Nuclear hormone receptors (NHRs) are transcription factors that work in concert with co-activators and co-repressors to regulate gene expression. Some examples of ligands for NHRs include endogenous c Show more
Nuclear hormone receptors (NHRs) are transcription factors that work in concert with co-activators and co-repressors to regulate gene expression. Some examples of ligands for NHRs include endogenous compounds such as bile acids, retinoids, steroid hormones, thyroid hormone, and vitamin D. This review describes the evolution of liver X receptors α and β (NR1H3 and 1H2, respectively), farnesoid X receptor (NR1H4), vitamin D receptor (NR1I1), pregnane X receptor (NR1I2), and constitutive androstane receptor (NR1I3). These NHRs participate in complex, overlapping transcriptional regulation networks involving cholesterol homeostasis and energy metabolism. Some of these receptors, particularly PXR and CAR, are promiscuous with respect to the structurally wide range of ligands that act as agonists. A combination of functional and computational analyses has shed light on the evolutionary changes of NR1H and NR1I receptors across vertebrates, and how these receptors may have diverged from ancestral receptors that first appeared in invertebrates. Show less
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 stu Show more
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 LXRalpha and LXRbeta 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. Show less