The gene encoding the human ileal bile acid-binding protein (I-BABP) is regulated by peroxisome proliferator-activated receptors.
Peroxisome proliferator-activator receptors (PPAR) are involved in cholesterol homeostasis through the regulation of bile acids synthesis, composition, and reclamation. As ileal bile acid-binding protein (I-BABP) is thought to play a crucial role in the enterohepatic circulation of bile acids, we investigated whether I-BABP gene expression could also be affected by PPAR. Indeed, treatment with the PPARalpha-PPARbeta/delta agonist bezafibrate led to the up-regulation of I-BABP mRNA levels in the human intestine-derived Caco-2 cells. Cotransfections of the reporter-linked human I-BABP promoter (hI-BABP-2769/+44) together with PPAR and RXR expression vectors demonstrated that the fibrate-mediated induction of the I-BABP gene is dependent on PPARalpha or PPARbeta/delta. Using progressive 5' deletions of the hI-BABP promoter and sequence analysis, we identified a putative PPAR-binding site located at the position -198 and -186 upstream of the transcription initiation site. Electrophoretic mobility shift assays showed that the PPAR/RXR heterodimer can specifically bind to this PPRE-like motif. The deletion of the PPRE within the hI-BABP promoter abolished the PPAR-mediated transactivation in transient transfection assays. The regulation of the I-BABP promoter by PPAR appears species-specific, as the mouse I-BABP promoter, which lacks a conserved PPRE, was not responsive to exogenous PPAR expression in the presence of bezafibrate. Our findings show that the I-BABP gene may be a novel target for PPAR in humans and further emphasize the role for PPAR in the control of bile acid homeostasis.
Landrier
J F
JF
Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation, UMR 5170 CESG CNRS/INRA/Université de Bourgogne, 1 Esplanade Erasme F-21000, Dijon, France.
Thomas
C
C
Grober
J
J
Zaghini
I
I
Petit
V
V
Poirier
H
H
Niot
I
I
Besnard
P
P
D000818:Animals; D001483:Base Sequence; D001629:Bezafibrate / Q000494:pharmacology; D001665:Binding Sites; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics*; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007082:Ileum / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000235:genetics*; D051379:Mice; D008969:Molecular Sequence Data; D047492:Peroxisome Proliferator-Activated Receptors / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D020218:Response Elements / Q000235:genetics; D013045:Species Specificity
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D047492:Peroxisome Proliferator-Activated Receptors; C037643:bile acid binding proteins; D001629:Bezafibrate