Evolution of the bile salt nuclear receptor FXR in vertebrates

Bile salts, the major end metabolites of cholesterol, vary significantly in structure across vertebrate species, suggesting that nuclear receptors binding these molecules may show adaptive evolutionary changes. We compared across species the bile salt specificity of the major transcriptional regulat...

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Bibliographic Details
Published in:Journal of lipid research 2008-07, Vol.49 (7), p.1577-1587
Main Authors: Reschly, Erica J, Ai, Ni, Ekins, Sean, Welsh, William J, Hagey, Lee R, Hofmann, Alan F, Krasowski, Matthew D
Format: Article
Language:English
Subjects:
Animals
Bile Acids and Salts - chemistry
Bile Acids and Salts - metabolism
Cattle
Cell Line
Crystallography, X-Ray
Evolution, Molecular
Ligands
Models, Molecular
Molecular Structure
RNA-Binding Proteins - chemistry
RNA-Binding Proteins - metabolism
Spectrometry, Mass, Electrospray Ionization
Vertebrates - genetics
Vertebrates - metabolism
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Summary:Bile salts, the major end metabolites of cholesterol, vary significantly in structure across vertebrate species, suggesting that nuclear receptors binding these molecules may show adaptive evolutionary changes. We compared across species the bile salt specificity of the major transcriptional regulator of bile salt synthesis, the farnesoid X receptor (FXR). We found that FXRs have changed specificity for primary bile salts across species by altering the shape and size of the ligand binding pocket. In particular, the ligand binding pockets of sea lamprey (Petromyzon marinus) and zebrafish (Danio rerio) FXRs, as predicted by homology models, are flat and ideal for binding planar, evolutionarily early bile alcohols. In contrast, human FXR has a curved binding pocket best suited for the bent steroid ring configuration typical of evolutionarily more recent bile acids. We also found that the putative FXR from the sea squirt Ciona intestinalis, a chordate invertebrate, was completely insensitive to activation by bile salts but was activated by sulfated pregnane steroids, suggesting that the endogenous ligands of this receptor may be steroidal in nature. Our observations present an integrated picture of the coevolution of bile salt structure and of the binding pocket of their target nuclear receptor FXR.
ISSN:0022-2275
1539-7262
DOI:10.1194/jlr.m800138-jlr200