Evolution of promiscuous nuclear hormone receptors: LXR, FXR, VDR, PXR, and CAR.
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.
Krasowski
Matthew D
MD
Department of Pathology, University of Iowa Hospitals and Clinics, RCP 6233, 200 Hawkins Drive, Iowa City, IA 52242, USA. mkrasows@healthcare.uiowa.edu
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Hagey
Lee R
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Ekins
Sean
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D000818:Animals; D001647:Bile Acids and Salts / Q000737:chemistry / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D004734:Energy Metabolism; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D012739:Gonadal Steroid Hormones / Q000737:chemistry / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007448:Invertebrates; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors / Q000235:genetics* / Q000378:metabolism; D010802:Phylogeny; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D011987:Receptors, Steroid / Q000235:genetics* / Q000378:metabolism; D012176:Retinoids / Q000737:chemistry / Q000378:metabolism; D012680:Sensitivity and Specificity; D013963:Thyroid Hormones / Q000737:chemistry / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014714:Vertebrates; D014807:Vitamin D / Q000737:chemistry / Q000378:metabolism; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D002784:Cholesterol; D000090702:Constitutive Androstane Receptor; D012739:Gonadal Steroid Hormones; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D012176:Retinoids; D013963:Thyroid Hormones; D014157:Transcription Factors; D014807:Vitamin D; D000099150:Receptor, Farnesoid X-Activated; C000605213:NR1H3 protein, human; C000625852:NR1I2 protein, human; C000716327:NR1I3 protein, human