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Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Marschall, HU; Wagner, M; Bodin, K; Zollner, G; Fickert, P; Gumhold, J; Silbert, D; Fuchsbichler, A; Sjövall, J; Trauner, M.
Fxr(-/-) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids.
J Lipid Res. 2006; 47(3):582-592
Doi: 10.1194/jlr.M500427-JLR200
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- Co-Autor*innen der Med Uni Graz
- Fickert Peter
- Silbert-Wagner Dagmar
- Sommer Judith
- Trauner Michael
- Wagner Martin
- Zollner Gernot
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- Abstract:
- Farnesoid X receptor knockout (Fxr(-/-)) mice cannot upregulate the bile salt export pump in bile acid loading or cholestatic conditions. To investigate whether Fxr(-/-) mice differ in bile acid detoxification compared with wild-type mice, we performed a comprehensive analysis of bile acids extracted from liver, bile, serum, and urine of naive and common bile duct-ligated wild-type and Fxr(-/-) mice using electrospray and gas chromatography mass spectrometry. In addition, hepatic and renal gene expression levels of Cyp2b10 and Cyp3a11, and protein expression levels of putative renal bile acid-transporting proteins, were investigated. We found significantly enhanced hepatic bile acid hydroxylation in Fxr(-/-) mice, in particular hydroxylations of cholic acid in the 1beta, 2beta, 4beta, 6alpha, 6beta, 22, or 23 position and a significantly enhanced excretion of these metabolites in urine. The gene expression level of Cyp3a11 was increased in the liver of Fxr(-/-) mice, whereas the protein expression levels of multidrug resistance-related protein 4 (Mrp4) were increased in kidneys of both genotypes during common bile duct ligation. In conclusion, Fxr(-/-) mice detoxify accumulating bile acids in the liver by enhanced hydroxylation reactions probably catalyzed by Cyp3a11. The metabolites formed were excreted into urine, most likely with the participation of Mrp4.
- Find related publications in this database (using NLM MeSH Indexing)
- Animals -
- Aryl Hydrocarbon Hydroxylases - metabolism
- Bile Acids and Salts - blood Bile Acids and Salts - metabolism
- Carrier Proteins - metabolism
- Cholestasis - metabolism Cholestasis - physiopathology
- Cytochrome P-450 CYP3A - metabolism
- DNA-Binding Proteins - genetics DNA-Binding Proteins - metabolism
- Kidney - metabolism
- Liver - metabolism
- Membrane Glycoproteins - metabolism
- Membrane Proteins - metabolism
- Metabolic Detoxication, Phase I -
- Mice -
- Mice, Inbred C57BL - genetics Mice, Inbred C57BL - metabolism
- Mice, Knockout -
- Multidrug Resistance-Associated Proteins - metabolism
- RNA, Messenger - metabolism
- Receptors, Cytoplasmic and Nuclear -
- Steroid Hydroxylases - metabolism
- Transcription Factors - genetics Transcription Factors - metabolism
- Find related publications in this database (Keywords)
- farnesoid X receptor knockout
- multidrug resistance-related protein 4
- cytochrome 3a11
- gas chromatography-mass spectrometry
- electrospray mass spectrometry