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Papers In Press, published online ahead of print July 1, 2008
J. Lipid Res., doi:10.1194/jlr.M800138-JLR200

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Journal of Lipid Research, Vol. 49, 1577-1587, July 2008
Copyright © 2008 by American Society for Biochemistry and Molecular Biology

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^1,*

^* Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261
Department of Pharmacology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854
Collaborations in Chemistry, Jenkintown, PA 19046
^** Department of Pharmaceutical Sciences, University of Maryland, Baltimore, MD 21202
Department of Medicine, University of California-San Diego, San Diego, CA 92093-0063

^* M.D.K. is supported by Grant K08 GM-074238 from the National Institutes of Health and the Competitive Medical Research Fund from the University of Pittsburgh Medical Center. W.J.W., S.E., and N.A. acknowledge support for this work provided by the Environmental Protection Agency-funded Environmental Bioinformatics and Computational Toxicology Center, under STAR Grant GAD R 832721-010 (this work has not been reviewed by and does not represent the opinions of the funding agency). A.F.H. and L.R.H. are supported by National Institutes of Health Grant DDK-64891 (to A.F.H.).

The online version of this article (available at http://www.jlr.org) contains supplementary data in the form of three figures and three tables.

Published, JLR Papers in Press, March 24, 2008.

¹ To whom correspondence should be addressed. e-mail: mdk24{at}pitt.edu

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.

Supplementary key words fishes • lampreys • lithocholic acid • molecular evolution • molecular models • nuclear hormone receptors • sequence homology • structure-activity relationship • Urochordata • farnesoid X receptor

Abbreviations: CDCA, chenodeoxycholic acid; FXR, farnesoid X receptor; LBD, ligand binding domain; LBP, ligand binding pocket; NHR, nuclear hormone receptor; PXR, pregnane X receptor; VDR, vitamin D receptor

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