The role and possible mechanism of FGF15/FGFR4 signal pathway in rifampicin-induced liver injury in mice

Abstract

Abstract: Objective This study was designed to explore the role and possible mechanism of Fibroblast Growth Factor 15 (FGF15)/Fibroblast Growth Gactor Receptor 4 (FGFR4) signal pathway in rifampicin-induced liver injury. Methods 28 C57BL6 mice were randomly divided into control group (n=7), model group (n=7), FGF15 group (n=7) and FGFR4 inhibitor (BLU9931) group (n=7). Except for the control group, rifampicin 200 mg·kg^-1·d^-1 was given to mice intragastrically for 7 days. Meanwhile, the BLU9931 group was given BLU9931 (10 mg·kg^-1) 6 hours before rifampicin was given and the FGF15 (0.1 mg·kg^-1·d^-1) was injected to FGF15 group intragastrically 1 hour after rifampicin was given. The mice were killed 7 days after the establishment of the model. Liver function indexes were detected by chemical method. Pathological changes of liver was observed by HE staining. Total cholesterol (TCHO), triglyceride (TG) and FGF15 in liver homogenate were detectded. Fibroblast growth factor receptor 4 (FGFR4), cholesterol 7α hydroxylase 1 (CYP7a1) and bile salts export pump (BSEP) protein expression levels in liver homogenate were measured by Western blot. Results Seurm total bilirubin (TBIL) in control group, model group, FGF15 group and BLU9931 group were respectively (2.63±0.51), (25.09±4.85), (19.57±3.72) and (39.53±7.14) μmol/L. Meanwhile, the levels of FGF15 in liver homogenate of these four groups were respectively (646.86±22.66), (580.40±11.30), (622.11±18.96) and (528.37±44.91) pg/g. The relative molecular expression levels of FGFR4 in liver tissues of these four groups were respectively (0.34±0.06), (0.16±0.02), (0.29±0.05) and (0.10±0.02). The relative molecular expression levels of CYP7a1 in liver tissues of these four groups were respectively (0.06±0.01), (0.38±0.06), (0.22±0.03) and (0.63±0.09), and the relative molecular expression levels of BSEP in liver tissues of these four groups were respectively (0.42±0.07), (0.26±0.04), (0.36±0.03) and (0.19±0.03). Compared with the control group, the difference of TBIL, FGF15, FGFR4, CYP7a1 and BSEP in the model group were significantly (all P<0.05). Compared with the model group, the difference of those factors in the FGF15 group were significantly (all P<0.05). Compared with the model group, the difference of those factors in the BLU9931 group were significantly (all P<0.05). Conclusion FGF15/FGFR4 signal pathway plays an important role in rifampicin-induced liver injury in mice, which may be related to the regulation of CYP7a1 and BSEP expression.

Key words: Rifampicin, Liver injury, Fibroblast growth factor 15, Fibroblast growth factor receptor 4, BLU9931

TU Qian-qian, WEI Xia, SONG Yu-lin. The role and possible mechanism of FGF15/FGFR4 signal pathway in rifampicin-induced liver injury in mice[J]. Chinese Hepatolgy, 2022, 27(5): 596-599.

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