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.
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.
Zollner
Gernot
G
Laboratory of Experimental and Molecular Hepatology, Div. of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University Graz, Auenbruggerplatz 15, Graz A-8036, Austria.
Wagner
Martin
M
Moustafa
Tarek
T
Fickert
Peter
P
Silbert
Dagmar
D
Gumhold
Judith
J
Fuchsbichler
Andrea
A
Halilbasic
Emina
E
Denk
Helmut
H
Marschall
Hanns-Ulrich
HU
Trauner
Michael
M
D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000378:metabolism; D001647:Bile Acids and Salts / Q000096:biosynthesis / Q000737:chemistry / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D019826:Cholic Acid / Q000494:pharmacology / Q000633:toxicity; D051544:Cytochrome P-450 CYP3A / Q000378:metabolism; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins / Q000235:genetics*; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D029363:Organic Anion Transporters, Sodium-Dependent; D011401:Promoter Regions, Genetic; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases / Q000378:metabolism; D027981:Symporters; D014157:Transcription Factors / Q000235:genetics*; D014580:Ursodeoxycholic Acid / Q000494:pharmacology; D000099150:Receptor, Farnesoid X-Activated
D001189:Aryl Hydrocarbon Hydroxylases; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D019826:Cholic Acid; D051544:Cytochrome P-450 CYP3A; D000072467:Cytochrome P450 Family 2; D004268:DNA-Binding Proteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D018160:Receptors, Cytoplasmic and Nuclear; D013250:Steroid Hydroxylases; D027981:Symporters; D014157:Transcription Factors; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C489540:Abcc4 protein, mouse; C476576:organic solute transporter alpha, mouse; C476578:organic solute transporter beta, mouse; C071908:sodium-bile acid cotransporter; C101679:Cyp2b10 protein, mouse; C496508:Cyp3a11 protein, mouse; C502772:Cyp7a1 protein, mouse