Abstract: Objective The aim of this experiment was to investigate the protective effect of bromo- and extra-terminal domain (BET) inhibitor, (+)-JQ1 on lipopolysaccharide / D-galactose (LPS / D-Gal) -induced acute liver failure (ALF) in mice and its mechanism. Methods 47 C57BL / 6 mice were randomly divided into control ((n=17), ALF model (n=15) and (+)-JQ1 intervention group (n=15). The ALF model were established by intraperitoneal injection of LPS / D-Gal, and mice in (+)-JQ1 intervention group were injected intraperitoneally with (+)-JQ1 2 hours before the induction of ALF. Four hours after LPS/D-Gal injection , 5 mice were sacrificed in each group and the remaining mice were fed for 72 hours to observe 72-hour survival rate. Serum TNF-α was detected by ELISA, and hepatic protein and gene mRNA were assayed by RT-qPCR and Western bloting, respectively. Results The 72-hour survival rate in model group was 16.7%(2/12), not significantly different compared to 60.0% (6/10,P>0.05) in (+)-JQ1-intervened group; serum ALT level in mice with ALF was (2779.0±200.6)U/L and serum AST level was (2885.0±143.6)U/L, both significantly higher than 【(44.9±2.5) U/L and (76.0±5.7) U/L,P＜0.05】 in control, while they decreased significantly to 【(948.7±46.3)U/L and (1704.0±42.1)U/L, respectively, P＜0.05】 in (+)-JQ1-intervened group; the hepatic tissue TNF-αmRNA was (103.7±23.0), significantly higher than 【(1.2±0.2),P＜0.05】, the IL-6 mRNA was (73.4±15.8) , much higher than 【(1.1±0.1), P＜0.05】, and the IL-1B mRNA was (13.5±2.7) , significantly higher than 【(1.0±0.1), P＜0.05】 in the control, while they decreased greatly to 【(12.8±1.2), ( 11.7±0.7) and (1.5±0.3), respectively, P＜0.05】 in (+)-JQ1-intervened group; serum TNF-α level was (631.6±57.5)U/L, much higher than 【(2.5±0.5)U/L, P＜0.05】 in the control, while it decreased to 【(139.8±8.1)U/L, P＜0.05】 in (+)-JQ1-intervened group; the expression of P65 and IKB in hepatic tissues in model intensified obviously, while they weaken greatly in (+)-JQ1-intervened group. Conclusion The bromo- and extra-terminal domain (BET) inhibitor, (+)-JQ1 has a protective effect on the liver in mice with LPS / D-Gal-induced ALF, which might be related to the regulation of NF-KB signaling pathway to reduce the expression of proinflammatory cytokines.

Key words: Acute liver failure, (+)-JQ1, Proinflammatory cytokine, NF-Kβ signaling pathway, Mice