Rapid Communication
Copyright ©2007 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastroenterol. Aug 21, 2007; 13(31): 4230-4235
Published online Aug 21, 2007. doi: 10.3748/wjg.v13.i31.4230
Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR
Wolfgang Wistuba, Carsten Gnewuch, Gerhard Liebisch, Gerd Schmitz, Thomas Langmann
Wolfgang Wistuba, Carsten Gnewuch, Gerhard Liebisch, Gerd Schmitz, Thomas Langmann, Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg 93053, Germany
Author contributions: All authors contributed equally to the work.
Correspondence to: Thomas Langmann, PhD, Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg 93053, Germany. thomas.langmann@klinik.uni-regensburg.de
Telephone: +49-941-9446201 Fax: +49-941-9446202
Received: April 12, 2007
Revised: June 1, 2007
Accepted: June 4, 2007
Published online: August 21, 2007
Abstract

AIM: To study the effect of the toxic secondary bile acid lithocholic acid (LCA) on the expression of fibroblast growth factor 19 (FGF19) in intestinal cells and to characterize the pregnane-X-receptor (PXR) response of the FGF19 promoter region.

METHODS: The intestinal cell line LS174T was stimulated with various concentrations of chenodeoxy-cholic acid and lithocholic acid for several time points. FGF19 mRNA levels were determined with quantitative realtime RT-PCR. FGF19 deletion promoter constructs were generated and the LCA response was analzyed in reporter assays. Co-transfections with PXR and RXR were carried out to study FGF19 regulation by these factors.

RESULTS: LCA and CDCA strongly up-regulate FGF19 mRNA expression in LS174T cells in a time and dose dependent manner. Using reporter gene assays with several deletion constructs we found that the LCA responsive element in the human FGF19 promoter maps to the proximal regulatory region containing two potential binding sites for PXR. Overexpression of PXR and its dimerization partner retinoid X receptor (RXR) and stimulation with LCA or the potent PXR ligand rifampicin leads to a significant induction of FGF19 promoter activity in intestinal cells.

CONCLUSION: LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.

Keywords: Pregnane X receptor; Detoxification; Fibroblast growth factor 19; Lithocholic acid