Activation of the constitutive androstane receptor promotes bilirubin clearance in a murine model of alcoholic liver disease
Background: Increased bilirubin level in the plasma has been reported in alcoholic liver disease (ALD) rat and different stage of ALD patients.The constitutive androstane receptor (CAR) is known as a xenobiotics receptor that induces the detoxification and transport of bilirubin.In our study, we are aimed to investigate systematic bilirubin transport regulatory mechanisms and the role of activation of CAR on hepatic and extrahepatic bilirubin clearance pathway in a murine model of ALD.Methods: Mice were fed Lieber-DeCarli ethanol diet or an isocaloric control diet for 4 weeks followed by administration of CAR agonists TCPOBOP and phenobarbital and their vehicles to study the effect of pharmacological activation of CAR on serum bilirubin level and bilirubin clearance pathway in ALD.Results: Chronic ethanol ingestion resulted in elevated serum bilirubin level, suppression of hepatic and renal OATPlal and hepatic MRP2 expression, and induction of UGT1A1 expression accompanied by impairment of CAR”s translocation to the nuclear.However, activation of CAR by different ligands TCPOBOP and phenobarbital downregulated serum bilirubin level and selectively upregulated OATP1a1, OATP1a4, UGT1A1 and MRP2 expression in a murine model of ALD.Conclusions: Our results reveal bilirubin transport regulatory mechanisms in a murine model of ALD, highlight the key role of CAR in the modulation of bilirubin clearance pathway and suggest a possible therapeutic value for CAR ligands in ALD treatment.
alcoholic liver disease bilirubin the constitutive androstane receptor Lieber-DeCarli ethanol diet
Xiuyan Wang Liyu Zheng Jinming Wu Xianfan Lin Wenzhi Wu Rong Jin Zhiming Huang Jiansheng Wu
Department of Gastroenterology,The First Affiliated Hospital of Wenzhou Medical University,Wenzhou,325000,Zhejiang Province,China
国内会议
第八届浙江国际消化病学术大会暨美国胃肠病协会第二届中国学术论坛
浙江绍兴
英文
31-49
2015-10-30（万方平台首次上网日期，不代表论文的发表时间）