Identification of intermediates in the bile acid synthetic pathway as ligands for the farnesoid X receptor.
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 7alpha-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.
Nishimaki-Mogami
Tomoko
T
National Institute of Health Sciences, Kamiyoga 1-18-1, Setagaya-ku, Tokyo 158-8501, Japan. mogami@nihs.go.jp
Une
Mizuho
M
Fujino
Tomofumi
T
Sato
Yoji
Y
Tamehiro
Norimasa
N
Kawahara
Yosuke
Y
Shudo
Koichi
K
Inoue
Kazuhide
K
D001647:Bile Acids and Salts / Q000096:biosynthesis*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D016231:Fluorescence Polarization Immunoassay; D006801:Humans; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D020349:Surface Plasmon Resonance; D014157:Transcription Factors / Q000378:metabolism*; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated