Role of nuclear bile acid receptor, FXR, in adaptive ABC transporter regulation by cholic and ursodeoxycholic acid in mouse liver, kidney and intestine.
OBJECTIVE
Adaptive changes in transporter expression in liver and kidney provide alternative excretory pathways for biliary constituents during cholestasis and may thus attenuate liver injury. Whether adaptive changes in ATP-binding cassette (ABC) transporter expression are stimulated by bile acids and their nuclear receptor FXR is unknown.


METHODS
Hepatic, renal and intestinal ABC transporter expression was compared in cholic acid (CA)- and ursodeoxycholic acid (UDCA)-fed wild-type (FXR(+/+)) and FXR knock-out mice (FXR(-/-)). Expression was assessed by reverse transcription-polymerase chain reaction, immunoblotting and immunofluorescence microscopy.


RESULTS
CA feeding stimulated hepatic Mrp2, Mrp3, Bsep and renal Mrp2 as well as intestinal Mrp2 and Mrp3 expression. Lack of Bsep induction by CA in FXR(-/-) was associated with disseminated hepatocyte necrosis which was not prevented by compensatory induction of Mrp2 and Mrp3. With the exception of Bsep, UDCA stimulated expression of hepatic, renal and intestinal ABC transporters independent of FXR without inducing liver toxicity.


CONCLUSIONS
Toxic CA and non-toxic UDCA induce adaptive ABC transporter expression, independent of FXR with the exception of Bsep. Stimulation of hepatic Mrp3 as well as intestinal and renal Mrp2 by UDCA may contribute to its therapeutic effects by inducing alternative excretory routes for bile acids and other cholephiles.
Zollner
Gernot
G
Division of Gastroenterology and Hepatology, Department of Medicine, Karl-Franzens University, Auenbruggerplatz 15, A-8036 Graz, Austria.
Fickert
Peter
P
Fuchsbichler
Andrea
A
Silbert
Dagmar
D
Wagner
Martin
M
Arbeiter
Silvia
S
Gonzalez
Frank J
FJ
Marschall
Hanns-Ulrich
HU
Zatloukal
Kurt
K
Denk
Helmut
H
Trauner
Michael
M
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000222:Adaptation, Physiological; D000818:Animals; D002467:Cell Nucleus / Q000378:metabolism; D019826:Cholic Acid / Q000494:pharmacology / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D007413:Intestinal Mucosa / Q000378:metabolism*; D007668:Kidney / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout / Q000235:genetics; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation; D014580:Ursodeoxycholic Acid / Q000494:pharmacology / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D026901:Membrane Transport Proteins; D000089762:Multidrug Resistance-Associated Protein 2; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014580:Ursodeoxycholic Acid; D000099150:Receptor, Farnesoid X-Activated; C490549:Abcb11 protein, mouse; C114462:multidrug resistance-associated protein 3