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目的:探讨丝裂原活化蛋白磷酸酶1(mitogen activated protein kinase phosphatase-1,MKP-1)调控法尼醇X受体(farnesoid X receptor,FXR)转录活性的作用。方法:采用实时定量PCR和蛋白印迹法,检测肥胖小鼠模型肝脏FXR和MKP-1的mRNA和蛋白表达;采用免疫共沉淀和荧光素酶报告基因实验,探讨MKP-1调控FXR转录活性的作用。结果:肥胖小鼠的肝脏组织中,FXR的表达显著下调(P<0.05),而MKP-1的表达则显著增加(P<0.05);免疫共沉淀和荧光素酶报告基因实验结果显示,MKP-1与FXR间存在蛋白-蛋白相互作用。MKP-1过表达后,可抑制FXR的转录活性(P<0.05),而干扰MKP-1的表达则可上调其转录活性(P<0.05)。结论:MKP-1可能作为FXR的辅抑制因子,从而参与肝脏糖脂代谢的调控。
Objective: To investigate the effect of mitogen activated protein kinase phosphatase-1 (MKP-1) on the transcriptional activity of farnesoid X receptor (FXR). Methods: The mRNA and protein expression of FXR and MKP-1 in the liver of obese mice were detected by real-time quantitative PCR and Western blotting. Immunoprecipitation and luciferase reporter assay were used to investigate the effect of MKP-1 on FXR transcriptional activity . Results: The expression of FXR was significantly down-regulated in liver tissues of obese mice (P <0.05), while the expression of MKP-1 was significantly increased (P <0.05). Immunoprecipitation and luciferase reporter assay showed that MKP -1 and FXR protein-protein interactions exist. Overexpression of MKP-1 could inhibit the transcriptional activity of FXR (P <0.05), while up-regulate the transcription of MKP-1 (P <0.05). CONCLUSION: MKP-1 may be a cofactor of FXR and may be involved in the regulation of hepatic glucose and lipid metabolism.