Regulation of the human bile acid UDP-glucuronosyltransferase 1A3 by the farnesoid X receptor and bile acids.
OBJECTIVE
Cholestasis is a serious complication of many liver diseases leading to increased serum bile acids (BA) and their conjugates. Chenodeoxycholic (CDCA) acid is a substrate of the human hepatic UDP-glucuronosyltransferase (UGT) 1A3. UGT1A3 may, therefore, be a BA-inducible gene relevant to BA regulation.


METHODS
BA and human bile were used to induce UGT1A3 in HepG2 cells. Genomic DNA was analyzed by PCR amplification and sequencing. Transcriptional regulation was studied by DNA mutagenesis, RT-PCR, luciferase reporter gene constructs and electrophoretic mobility shift assays (EMSA).


RESULTS
CDCA differentially induced UGT1A3 but not UGT1A4 expression. Bile from ursodeoxycholic acid (UDCA)-treated and untreated patients differentially induced UGT1A3. A farnesoid X receptor (FXR) half-site DNA motif was identified in the UGT1A3 5' upstream region. The FXR inducer GW4064 activated UGT1A3 transcription, and electrophoretic mobility shift assays identified UGT1A3 as a FXR target gene.


CONCLUSIONS
Transcriptional regulation of the human bile acid and xenobiotic UGT1A3 by its substrate CDCA and FXR is shown. CDCA glucuronidation can be controlled by feed back inhibition proceeding via the glucuronidation of CDCA. UDCA does not induce UGT1A3 transcription. Since UGT1A3 is significantly induced by xenobiotics this physiologically links xenobiotic and bile acid metabolism to cholestasis.
Erichsen
Thomas J
TJ
Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Carl-Neuberg Str. 1, Hannover, Germany.
Aehlen
André
A
Ehmer
Ursula
U
Kalthoff
Sandra
S
Manns
Michael P
MP
Strassburg
Christian P
CP
D001647:Bile Acids and Salts / Q000378:metabolism* / Q000494:pharmacology; D002635:Chenodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology; D002779:Cholestasis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D015870:Gene Expression / Q000502:physiology; D017930:Genes, Reporter / Q000502:physiology; D014644:Genetic Variation; D014453:Glucuronosyltransferase / Q000235:genetics* / Q000378:metabolism*; D056945:Hep G2 Cells; D006801:Humans; D008095:Lithocholic Acid / Q000378:metabolism / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D014580:Ursodeoxycholic Acid / Q000378:metabolism / Q000494:pharmacology; D015262:Xenobiotics / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002635:Chenodeoxycholic Acid; D014453:Glucuronosyltransferase; D008095:Lithocholic Acid; D008156:Luciferases; D018160:Receptors, Cytoplasmic and Nuclear; D014580:Ursodeoxycholic Acid; D015262:Xenobiotics; D000099150:Receptor, Farnesoid X-Activated; C122075:UDP-glucuronosyltransferase, UGT1A3