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• W2117627495 abstract "for detoxification and elimination by glucuronidation, which is also regulated via the xenobiotic-activated arylhydrocarbon receptor (AhR) and the oxidative stress sensor nuclear factor erythroid 2-related factor 2 (Nrf2). Aim of this study was to elucidate transcriptional UGT1A regulation in vivo during obstructive cholestasis and the effects of exposure to the potentially beneficial FXR agonist GW4064. Methods: TgUGT1A WT mice were subjected to BDL for 5 days, 4 days intraperitoneal (i.p.) injection of GW4064, or 4 days i.p. GW4064 injection after BDL. Liver histology, serum bilirubin levels and aminotransferase activities (AST, ALT) as well as UGT1A gene expression (TaqMan-PCR in liver, jejunum and colon) were determined. Additionally, hepatic AhR-, Nrf2-, FXR-, IL6and TNFa-mRNA-expression was quantified. Results: In BDL/BDL+GW4064 mice, upregulation of hepatic IL6 and TNFa expression (2.7-, 2.4-fold) was observed in addition to significantly increased bilirubin and AST/ALT levels correlating with increased histological injury. While no effect on hepatic Nrf2 expression was seen in BDL/BDL+GW4064 mice, AhR expression in the liver was profoundly reduced. In GW4064 treated mice, UGT1A gene expression was significantly activated in the liver (2–5-fold) and colon (2.4–45-fold). After BDL, hepatic UGT1A genes showed a 2–4-fold increase, contrasting intestinal activation observed only for UGT1A3 (3–7-fold) and UGT1A4 (2–27-fold). In BDL+GW4064 mice, only UGT1A4 (6-fold) and UGT1A6 (1.4-fold) were significantly induced in colon; no further significant induction was observed in liver or jejunum. Conclusion: Unexpectedly, administration of the putative protective FXR agonist GW4064 during cholestasis resulted in an increased inflammatory response (IL6, TNFa), increased liver injury (ALT/AST, histology) and inhibition of hepatic AhR expression, rather than FXR-mediated UGT1A upregulation. As previously shown (Kalthoff et al. JBC, 2010), transcriptional UGT1A activation requires coactivation of both Nrf2 and AhR, which is impaired by eliminating an AhR response demonstrated in this study. This inhibits a protective UGT1A response. Therefore, the development of more specific candidate substances for the treatment of cholestatic liver diseases is needed." @default.
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• W2117627495 date "2013-04-01" @default.
• W2117627495 modified "2023-09-26" @default.
• W2117627495 title "961 EFFECT OF URSODEOXYCHOLIC ACID WITHDRAWAL IN PATIENTS WITH PRIMARY SCLEROSING CHOLANGITIS" @default.
• W2117627495 doi "https://doi.org/10.1016/s0168-8278(13)60963-0" @default.
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