| Objective1.To explore the role and possible mechanism of FGF15（Fibroblast Growth Factor15）/FGFR4（fibroblast growth factor receptor 4）signal pathway in mouse liver injury induced by rifampicin.2.To explore the role of pyroptosis in rifampicin-induced mouse liver injury.3.To investigate the effect of FGF15 and BLU9931 on pyroptosis and the release of IL-1βin rifampicin-induced liver injury in mice.Methods1.28 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(200mg·kg-1·d-1)was given to mice intragastrically for 7days.Meanwhile,the BLU9931 group was given BLU9931(10mg·kg-1)6 hours before and the FGF15(0.1mg·kg-1·d-1)was injected to FGF15 group intragastrically for 1 hour after rifampicin was given.The mice were killed 7 days after the establishment of the model.Liver function index were detected by chemical method.Pathological changes of liver was observed by HE staining.Total cholesterol（TCHO）and triglyceride（TG）in liver homogenate were detectded.IL-1βand FGF15 of liver homogenate was measured by ELISA.Fibroblast growth factor receptor 4（FGFR4）,cholesterol 7αhydroxylase 1（CYP7a1）,bile salts export pump（BSEP）,Caspase-1 and GSDMD protein expression levels were measured by Western blot.Results1.Seurm 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）umol/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 those factors 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 significant（all P<0.05）;compared with the model group,the difference of those factors in the BLU9931 group were significant（all P<0.05）.2.Western blotting showed that the relative molecular expression levels of Caspase-1in liver tissues of normal group,model group,FGF15 group and BLU9931 group were respectively（0.390±0.044）,（0.487±0.050）,（0.366±0.032）and（0.662±0.074）;the relative molecular expression levels of GSDMD in liver tissues of these four groups were respectively（0.157±0.011）,（0.483±0.043）,（0.314±0.037）and（0.782±0.091）.Meanwhile,the levels of IL-1βin liver homogenate of these three groups were respectively（339.87±21.98）,（408.28±15.20）,（357.65±43.89）and（421.61±9.22）pg/g.Compared with the control group,the difference of those factors in the model group were significant（all P<0.05）;compared with the model group,the difference of those factors in the FGF15 group were significant（all P<0.05）except for the levels of IL-1β.Conclusion1.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 expressions.2.Pyroptosis and increase of IL-1βexisted in rifampicin-induced liver injury in mice.3.FGF15 improved rifampicin-induced liver injury in mice by inhibiting pyroptosis and reducing IL-1βproduction,and BLU9931 aggravate rifampicin-induced liver injury in mice by activating pyroptosis. |
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