肾脏法尼酯X受体激活改善FK506诱导的血脂代谢紊乱

Improvement of FK506-induced dyslipidemia by FXR activation in human renal tubular epithelial cells

目的:研究法尼酯X受体(farnesoid X receptor,FXR)激活改善FK506诱导的血脂代谢紊乱及其分子机制。方法:人肾小管上皮细胞HK-2分为对照组和15μmol·L^(-1)FK506处理组,孵育24 h和48 h后,检测血脂生成基因(CHREBP、SREBP-1c、SCD-1)表达。qRT-PCR检测细胞中FXR的mRNA表达水平,细胞免疫荧光及western blot检测细胞中FXR的蛋白表达水平。采取FK506灌胃90 d诱导小鼠高血脂模型,检测FK506+GW4064组小鼠三酰甘油和总胆固醇水平。qRTPCR检测FXR激动剂对FXR的表达及脂生成基因(CHREBP、SREBP-1c和SCD-1)表达影响。结果:与对照组相比,FK506组孵育24 h和48 h后,血脂生成基因(CHREBP、SREBP-1c、SCD-1)表达明显增高(P<0.05);细胞中FXR的mRNA表达、蛋白表达均表现显著下降趋势(P<0.05);动物实验中,与FK506组相比,FK506+GW4064组三酰甘油和总胆固醇浓度明显降低(P<0.05),血脂生成基因(CHREBP、SREBP-1c、SCD-1)均表现不同程度下降(P<0.05)。结论:FXR激活能够改善FK506诱导的血脂升高,纠正血脂代谢紊乱。

OBJECTIVE To study the improvement of FXR activation and its molecular mechanism in FK506-induced dyslipidemia.METHODS Human renal tubular epithelial cells HK-2 were divided into normal control group and15μmol·L^(-1)FK506 treatment group.After 24 and 48 hours of incubation,the expression of lipid generating genes(CHREBP,SREBP-1c,SCD-1)was detected.qRT-PCR was used to detect the mRNA expression of FXR,cell immunofluorescence and western blot were used to detect the expression of FXR protein.FK50690-day intragastric administration was applied to inducing hyperlipidemia in mice,and the levels of triglycerides and total cholesterol were detected in FK506+GW4064 group mice.qRT-PCR was used to detect the effects of FXR agonists on the expression of FXR and lipogenic genes(CHREBP,SREBP-1c,SCD-1).RESULTS Compared with the control group,in the FK506 group after 24 and 48 h,the expression of lipid-generating genes(CHREBP,SREBP-1c,SCD-1)was significantly increased(P<0.05),the mRNA expression and protein expression of FXR were significantly decreased(P<0.05).In animal experiments,compared with those in the FK506 group,triglyceride and total cholesterol concentrations in the FK506+GW4064 group were significantly lower(P<0.05),and lipid-generating genes(CHREBP,SREBP-1c,SCD-1)showed varying degrees of decline(P<0.05).CONCLUSION FXR activation can ameliorate the elevation of blood lipids induced by FK506 and correct the disorder of blood lipid metabolism.