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Journal of Lipid Research, Vol. 45, 1538-1545, August 2004
Copyright © 2004 by American Society for Biochemistry and Molecular Biology

Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor

Tomoko Nishimaki-Mogami^1,*, Mizuho Une, Tomofumi Fujino^*, Yoji Sato^*, Norimasa Tamehiro^*, Yosuke Kawahara^*, Koichi Shudo^* and Kazuhide Inoue^*

^* National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan
Laboratory of Organic and Biomolecular Chemistry, Faculty of Pharmaceutical Sciences, Hiroshima International University, 5-5-1 Hirokoshinkai, Kure, Hiroshima 737-0112, Japan

¹ To whom correspondence should be addressed. e-mail: 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 activated by bile acids. Synthesis via the classic pathway is initiated by a series of cholesterol ring modifications and followed by the side chain cleavage. Several intermediates accumulate or are excreted as end products of the pathway in diseases involving defective bile acid biosynthesis. In this 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 a 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-hydroxylase mRNA level and induced the small heterodimer partner and the bile salt export pump mRNA, indicating the ability to regulate bile acid synthesis and excretion.

Because 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.

Abbreviations: BSEP, bile acid export pump; CA, cholic acid; CDCA, chenodeoxycholic acid; CTX, cerebrotendinous xanthomatosis; CYP27, sterol 27-hydroxylase; CYP7A1, cholesterol 7-hydroxylase; DHC, 5ß-cholestane-3,7-diol; DHCA, 3,7-dihydroxy-5ß-cholestanoic acid; FXR, farnesoid X receptor; FXRE, FXR response element; LBD, ligand binding domain; LXR, liver X receptor; LXRE, LXR response element; MRP2, multidrug resistance-associated protein 2; 26-OH-DHC, 5ß-cholestane-3,7,26-triol; 24-OH-DHCA, 3,7,24-trihydroxy-5ß-cholestanoic acid; 25-OH-THC, 5ß-cholestane-3,7,12,25-tetrol; 26-OH-THC, 5ß-cholestane-3,7,12,26-tetrol; 24-OH-THCA, 3,7,12,24-tetrahydroxy-5ß-cholestanoic acid; SHP, small heterodimer partner; SPR, surface plasmon resonance; THC, 5ß-cholestane-3,7,12-triol; THCA, 3,7,12-trihydroxy-5ß-cholestanoic acid; ²⁴-THCA, 3,7,12-trihydroxy-5ß-cholest-24-enoic acid

Supplementary key words bile alcohol • liver X receptor • cholesterol 7-hydroxylase • small heterodimer partner • bile acid export pump

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