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J. Biol. Chem., Vol. 277, Issue 2, 1324-1331, January 11, 2002

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Sterol Regulatory Element-binding Protein-1c Is Responsible for Cholesterol Regulation of Ileal Bile Acid-binding Protein Gene in Vivo
POSSIBLE INVOLVEMENT OF LIVER-X-RECEPTOR^*

Isabelle Zaghini^§, Jean-François Landrier^§, Jacques Grober, Stéphane Krief^¶, Stacey A. Jones, Marie-Claude Monnot, Isabelle Lefrère^¶, Michael A. Watson, Jon L. Collins^**, Hiroshi Fujii, and Philippe Besnard^§§

From the  Physiologie de la Nutrition, Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation (ENSBANA), FRE 2049 CNRS/Université de Bourgogne, F-21000, Dijon, France, ^¶ Bioprojet Biotech, 4, rue du Chesnay-Beauregard F-35760 Saint Grégoire, France,  Systems Research, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, ^** Medicinal Chemistry, GlaxoSmithKline Research and Development, Research Triangle Park, North Carolina 27709, the  Department of Biochemistry, Niigata University School of Medecine, 1-757 Asahimashi-dori, Niigata 951, Japan

Ileal bile acid-binding protein (I-BABP) is a cytosolic protein that binds bile acid (BA) specifically. In the ileum, it is thought to be implied in their enterohepatic circulation. Because the fecal excretion of BA represents the main physiological way of elimination for cholesterol (CS), the I-BABP gene could have a major function in CS homeostasis. Therefore, the I-BABP gene expression might be controlled by CS. I-BABP mRNA levels were significatively increased when the human enterocyte-like CaCo-2 cells were CS-deprived and repressed when CS were added to the medium. A highly conserved sterol regularory element-like sequence (SRE) and a putative GC box were found in human I-BABP gene promoter. Different constructs of human I-BABP promoter, cloned upstream of a chloramphenicol acetyltransferase (CAT) reporter gene, have been used in transfections studies. CAT activity of the wild type promoter was increased in presence of CS-deprived medium, and conversely, decreased by a CS-supplemented medium. The inductive effect of CS depletion was fully abolished when the putative SRE sequence and/or GC box were mutated or deleted. Co-transfections experiments with the mature isoforms of human sterol responsive element-binding proteins (SREBPs) and Sp1 demonstrate that the CS-mediated regulation of I-BABP gene was dependent of these transcriptional factors. Paradoxically, mice subjected to a standard chow supplemented with 2% CS for 14 days exhibited a significant rise in both I-BABP and SREBP1c mRNA levels. We show that in vivo, this up-regulation could be explained by a recently described regulatory pathway involving a positive regulation of SREBP1c by liver-X-receptor following a high CS diet.

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