Abstract: Objective To explore the effect and underlying mechanism of transcription factor activator protein-1 (AP-1) in cholestatic liver injury. Methods ICR mice were randomly divided into control group, cholestatic liver injury model group and AP-1 inhibitor(T-5244) intervention model group(5 in each group). α-naphthyl isothiocyanate(ANIT) and T-5224 were dissolved in corn oil respectively. The mice were fasted for 12 h overnight before the experiment. The control group was treated with corn oil by oral gavage. The cholestatic liver injury model group and the T-5244 intervention model group were treated with ANIT 120 mg/kg(a single dose). The T-5244 intervention group was intraperitoneally injected with T-5224 inhibitor AP-1 100 mg/kg 0.5~1 h before ANIT treatment. The T-5224 treatment was repeated 24 h later. After 48 hrs, all mice were sacrificed to collect serum, liver and gallbladder. The biochemical markers, histopathological changes and liver injury among different groups were analyzed and compared. Results Compared with the control group, the biomarker of liver injury, aspartate alanine aminotransferase (ALT), and aminotransferase (AST), increased from (7.2±1.6)μmol/L and (2.5±0.5) μmol/L to (132.0±48.4)μmol/L and (94.2±22.2)μmol/L in cholestatic liver injury group. It confirmed a successful development of cholestatic model. In contrast with the cholestatic liver injury group, the two biomarkers in the T-5224 intervention group were reduced to (48.4±12.8)μmol/L and (23.1±2.6)μmol/L respectively. At the protein level, activation of AP-1 was inhibited. Expression of CXCL10, CCL2 were inhibited by 90% and 79% respectively in the T-5224 intervention group, and liver injury was significantly reversed. Conclusions AP-1 mediated chemotaxis plays an important role in ANIT-induced cholestatic liver injury.

Key words: activator protein-1(AP-1), cholestasis, liver injury, chemotaxis