen and deformed cells also significantly decreased;the mRNA transcription and relative protein expression levels of GRP78,PERK,eIF2α,ATF4 and CHOP decreased significantly(t=6.19～22.43,each P＜0.05)and the expression level of Caspasel2 protein showed no significant decrease(t=0.34,P＞0.05).Conclusion SRT1720 improved APAP-induced liver injury in mice,possibly by inhibiting PERK-eIF2α-CHOP signaling pathway in endoplasmic reticulum stress(ERS).
Activator of silent information regulator 2-related enzymes 1(SIRT1)SRT1720Acetaminophen(APAP)Acute liver injuryPERK-eIF2α-CHOP signaling pathway
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