Evolution of the bile salt nuclear receptor FXR in vertebrates

Erica J Reschly; Ni Ai; Sean Ekins; William J Welsh; Lee R Hagey; Alan F Hofmann; Matthew D Krasowski

doi:10.1194/jlr.M800138-JLR200

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Evolution of the bile salt nuclear receptor FXR in vertebrates

Journal article

Open access

Peer reviewed

Evolution of the bile salt nuclear receptor FXR in vertebrates

Erica J Reschly, Ni Ai, Sean Ekins, William J Welsh, Lee R Hagey, Alan F Hofmann and Matthew D Krasowski

Journal of lipid research, Vol.49(7), pp.1577-1587

07/2008

DOI: 10.1194/jlr.M800138-JLR200

PMCID: PMC2431107

PMID: 18362391

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Abstract

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.

Cell Line

Vertebrates - genetics

RNA-Binding Proteins - chemistry

Bile Acids and Salts - chemistry

Models, Molecular

Bile Acids and Salts - metabolism

Crystallography, X-Ray

Animals

Spectrometry, Mass, Electrospray Ionization

Cattle

Ligands

Molecular Structure

Vertebrates - metabolism

RNA-Binding Proteins - metabolism

Evolution, Molecular

Details

Title: Subtitle: Evolution of the bile salt nuclear receptor FXR in vertebrates
Creators: Erica J Reschly - Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA
Ni Ai
Sean Ekins
William J Welsh
Lee R Hagey
Alan F Hofmann
Matthew D Krasowski
Resource Type: Journal article
Publication Details: Journal of lipid research, Vol.49(7), pp.1577-1587
DOI: 10.1194/jlr.M800138-JLR200
PMID: 18362391
PMCID: PMC2431107
NLM abbreviation: J Lipid Res
ISSN: 0022-2275
eISSN: 1539-7262
Publisher: United States
Grant note: K08 GM-074238 / NIGMS NIH HHS K08 GM074238 / NIGMS NIH HHS DDK-64891 / PHS HHS
Language: English
Date published: 07/2008
Academic Unit: Pathology
Record Identifier: 9984047768102771

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