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

• Published in: The Journal of biological chemistry Vol. 274; no. 42; pp. 29749 - 29754
• Main Authors: Grober, J, Zaghini, I, Fujii, H, Jones, S A, Kliewer, S A, Willson, T M, Ono, T, Besnard, P
• Format: Journal Article
• Language: English
• Published: United States 15.10.1999
• Subjects: Animals; Base Sequence; Bile Acids and Salts - metabolism; Carrier Proteins - genetics; Dimerization; DNA Primers; DNA-Binding Proteins - genetics; DNA-Binding Proteins - metabolism; farnesoid X receptors; Humans; Hydroxysteroid Dehydrogenases; I-BABP protein; Ileum - metabolism; intestinal bile acid-binding protein; Membrane Glycoproteins; Mice; Promoter Regions, Genetic; Receptors, Cytoplasmic and Nuclear; Receptors, Retinoic Acid - genetics; Receptors, Retinoic Acid - metabolism; Sequence Homology, Nucleic Acid; Transcription Factors - genetics; Transcription Factors - metabolism
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.274.42.29749

Intestinal bile acid-binding protein (I-BABP) is a cytosolic protein that binds bile acids (BAs) with a high affinity. In the small intestine, its expression is restricted to the ileum where it is involved in the enterohepatic circulation of BAs. Using the human enterocyte-like Caco-2 cell line, we have recently shown that BAs increased I-BABP gene expression. To determine whether this regulation occurs in vivo, the effect of BA depletion or supplementation 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 physiological 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 determine 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 FXR and RXRalpha is required to obtain the full transactivation of the I-BABP promoter by BAs. Deletion and mutation analyses demonstrate that the FXR/RXRalpha heterodimer activates transcription through an inverted repeat bile acid responsive element located in position -160/-148 of the human I-BABP promoter. In conclusion, we show that FXR is a physiological BA sensor that is likely to play an essential role in BA homeostasis through the regulation of genes involved in their enterohepatic circulation.