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Transactivation of Rat Apical Sodium-Dependent Bile Acid Transporter and Increased Bile Acid Transport by 1,25-Dihydroxyvitamin D₃ via the Vitamin D Receptor

Departments of Pharmacology (X.C., K.S.P.) and Pharmaceutical Science (S.L., K.S.P.), University of Toronto, Toronto, Ontario, Canada; Division of Pediatric Hepatology, Department of Pediatrics, Mount Sinai School of Medicine, New York, New York (F.C., B.L.S.); Division of Clinical Pharmacology, School of Medicine, Vanderbilt University, Nashville, Tennessee (H.G., R.B.K.); Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina (P.A.D.), and Division of Gastroenterology, School of Medicine, University of California at San Diego, La Jolla, California (A.F.H.)

Transactivation of the rat apical sodium-dependent bile acid transporter (ASBT; Slc10a2) by 1,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] via the vitamin D receptor (VDR), was studied. Levels of ASBT protein and mRNA were low in the duodenum and high in the ileum, and both were induced by 1,25(OH)₂D₃. The nuclear receptor protein, VDR, was present uniformly in the duodenum, jejunum, and ileum of the rat small intestine. The physiological relevance of ASBT induction by 1,25(OH)₂D₃ was assessed by measuring absorption of cholylsarcosine, a non-metabolized synthetic bile acid analog, from duodenal or ileal closed loops of the perfused rat small intestine preparation. Absorption of cholylsarcosine was much greater from the ileal segment (28-fold that of the duodenum under control conditions) and was enhanced with 1,25(OH)₂D₃ treatment. Transient transfection analysis of the rat ASBT promoter in Caco-2 cells revealed concentration-dependent enhancement of luciferase reporter activity after treatment with 1,25(OH)₂D₃. The activation by 1,25(OH)₂D₃ was abrogated after site-directed mutagenesis or deletion of the vitamin D response element (VDRE) in the ASBT promoter. Gel-shift mobility assays of nuclear extracts from rat ileum showed that both rat retinoid X receptor and VDR were bound to the VDRE. The results indicate that rat ASBT gene expression is activated by 1,25(OH)₂D₃ by specific binding to the VDRE and that such activation enhances ileal bile acid transport. Human ABST mRNA and promoter activity were also increased in Caco-2 cells treated with 1,25(OH)₂D₃, suggesting a physiological role of VDR in human ileal bile acid homeostasis.

Address correspondence to: Dr. K. Sandy Pang, Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, ON M5S 2S2, Canada. E-mail: ks.pang{at}utoronto.ca

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