The gene encoding the human ileal bile acid-binding protein (I-BABP) is regulated by peroxisome proliferator-activated receptors

• Published in: Biochimica et biophysica acta Vol. 1735; no. 1; pp. 41 - 49
• Main Authors: Landrier, J.F., Thomas, C., Grober, J., Zaghini, I., Petit, V., Poirier, H., Niot, I., Besnard, P.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 15.06.2005; Elsevier
• Subjects: Animals; Base Sequence; Bezafibrate - pharmacology; Bile acid; Binding Sites; Caco-2 Cells; Carrier Proteins - biosynthesis; Carrier Proteins - genetics; Fibrate; Food and Nutrition; Gene Expression Regulation - drug effects; Humans; I-BABP; Ileum - metabolism; Life Sciences; Membrane Glycoproteins - biosynthesis; Membrane Glycoproteins - genetics; Mice; Molecular Sequence Data; Peroxisome Proliferator-Activated Receptors - metabolism; PPAR; Promoter Regions, Genetic - genetics; Response Elements - genetics; Species Specificity; CDCA; FXR; DR1; SREBP; Fibrate; LXR; BARE; CYP7A1; CYP8B1; RXR; CYP27A1; PPAR; PPRE; EMSA; Bile acid; CAT; ASBT; I-BABP
• ISSN: 1388-1981; 0006-3002; 1879-2618
• DOI: 10.1016/j.bbalip.2005.05.002

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 PPARα-PPARβ/δ 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 PPARα or PPARβ/δ. 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.