Role of farnesoid X receptor in determining hepatic ABC transporter expression and liver injury in bile duct-ligated mice
| Autor: | Michael Trauner, Martin Wagner, Kurt Zatloukal, Frank J. Gonzalez, Hanns-Ulrich Marschall, Dagmar Silbert, John D. Schuetz, Oleksiy Tsybrovskyy, Helmut Denk, Peter Fickert, Andrea Fuchsbichler, Grace L. Guo, Gernot Zollner |
|---|---|
| Rok vydání: | 2003 |
| Předmět: |
medicine.medical_specialty
medicine.drug_class Receptors Cytoplasmic and Nuclear Apoptosis Biology digestive system Tight Junctions Mice Necrosis Cholestasis Internal medicine medicine Animals RNA Messenger Ligation ATP Binding Cassette Transporter Subfamily B Member 11 Hepatology Bile acid Bile duct Liver cell Gastroenterology medicine.disease G protein-coupled bile acid receptor Bile Salt Export Pump DNA-Binding Proteins Mice Inbred C57BL medicine.anatomical_structure Endocrinology Liver Biliary tract Farnesoid X receptor ATP-Binding Cassette Transporters Multidrug Resistance-Associated Proteins Cell Division Transcription Factors |
| Zdroj: | Gastroenterology. 125(3) |
| ISSN: | 0016-5085 |
| Popis: | Background & Aims: Cholestasis induces changes in hepatic adenosine triphosphate-binding cassette (ABC) transporter expression. We aimed to investigate the role of the nuclear bile acid receptor (farnesoid X receptor [FXR]) in mediating changes in ABC transporter expression and in determining liver injury. Methods: Hepatic ABC transporter (multidrug resistance-associated proteins [Mrp] 2–4 and bile salt export pump [Bsep]) expression and localization were studied in common bile duct-ligated (CBDL) FXR knockout (FXR −/− ), wild-type (FXR +/+ ), and sham-operated mice. Serum alanine aminotransferase, alkaline phosphatase, bilirubin and bile acid levels, hepatic bile acid composition, and liver histology were investigated. Cholangiomanometry and bile duct morphometry were performed. Results: CBDL induced expression of Mrp 3 and Mrp 4 in FXR +/+ and even more in FXR −/− , whereas Mrp 2 expression remained unchanged. Bsep expression was maintained in CBDL FXR +/+ but remained undetectable in CBDL FXR −/− . Alanine aminotransferase levels and mortality rates did not differ between CBDL FXR +/+ and FXR −/− . CBDL increased biliary pressure and induced bile ductular proliferation and bile infarcts in FXR +/+ , whereas FXR −/− had lower biliary pressures, less ductular proliferation, and developed disseminated liver cell necroses. Conclusions: Overexpression of Mrp 3 and Mrp 4 in CBDL mice is FXR independent and could play an important role in the adaptive hepatic ABC transporter response to cholestasis. Maintenance of Bsep expression strictly depends on FXR and is a critical determinant of the cholestatic phenotype. Lack of bile infarcts in CBDL FXR −/− suggests that development of bile infarcts is related to bile acid-dependent bile flow and biliary pressure. This information is relevant for the potential use of FXR modulators in the treatment of cholestatic liver diseases. |
| Databáze: | OpenAIRE |
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