Fxr(-/-) mice adapt to biliary obstruction by enhanced phase I detoxification and renal elimination of bile acids.
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.
Marschall
Hanns-Ulrich
HU
Karolinska Institutet, Department of Medicine at Karolinska University Hospital Huddinge, S-14186 Stockholm, Sweden. hanns-ulrich.marschall@medhs.ki.se
Wagner
Martin
M
Bodin
Karl
K
Zollner
Gernot
G
Fickert
Peter
P
Gumhold
Judith
J
Silbert
Dagmar
D
Fuchsbichler
Andrea
A
Sjövall
Jan
J
Trauner
Michael
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000097:blood / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002779:Cholestasis / Q000378:metabolism / Q000503:physiopathology*; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D050216:Metabolic Detoxication, Phase I; D051379:Mice; D008810:Mice, Inbred C57BL / Q000235:genetics / Q000378:metabolism; D018345:Mice, Knockout; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C489540:Abcc4 protein, mouse; C037643:bile acid binding proteins; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse