Expression of the bile acid receptor FXR in Barrett's esophagus and enhancement of apoptosis by guggulsterone in vitro.
BACKGROUND
Barrett's esophagus, a risk factor for esophageal adenocarcinoma, is associated with reflux disease. The aim of this study was to assess the expression of bile acid receptors in the esophagus (normal, esophagitis, Barrett's esophagus and adenocarcinoma) and to investigate their possible function.


RESULTS
the expression of the bile acid receptors FXR and VDR in esophageal biopsies from patients with a normal mucosa, esophagitis, Barrett's esophagus or adenocarcinoma (n = 6 per group) and in cell lines derived from Barrett's esophagus and esophageal adenocarcinoma, was assessed by real time Q-PCR and immunohistochemistry. The effect of guggulsterone, an antagonist of bile acid receptors, on apoptosis of Barrett's esophagus-derived cells was assessed morphologically, by flow cytometry and by measuring caspase 3 activity. The expression of FXR was increased in esophagitis, Barrett's esophagus and adenocarcinoma compared to normal mucosa by a mean of 44, 84 and 16, respectively. Immunohistochemistry showed a weak expression in normal esophagus, a strong focal reactivity in Barrett's esophagus, and was negative in adenocarcinoma. VDR expression did not significantly differ between groups. In cell cultures, the expression of FXR was high in Barrett's esophagus-derived cells and almost undetectable in adenocarcinoma-derived cells, whereas VDR expression in these cell lines was not significantly different. In vitro treatment with guggulsterone was associated with a significant increase in the percentage of apoptotic cells and of the caspase 3 activity.


CONCLUSIONS
the bile acid receptor FXR is significantly overexpressed in Barrett's esophagus compared to normal mucosa, esophagitis and esophageal adenocarcinoma. The induction of apoptosis by guggulsterone in a Barrett's esophagus-derived cell line suggests that FXR may contribute to the regulation of apoptosis.
De Gottardi
Andrea
A
Division of Gastroenterology, University Hospital, Micheli-du-Crest 24, 1205 Geneva, Switzerland. andrea.degottardi@hcuge.ch
Dumonceau
Jean-Marc
JM
Bruttin
Fabien
F
Vonlaufen
Alain
A
Morard
Isabelle
I
Spahr
Laurent
L
Rubbia-Brandt
Laura
L
Frossard
Jean-Louis
JL
Dinjens
Winand N M
WN
Rabinovitch
Peter S
PS
Hadengue
Antoine
A
D000230:Adenocarcinoma / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017209:Apoptosis / Q000187:drug effects*; D001471:Barrett Esophagus / Q000378:metabolism*; D001706:Biopsy; D018929:Cell Culture Techniques; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004938:Esophageal Neoplasms / Q000378:metabolism; D004942:Esophagitis, Peptic / Q000378:metabolism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D011230:Precancerous Conditions / Q000378:metabolism; D011282:Pregnenediones / Q000494:pharmacology*; D018167:Receptors, Calcitriol / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014157:Transcription Factors / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D004268:DNA-Binding Proteins; D011282:Pregnenediones; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C023617:pregna-4,17-diene-3,16-dione