MK571通过激活法尼醇X受体抑制肝脏胆汁酸合成

MK571 inhibits bile acids synthesis in liver by activating farnesoid X recepto

【目的】基于法尼醇X受体,探究MK571对肝脏胆汁酸合成的影响.【方法】按体质量将24只健康大鼠随机分为MK571低、中、高剂量组和对照组,每组6只,分别每天腹腔注射5、10、20 mg/kg MK571和等体积生理盐水,连续给药7 d。采用全自动生化分析仪检测血清肝功能生化指标;HE染色观察肝脏病理学变化;LC-MS/MS检测血清和肝脏胆汁酸含量;蛋白免疫印迹法检测大鼠肝脏胆汁酸相关调节蛋白表达。【结果】与对照组相比,MK571干预后,血清丙氨酸转氨酶(ALT)、总胆红素(TBIL)和总胆汁酸(TBA)含量均显著下降(P<0.05);病理结果显示肝脏出现炎症损伤;胆汁酸检测结果显示:血清和肝脏甘氨熊去氧胆酸、甘氨脱氧胆酸、甘氨脱氧胆酸、甘氨胆酸和鹅去氧胆酸含量均显著下降(P<0.05);此外蛋白免疫印迹法结果显示:法尼醇X受体(Farnesoid X receptor,FXR)和胆盐输出泵(Bile salt export pump,BSEP)表达量均显著上升(均P<0.05),而胆固醇-7α-羟化酶(Cholesterol-7α-hydroxylase,CYP7A1)、胆固醇-12α-羟化酶(Cholesterol-12α-hydroxylase,CYP8B1)和胆固醇-27α-羟化酶(Cholesterol-27α-hydroxylase,CYP27A1)表达量均显著下降(P<0.05)。【结论】MK571可以抑制肝脏胆汁酸合成,其作用机制可能与激活FXR,下调CYP27A1,CYP7A1和CYP8B1表达,上调BSEP表达有关。

【Objective】The study aimed to investigate the effect of MK571 on liver bile acids synthesis based on the farnesoid X receptor.【Method】Twenty four healthy rats were employed and randomly divided into 4 groups according to body weight,i.e.,MK571 low-dose,middle-dose,and high-dose groups and control group,with 6 rats in each group.The rates of four groups were intraperitoneally injected with 5,10 and 20 mg/kg of MK571 and an equal volume of normal saline,respectively,for 7 days.The biochemical indexes of serum liver function were detected by automatic biochemical analyzer;the pathological change of liver was observed by using HE staining;the content of bile acid in serum and liver was determined by LCMS/MS;and the expression of bile acid-related regulatory proteins in rat liver was measured by Western blot.【Result】Compared with the control group,the levels of serum alanine aminotransferase(ALT),total bilirubin(TBIL)and total bile acid(TBA)were significantly decreased after MK571 intervention(P<0.05).Pathological results showed that the inflammatory damage occurred in the liver.The detection of bile acids showed that glycosodeoxycholic acid,glycideoxycholic acid,glycideoxycholic acid,Glycinocholic acid,and Chenodeoxycholic acid both in serum and liver were significantly decreased(P<0.05).In addition,the results of Western blot showed that both farnesoid X receptor(FXR)and bile salt export pump(BSEP)expressions significantly increased(P<0.05),while the expression of either cholesterol-7α-Cholesterol-7α-hydroxylase(CYP7A1),cholesterol-12α-hydroxylase(CYP8B1),or cholesterol-27α-hydroxylase(CYP27A1)significantly decreased(P<0.05).【Conclusion】It was indicated that MK-571 could inhibited bile acids synthesis in liver,which might be associated with activating FXR,the down-regulated expressions of CYP27A1,CYP7A1 and CYP8B1,and the up-regulated expression of BSEP.