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Papers In Press, published online ahead of print May 16, 2004
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National Institute of Health Sciences, Tokyo 158-8501
Corresponding Author: mogami{at}nihs.go.jp
Bile acid synthesis from cholesterol is tightly regulated via a feedback mechanism mediated by the farnesoid X receptor (FXR), a nuclear receptor that is activated by bile acids. Synthesis via the classic pathway is initiated by a series of cholesterol ring modifications and followed by oxidative cleavage of the side chain. Several intermediates accumulate or are excreted as end products of the pathway in diseases involving defective bile acid biosynthesis. In the present study we investigated the ability of these intermediates to activate human FXR. In a cell-based reporter assay and coactivator recruitment assays in vitro, early intermediates possessing an intact cholesterol side chain were inactive, whereas 26- or 25-hydroxylated bile alcohols and C27 bile acids were highly efficacious ligands for FXR at level comparable to that of the most potent physiological ligand, chenodeoxycholic acid. Treatment of HepG2 cells with these precursors repressed the rate-limiting cholesterol 7
Revised on April 26, 2004
Accepted on May 6, 2004
Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor
-hydroxylase mRNA level and induced the small heterodimer partner and the bile salt export pump mRNA. These findings indicate that C27 intermediates having both a bile-acid type nucleus and an oxygen at either the C-25 or C-26 position in the side chain possess the ability to activate FXR and regulate bile acid synthesis as end-product C24 bile acids. Since 26-hydroxylated bile alcohols and C27 bile acids are known to be evolutionary precursors of bile acids in mammals, our findings suggest that human FXR may have retained affinity to these precursors during evolution.
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