TLR protects liver against acetaminophen-induced Hepatotoxicitin via activating the Nrf2 antioxidant signaling pathway

Abstract

Abstract: Objective To investigate the protective effect of Lipopolysaccharide (LPS) and toll-like receptors (TLRs) on acetaminophen (APAP)-induced liver injury and its potential mechanism.Methods Forty male mice were randomly divided into 4 groups. Mice in control group were intraperitneally (i.p.) injected with saline, in LPS group were i.p. given with 10 μg/kg LPS, and in APAP group were i.p. administrated with APAP (300 mg/kg). LPS+APAP group were i.p. pretreated with LPS (10 μg/kg) 16 h before APAP (300 mg/kg) injection. Serum and liver tissue among 4 groups were collected for further analysis. Liver injury was assessed by detection of serum ALT and AST levels and HE staining of liver tissue. The oxidative stress was evaluated by measuring hepatic glutathione (GSH) and malondialdehyde (MDA) levels, and Dihydroethidium (DHE) staining. Expression of Nrf2, Gclc and HO-1 were measured by western blot and real time-polymerase chain reaction.Results Compared with APAP groups, LPS+APAP group showed lower serum levels of ALT (518.3±142.3 vs. 4542±498.4 U/L, P＜0.05) and AST (643.3±105.6 vs. 5432.1±569.2 U/L, P＜0.05), milder liver tissue damage, lower MDA levels (78.0±14.5 vs.141.7±26.4 mmol/mg tissue, P＜0.05) and higher GSH levels (6.2±1.7 vs. 3.5±1.0 μmol/g tissue, P＜0.05), which revealed that APAP-induced liver injury and oxidative stress response were significantly attenuated by LPS pretreatment. Moreover, LPS pretreatment could enhance the expression of Nrf2 and other antioxidant genes significantly.Conclusion LPS plays an important role in protection against APAP-induced hepatotoxicity in mice via activating antioxidant signaling pathway of Nrf2, which might become a new strategy for APAP-induced liver injury therapy.

Key words: Acetaminophen, Drug induced liver injury, Oxidative stress, Nrf2, HO-1

GU Jia-yi, YU Feng-rong. TLR protects liver against acetaminophen-induced Hepatotoxicitin via activating the Nrf2 antioxidant signaling pathway[J]. Chinese Hepatolgy, 2016, 21(8): 636-640.

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