title: Constitutive androstane receptor activation promotes bilirubin clearance in a murine model of alcoholic liver disease.
abstract: Increased plasma levels of bilirubin have been reported in rat models and patients with alcoholic liver disease (ALD). The constitutive androstane receptor (CAR) is a known xenobiotic receptor, which induces the detoxification and transport of bilirubin. In the present study, the bilirubin transport regulatory mechanisms, and the role of CAR activation in hepatic and extrahepatic bilirubin clearance were investigated in a murine model of ALD. The mice were fed a Lieber-DeCarli ethanol diet or an isocaloric control diet for 4 weeks, followed by the administration of CAR agonists, 1,4-bis-[2‑(3,5-dichlorpyridyloxy)]benzene (TCPOBOP) and phenobarbital (PB), and their vehicles to examine the effect of the pharmacological activation of CAR on serum levels of bilirubin and on the bilirubin clearance pathway in ALD by serological survey, western blotting and reverse transcription‑quantitative polymerase chain reaction. The results showed that chronic ethanol ingestion impaired the nuclear translocation of CAR, which was accompanied by elevated serum levels of bilirubin, suppression of the expression of hepatic and renal organic anion transporting polypeptide (OATP) 1A1 and hepatic multidrug resistance‑associated protein 2 (MRP2), and induction of the expression of UDP-glucuronosyltransferase (UGT) 1A1. The activation of CAR by TCPOBOP and PB resulted in downregulation of the serum levels of bilirubin followed by selective upregulation of the expression levels of OATP1A1, OATP1A4, UGT1A1 and MRP2 in ALD. These results revealed the bilirubin transport regulatory mechanisms and highlighted the importance of CAR in modulating the bilirubin clearance pathway in the ALD mouse model.
authors.affiliation: Department of Gastroenterology, Wenzhou People's Hospital, Wenzhou, Zhejiang 325000, P.R. China.
authors.forename: Xiuyan
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
authors.forename: Liyu
authors.initials: L
authors.lastname: Zheng
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
authors.forename: Jinming
authors.initials: J
authors.lastname: Wu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Tang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
authors.forename: Mengqin
authors.initials: M
authors.lastname: Zhang
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
authors.forename: Debin
authors.initials: D
authors.lastname: Zhu
authors.affiliation: Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.
authors.forename: Xianfan
authors.initials: X
authors.lastname: Lin
mesh_terms: D000818:Animals; D001663:Bilirubin / Q000378:metabolism*; D015415:Biomarkers; D000090702:Constitutive Androstane Receptor; D004195:Disease Models, Animal; D015870:Gene Expression; D007150:Immunohistochemistry; D008658:Inactivation, Metabolic / Q000235:genetics; D008024:Ligands; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008111:Liver Function Tests; D008297:Male; D051379:Mice; D021381:Protein Transport; D011725:Pyridines / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D000090702:Constitutive Androstane Receptor; D008024:Ligands; D011725:Pyridines; D018160:Receptors, Cytoplasmic and Nuclear; C028474:1,4-bis(2-(3,5-dichloropyridyloxy))benzene; D001663:Bilirubin