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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Zollner, G; Wagner, M; Moustafa, T; Fickert, P; Silbert, D; Gumhold, J; Fuchsbichler, A; Halilbasic, E; Denk, H; Marschall, HU; Trauner, M.
Coordinated induction of bile acid detoxification and alternative elimination in mice: role of FXR-regulated organic solute transporter-alpha/beta in the adaptive response to bile acids.
Am J Physiol Gastrointest Liver Physiol. 2006; 290(5):G923-G932 Doi: 10.1152/ajpgi.00490.2005 [OPEN ACCESS]
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Führende Autor*innen der Med Uni Graz
Trauner Michael
Zollner Gernot
Co-Autor*innen der Med Uni Graz
Denk Helmut
Fickert Peter
Halilbasic Emina
Moustafa Tarek
Silbert-Wagner Dagmar
Sommer Judith
Wagner Martin
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Abstract:
The bile acid receptor farnesoid X receptor (FXR) is a key regulator of hepatic defense mechanisms against bile acids. A comprehensive study addressing the role of FXR in the coordinated regulation of adaptive mechanisms including biosynthesis, metabolism, and alternative export together with their functional significance is lacking. We therefore fed FXR knockout (FXR(-/-)) mice with cholic acid (CA) and ursodeoxycholic acid (UDCA). Bile acid synthesis and hydroxylation were assessed by real-time RT-PCR for cytochrome P-450 (Cyp)7a1, Cyp3a11, and Cyp2b10 and mass spectrometry-gas chromatography for determination of bile acid composition. Expression of the export systems multidrug resistance proteins (Mrp)4-6 in the liver and kidney and the recently identified basoalteral bile acid transporter, organic solute transporter (Ost-alpha/Ost-beta), in the liver, kidney, and intestine was also investigated. CA and UDCA repressed Cyp7a1 in FXR(+/+) mice and to lesser extents in FXR(-/-) mice and induced Cyp3a11 and Cyp2b10 independent of FXR. CA and UDCA were hydroxylated in both genotypes. CA induced Ost-alpha/Ost-beta in the liver, kidney, and ileum in FXR(+/+) but not FXR(-/-) mice, whereas UDCA had only minor effects. Mrp4 induction in the liver and kidney correlated with bile acid levels and was observed in UDCA-fed and CA-fed FXR(-/-) animals but not in CA-fed FXR(+/+) animals. Mrp5/6 remained unaffected by bile acid treatment. In conclusion, we identified Ost-alpha/Ost-beta as a novel FXR target. Absent Ost-alpha/Ost-beta induction in CA-fed FXR(-/-) animals may contribute to increased liver injury in these animals. The induction of bile acid hydroxylation and Mrp4 was independent of FXR but could not counteract liver toxicity sufficiently. Limited effects of UDCA on Ost-alpha/Ost-beta may jeopardize its therapeutic efficacy.
Find related publications in this database (using NLM MeSH Indexing)
Animals -
Aryl Hydrocarbon Hydroxylases - metabolism
Bile Acids and Salts - biosynthesis Bile Acids and Salts - chemistry Bile Acids and Salts - metabolism
Cholesterol 7-alpha-Hydroxylase - metabolism
Cholic Acid - pharmacology Cholic Acid - toxicity
Cytochrome P-450 CYP3A - metabolism
DNA-Binding Proteins - genetics
Gene Expression Regulation -
Kidney - metabolism
Liver - metabolism
Male -
Membrane Proteins - metabolism
Membrane Transport Proteins - metabolism
Mice -
Mice, Inbred C57BL -
Models, Biological -
Multidrug Resistance-Associated Proteins - metabolism
Organic Anion Transporters, Sodium-Dependent -
Promoter Regions, Genetic -
Receptors, Cytoplasmic and Nuclear -
Steroid Hydroxylases - metabolism
Symporters -
Transcription Factors - genetics
Ursodeoxycholic Acid - pharmacology

Find related publications in this database (Keywords)
nuclear receptors
cholestrasis
liver
kidney
intestine
farnesoid X receptor
cholic acid
ursodeoxycholic acid
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