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目的:探讨降脂药物非诺贝特激活法尼醇X受体FXR的机制。方法 :分离小鼠肝脏原代细胞,予非诺贝特处理,通过实时定量PCR检测FXR下游基因的表达情况,并通过荧光素酶双报告基因实验,分析非诺贝特对FXR下游基因调控的机制。结果:①非诺贝特处理可诱导FXR下游靶基因SHP和BSEP的表达,进而降低三酰甘油合成关键转录因子SREBP1c的表达。②非诺贝特能促进FXR上调SHP和BSEP启动子活性,而FXR配体结合区域及转录激活域缺失型则丧失该功能。结论:非诺贝特可能是潜在的FXR激动型配体,可通过激活FXR信号通路,降低三酰甘油合成基因的表达,从而抑制肝脏三酰甘油的沉积。
OBJECTIVE: To investigate the mechanism of lipid lowering drug fenofibrate activation of farnesol X receptor FXR. Methods: Primary mouse liver cells were isolated and treated with fenofibrate. Real-time quantitative PCR was used to detect the expression of FXR downstream genes. Luciferase reporter assay was used to analyze the effect of fenofibrate on FXR downstream genes mechanism. Results: (1) Fenofibrate induced the expression of target genes of FXR, SHP and BSEP, and decreased the expression of SREBP1c, a key transcription factor of triglyceride. Fenofibrate can promote FXR up-regulation of SHP and BSEP promoter activity, while FXR ligand binding domain and transcriptional activation domain deletion loss this function. Conclusion: Fenofibrate may be a potential FXR agonist ligand, which can inhibit the deposition of triglyceride in liver by activating the FXR signaling pathway and decreasing the expression of triglyceride synthesis genes.