Role of the specific inhibitor of 5-lipoxygenase-activating protein MK886 in inhibiting alcoholic liver disease in mice

Objective To investigate the effect of MK886, a specific inhibitor of 5-lipoxygenase-activating protein (FLAP) , on alcoholic liver disease (ALD) in mice. Methods A total of 48 male Kunming mice were randomly divided into ALD group, ALD/MK886 group, control group, and normal group. The mice in the ALD group and the ALD/MK886 group were fed with Tipoe-Nanji alcohol liquid diet and were given alcohol by gavage 6 weeks later to establish a model of acute ALD. The mice in the control group were given control diet without alcohol, and those in the normal group were given normal diet. After 2 days of alcohol intake, the mice in the ALD/MK886 group were given intraperitoneally injected MK886 (0. 01 mg/10 g) once a day. The mice were sacrificed at 9 hours after the administration of alcohol by gavage. Serum levels of aspartate aminotransferase (AST) , alanine aminotransferase (ALT) , lactate dehydrogenase (LDH) , and triglyceride (TG) and the levels of TG and malondialdehyde (MDA) in liver tissue were measured. HE staining was performed for liver tissue and pathological score was determined. Western blot was used to measure the expression of FLAP and 5-lipoxygenase (5-LO) in liver tissue and Thp-1 cells, and flow cytometry was used to measure the apoptosis of Thp-1 cells. One-way ANOVA was used for comparison between groups; the least significant difference t-test was used for comparison of data with homogeneity of variance, and the Tamhane's T2 test was used for comparison of data with heterogeneity of variance. Results The ALD group and the ALD/MK886 group had a reduction in body weight within the first week of modeling, followed by a gradual increase; at the end of modeling, the ALD group had significantly lower bodyweight and liver index than the normal group and the control group (all P < 0. 05) , and the ALD/MK886 group had significantly higher body weight and liver index than the ALD group (both P < 0. 05) . Compared with the normal group and the control group, the ALD group had significant increases in the levels of AST, ALT, LDH, and TG in serum and the levels of TG and MDA in liver tissue (all P < 0. 05) , and compared with the ALD group, the ALD/MK886 group had significant reductions in the above indices (all P < 0. 05) . The ALD group had a significantly higher score of hepatic steatosis than the normal group and the control group (both P < 0. 05) , and compared with the ALD group, the ALD/MK886 group had a significant reduction in this score (P < 0. 05) . Compared with the normal group and the control group, the ALD group had significant increases in the expression of 5-LO and FLAP in the liver (all P < 0. 05) , and the ALD/MK886 group had significant reductions compared with the ALD group (P < 0. 05) . Lipopolysaccharide (LPS) upregulated the expression of FLAP and 5-LO in Thp-1 cells, and MK886 alleviated such effect of LPS (all P < 0. 05) ; MK886 promoted the apoptosis of Thp-1 cells, and LPS alleviated the effect of MK886 in promoting cell apoptosis (all P < 0. 01) . Conclusion MK886 can inhibit the expression of 5-LO, induce the apoptosis of Kupffer cells, and thus exert a therapeutic effect on ALD in mice.