The evolution of farnesoid X, vitamin D, and pregnane X receptors: insights from the green-spotted pufferfish (Tetraodon nigriviridis) and other non-mammalian species

摘要

Background: The farnesoid X receptor (FXR), pregnane X receptor (PXR), and vitamin D receptor (VDR) are threeclosely related nuclear hormone receptors in the NR1H and 1I subfamilies that share the property of beingactivated by bile salts. Bile salts vary significantly in structure across vertebrate species, suggesting that receptorsbinding these molecules may show adaptive evolutionary changes in response. We have previously shown thatFXRs from the sea lamprey (Petromyzon marinus) and zebrafish (Danio rerio) are activated by planar bile alcoholsfound in these two species. In this report, we characterize FXR, PXR, and VDR from the green-spotted pufferfish(Tetraodon nigriviridis), an actinopterygian fish that unlike the zebrafish has a bile salt profile similar to humans. Weutilize homology modelling, docking, and pharmacophore studies to understand the structural features of theTetraodon receptors.Results: Tetraodon FXR has a ligand selectivity profile very similar to human FXR, with strong activation by thesynthetic ligand GW4064 and by the primary bile acid chenodeoxycholic acid. Homology modelling and dockingstudies suggest a ligand-binding pocket architecture more similar to human and rat FXRs than to lamprey orzebrafish FXRs. Tetraodon PXR was activated by a variety of bile acids and steroids, although not by the largersynthetic ligands that activate human PXR such as rifampicin. Homology modelling predicts a larger ligand-bindingcavity than zebrafish PXR. We also demonstrate that VDRs from the pufferfish and Japanese medaka were activatedby small secondary bile acids such as lithocholic acid, whereas the African clawed frog VDR was not.Conclusions: Our studies provide further evidence of the relationship between both FXR, PXR, and VDR ligandselectivity and cross-species variation in bile salt profiles. Zebrafish and green-spotted pufferfish provide a clearcontrast in having markedly different primary bile salt profiles (planar bile alcohols for zebrafish and sterically bentbile acids for the pufferfish) and receptor selectivity that matches these differences in endogenous ligands. Ourobservations to date present an integrated picture of the co-evolution of bile salt structure and changes in thebinding pockets of three nuclear hormone receptors across the species studied.