Identification of a bile acid-responsive element in the human ileal bile acid-binding protein gene - Involvement of the farnesoid X receptor/9-cis-retinoic acid receptor heterodimer

Intestinal bile acid-binding protein (I-BABP) iis a cytosolic protein that binds bile acids (BAs) with a high affinity. In the small intestine, its ex pression is restricted to the ileum where it is involved in the enterohepat ic circulation of BAs, Using the human enterocyte-like Caco-2 cell line, we have recently shown that BAs increased I-BABP gene expression. To determin e whether this regulation occurs in vivo, the effect of BA depletion or sup plementation was studied in mice, A dramatic drop in I-BABP mRNA levels was observed in mice treated with the BA-binding resin cholestyramine, whereas an increase was found in animals fed with taurocholic acid. BAs are physio logical ligands for the nuclear farnesoid X receptor (FXR), Both FXR and I- BABP are co-expressed along the small intestine and in Caco-2 cells. To det ermine the role of FXR in the regulation of I-BABP expression, the promoter of the human I-BABP gene was cloned. In Caco-2 cells, cotransfection of FX R and RXR alpha is required to obtain the full transactivation of the I-BAB P promoter by BAs, Deletion and mutation analyses demonstrate that the FXR/ RXR alpha heterodimer activates transcription through an inverted repeat bi le acid responsive element located in position -160/-148 of the human I-BAB P promoter. In conclusion, we show that FXR is a physiological BA sensor th at is likely to play an essential role in BA homeostasis through the regula tion of genes involved in their enterohepatic circulation.