FGF15/FGFR4信号通路在利福平所致肝损伤中的作用及可能机制

摘要/Abstract

摘要： 目的探讨成纤维细胞生长因子15(FGF15)/成纤维细胞生长因子受体4(FGFR4)信号通路在利福平所致肝损伤中的作用机制。方法 28只小鼠随机分正常组、模型组、FGF15组及FGFR4抑制剂(BLU9931)组,每组7只。除正常组外,其他3组均给予利福平(200 mg·kg^-1·d^-1 )灌胃,连续7 d,BLU9931组在第1天利福平灌胃前6 h予以BLU9931(10 mg·kg^-1)灌胃;FGF15组在利福平灌胃1 h后予以FGF15 (0.1 mg·kg^-1·d^-1)腹腔注射,连续7 d。造模7 d后检测肝功能,观察肝脏的病理学改变,检测肝脏甘油三酯(TG)、总胆固醇(TCHO)和FGF15水平,用蛋白质免疫印迹法检测肝脏FGFR4、胆固醇7α羟化酶1(CYP7a1)及胆汁输出泵(BSEP)的表达水平。结果正常组、模型组、FGF15组和BLU9931组的血清总胆红素(TBil)分别为(2.63±0.51)、(25.09±4.85)、(19.57±3.72)和(39.53±7.14)μmol/L;肝组织FGF15表达量分别为(646.86±22.66)、(580.40±11.30)、(622.11±18.96)和(528.37±44.91)pg/g;肝组织FGFR4的表达量分别为(0.34±0.06)、(0.16±0.02)、(0.29±0.05)和(0.10±0.02);肝组织CYP7a1的表达量分别为(0.06±0.01)、(0.38±0.06)、(0.22±0.03)和(0.63±0.09);肝组织BSEP的表达量分别为(0.42±0.07)、(0.26±0.04)、(0.36±0.03)和(0.19±0.03)。各组与模型组比较,差异均有统计学意义(均P<0.05)。结论 FGF15/FGFR4信号通路在利福平所致小鼠肝损伤中起着重要作用,可能与其调控CYP7a1、BSEP表达有关。

关键词: 利福平, 肝损伤, 成纤维细胞生长因子15, 成纤维细胞生长因子受体4, BLU9931

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

涂倩倩, 卫霞, 宋育林. FGF15/FGFR4信号通路在利福平所致肝损伤中的作用及可能机制[J]. 肝脏, 2022, 27(5): 596-599.

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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