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

Abstract : 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.
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Submitted on : Friday, November 9, 2018 - 10:09:49 AM
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Jean-Francois Landrier, Charles Thomas, Jacques Grober, I. Zaghini, Valérie Petit, et al.. The gene encoding the human ileal bile acid-binding protein (I-BABP) is regulated by peroxisome proliferator-activated receptors. Biochimica et Biophysica Acta Molecular and Cell Biology of Lipids, Elsevier, 2005, 1735 (1), pp.41 - 49. ⟨10.1016/j.bbalip.2005.05.002⟩. ⟨hal-01917098⟩

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