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

Jacques Grobert, Isabelle Zaghini, Hiroshi Fujii, Stacey A. Jones, Steven A. Kliewer, Timothy M. Willson, Teruo Ono, Philippe Besnard

Research output: Contribution to journalArticle

266 Citations (Scopus)

Abstract

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 RXRα is required to obtain the full transactivation of the I-BABP promoter by BAs. Deletion and mutation analyses demonstrate that the FXR/RXRα 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.

Original languageEnglish (US)
Pages (from-to)29749-29754
Number of pages6
JournalJournal of Biological Chemistry
Volume274
Issue number42
DOIs
StatePublished - Oct 15 1999

Fingerprint

Retinoid X Receptors
Bile Acids and Salts
Genes
Caco-2 Cells
Enterohepatic Circulation
Small Intestine
human AKR1C2 protein
bile acid binding proteins
Cholestyramine Resin
Taurocholic Acid
Enterocytes
Sequence Deletion
Transcription
Ileum
Gene expression
Transcriptional Activation
Animals
Homeostasis
Ligands

ASJC Scopus subject areas

  • Biochemistry

Cite this

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. / Grobert, Jacques; Zaghini, Isabelle; Fujii, Hiroshi; Jones, Stacey A.; Kliewer, Steven A.; Willson, Timothy M.; Ono, Teruo; Besnard, Philippe.

In: Journal of Biological Chemistry, Vol. 274, No. 42, 15.10.1999, p. 29749-29754.

Research output: Contribution to journalArticle

Grobert, Jacques ; Zaghini, Isabelle ; Fujii, Hiroshi ; Jones, Stacey A. ; Kliewer, Steven A. ; Willson, Timothy M. ; Ono, Teruo ; Besnard, Philippe. / 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. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 42. pp. 29749-29754.
@article{8d412975f1ae41c8b00640c2969bb714,
title = "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",
abstract = "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 RXRα is required to obtain the full transactivation of the I-BABP promoter by BAs. Deletion and mutation analyses demonstrate that the FXR/RXRα 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.",
author = "Jacques Grobert and Isabelle Zaghini and Hiroshi Fujii and Jones, {Stacey A.} and Kliewer, {Steven A.} and Willson, {Timothy M.} and Teruo Ono and Philippe Besnard",
year = "1999",
month = "10",
day = "15",
doi = "10.1074/jbc.274.42.29749",
language = "English (US)",
volume = "274",
pages = "29749--29754",
journal = "Journal of Biological Chemistry",
issn = "0021-9258",
publisher = "American Society for Biochemistry and Molecular Biology Inc.",
number = "42",

}

TY - JOUR

T1 - 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

AU - Grobert, Jacques

AU - Zaghini, Isabelle

AU - Fujii, Hiroshi

AU - Jones, Stacey A.

AU - Kliewer, Steven A.

AU - Willson, Timothy M.

AU - Ono, Teruo

AU - Besnard, Philippe

PY - 1999/10/15

Y1 - 1999/10/15

N2 - 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 RXRα is required to obtain the full transactivation of the I-BABP promoter by BAs. Deletion and mutation analyses demonstrate that the FXR/RXRα 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.

AB - 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 RXRα is required to obtain the full transactivation of the I-BABP promoter by BAs. Deletion and mutation analyses demonstrate that the FXR/RXRα 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.

UR - http://www.scopus.com/inward/record.url?scp=0033570028&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0033570028&partnerID=8YFLogxK

U2 - 10.1074/jbc.274.42.29749

DO - 10.1074/jbc.274.42.29749

M3 - Article

VL - 274

SP - 29749

EP - 29754

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 42

ER -