Ligand specificity and evolution of liver X receptors

Abstract

Liver X receptors (LXRs) are key regulators of lipid and cholesterol metabolism in mammals. Little is known, however, about the function and evolution of LXRs in non-mammalian species. The present study reports the cloning of LXRs from African clawed frog (Xenopus laevis), Western clawed frog (Xenopus tropicalis), and zebrafish (Danio rerio), and their functional characterization and comparison with human and mouse LXRs. Additionally, an ortholog of LXR in the chordate invertebrate Ciona intestinalis was cloned and functionally characterized. Ligand specificities of the frog and zebrafish LXRs were very similar to LXRα and LXRβ from human and mouse. All vertebrate LXRs studied were activated robustly by the synthetic ligands T-0901317 and GW3965 and by a variety of oxysterols. In contrast, Ciona LXR was not activated by T-0901317 or GW3965 but was activated by a limited number of oxysterols, as well as some androstane and pregnane steroids. Pharmacophore analysis, homology modeling, and docking studies of Ciona LXR predict a receptor with a more restricted ligand-binding pocket and less intrinsic disorder in the ligand-binding domain compared to vertebrate LXRs. The results suggest that LXRs have a long evolutionary history, with vertebrate LXRs diverging from invertebrate LXRs in ligand specificity.

Evolution of the bile salt nuclear receptor FXR in vertebrates*

“…2C). This bile profile is quite similar to our prior analysis of biliary bile from Silurana tropicalis (Western clawed frog, also known as Xenopus tropicalis), a related frog species (40). GC-MS analysis (data not shown) showed that most of the bile salts from African clawed frog were in the 5b (A/B cis) orientation, with only a minor fraction (,10%) in the 5a orientation.…”

“…It is also worth noting that the variability of FXRs across vertebrate species contrasts markedly with the liver X receptors, closely related NHRs whose endogenous ligands are oxysterols (4). Liver X receptors a and b (NR1H3 and NR1H2, respectively) are much more highly conserved in sequence and pharmacology across vertebrates than FXRs (30,40).…”

Bile salts of vertebrates: structural variation and possible evolutionary significance

“…Amphibian species have some of the most complex biliary bile salt profi les found within vertebrates, with some species having signifi cant amounts of C 27, C 26 , C 28 , or other side chain length bile alcohols as well as C 27 bile acids and C 24 bile acids ( 9,22,(72)(73)(74). The complexity of anuran bile salt profi les makes it diffi cult to summarize patterns of variation.…”

Inhibition of cytochrome P4501-dependent clearance of the endogenous agonist FICZ as a mechanism for activation of the aryl hydrocarbon receptor

“…Moreover, FICZ is conjugated metabolically with sulfate, and such conjugates have been detected in human urine (3), further verifying the presence of the parent compound in vivo. In addition to its efficient activation of AHR signaling, FICZ appears to be a potent activator of signaling involving the liver X receptor or pregnane X receptor pathways (35,36). On the basis of such findings, we propose that FICZ should be added to the list of bioactive signaling substances derived from Trp that now includes serotonin, melatonin, and the plant growth hormone indole-3-acetic acid.…”