Lithocholic acid induction of the FGF19 promoter in intestinal cells is mediated by PXR.
OBJECTIVE
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.


CONCLUSIONS
LCA induced feedback inhibition of bile acid synthesis in the liver is likely to be regulated by PXR inducing intestinal FGF19 expression.
Wistuba
Wolfgang
W
Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Franz-Josef-Strauss-Allee 11, Regensburg 93053, Germany.
Gnewuch
Carsten
C
Liebisch
Gerhard
G
Schmitz
Gerd
G
Langmann
Thomas
T
D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D001483:Base Sequence; D045744:Cell Line, Tumor; D003902:Detergents / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D025461:Feedback, Physiological / Q000502:physiology; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008095:Lithocholic Acid / Q000494:pharmacology*; D008969:Molecular Sequence Data; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism*; D012293:Rifampin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects
D003902:Detergents; D004791:Enzyme Inhibitors; C117476:FGF19 protein, human; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D008095:Lithocholic Acid; D005346:Fibroblast Growth Factors; D012293:Rifampin
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