Human ileal bile acid transporter gene ASBT (SLC10A2) is transactivated by the glucocorticoid receptor.
BACKGROUND
Patients with Crohn's disease suffer from intestinal bile acid malabsorption. Intestinal bile acid absorption is mediated by the apical sodium dependent bile acid transporter ASBT/IBAT (SLC10A2). In rats, ASBT is induced by glucocorticoids.


OBJECTIVE
To study whether human ASBT is activated by glucocorticoids and to elucidate the mechanism of regulation.


METHODS
ASBT expression in ileal biopsies from patients with Crohn's disease and from healthy subjects was quantified by western blot. ASBT promoter function was studied in luciferase assays and by electrophoretic mobility shift assay.


RESULTS
In 16 patients with Crohn's disease, ASBT expression was reduced to 69 (7.5)% compared with healthy controls (mean (SEM); p = 0.01). In 10 healthy male volunteers, ASBT protein expression was increased 1.34 (0.11)-fold (mean (SEM); p<0.05) after 21 days' intake of budesonide (9 mg/day) whereas expression of the peptide transporter 1 was unaffected. Reporter constructs of the human ASBT promoter were activated 15-20-fold by coexpression of the glucocorticoid receptor (GR) and exposure to the GR ligands dexamethasone or budesonide. Two glucocorticoid response elements in the ASBT promoter, arranged as inverted hexanucleotide repeats (IR3 elements), conferred inducibility by GR and dexamethasone in a heterologous promoter context and were shown to bind GR in mobility shift assays.


CONCLUSIONS
Human ASBT is induced by glucocorticoids in vitro and in vivo. Induction of ASBT by glucocorticoids could be beneficial in patients with Crohn's disease who exhibit reduced ASBT expression. This study identifies ASBT as a novel target of glucocorticoid controlled gene regulation in the human intestine.
Jung
D
D
Laboratory of Molecular Gastroenterology and Hepatology, University Hospital, CH-8091 Zurich, Switzerland.
Fantin
A C
AC
Scheurer
U
U
Fried
M
M
Kullak-Ublick
G A
GA
D000328:Adult; D000893:Anti-Inflammatory Agents / Q000494:pharmacology; D001647:Bile Acids and Salts; D015153:Blotting, Western; D019819:Budesonide / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D003424:Crohn Disease / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005765:Gastrointestinal Agents / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D008024:Ligands; D008297:Male; D029363:Organic Anion Transporters, Sodium-Dependent; D011401:Promoter Regions, Genetic; D011965:Receptors, Glucocorticoid / Q000378:metabolism / Q000502:physiology; D027981:Symporters; D015533:Transcriptional Activation / Q000187:drug effects*
D000893:Anti-Inflammatory Agents; D001647:Bile Acids and Salts; D002352:Carrier Proteins; D005765:Gastrointestinal Agents; D005938:Glucocorticoids; D008024:Ligands; D029363:Organic Anion Transporters, Sodium-Dependent; D011965:Receptors, Glucocorticoid; D027981:Symporters; C071908:sodium-bile acid cotransporter; D019819:Budesonide; D003907:Dexamethasone