1F. Retinoic acid-related orphans: Introduction

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The IUPHAR Compendium of the Pharmacology and Classification of the Nuclear Receptor Superfamily 2006 provides a useful general overview on nuclear hormone receptors. This volume is available online from Pharmacological Reviews. The following chapters from the compendium may be of interest for this particular set of receptors [4,17].

The retinoic acid-related orphan receptors alpha, beta, and gamma (RORα-γ or NR1F1-3) constitute a subfamily of nuclear receptors [28,30,73]. Each gene generates several isoforms that regulate different genes and biological processes. RORs function as ligand-dependent transcription factors that regulate the transcription of target genes by binding as monomers to ROR response elements (ROREs). Genome-wide mapping of cis-acting binding sites (cistrome) in liver and Th17 cells, identified the RORE consensus in vivo as well as genes directly regulated by RORα and/or RORγ, including several clock genes, glucose and lipid metabolic genes, and Th17 related genes [25,80,82,95].


ROR ligands

Initial crystallographic studies identified cholesterol and several of its analogs as RORα agonists [33-34] and several retinoids as inverse agonists of RORβ [76]. Studies realizing the potential of RORs antagonists in the management of autoimmune disease, metabolic syndrome, insulin resistance, and neuropsychiatric disorders [16,22-23,36,38,41,48,70,72,82,85,95-96] provided an incentive for many to identify novel ROR ligands. This led to the discovery of many ROR (ant)agonists of various chemical classes and include various oxysterols [31,91-92], other cholesterol-related compounds [96], vitamin D metabolites [71], derivatives of LXR agonist T0901317 [38-39,75], digoxin and its analogs [22], and a number of different sulfonamides [13,88]. A comprehensive summary on ROR ligands can be found in several recent reviews [13,38,45,73]. Recent studies demonstrated that intermediates of the cholesterol biosynthetic pathway can bind and regulate RORγ activity and function as endogenous ligands for RORγ and include desmosterol and its sulfate, and 4α-carboxy, 4β-methyl-zymosterol (4ACD8) [21,63].

Crystal structure analyses revealed that RORs contain a large ligand binding pocket (>700Å3) that can accommodate large ligands, such as cholesterol sulfate [31,34,63,73,76,91-92]. Analysis of ROR-agonist crystal structures further revealed that the H12 was in the active conformation thereby allowing co-activator interaction, whereas binding of inverse agonists inhibited this interaction. Certain inverse agonists were found to inhibit the binding of RORγ to ROREs, whereas the ability of RORγ to bind DNA target sites was mostly preserved with others [95]. ROR antagonists have been shown to inhibit the expression of a number of ROR target genes, including several clock genes, various glucose and lipid metabolic genes, and Th17 related genes [5,22,75,80-83,92-93,96-97].


RORγ Immune Functions

Early studies revealed that the RORγt isoform is critical for thymopoiesis and the development of secondary lymphoid organs, Peyer’s patches, and intestinal lymphoid follicles [37,40,78]. This was shown to be due to the absence of a subset of type 3 innate lymphoid cells (ILC3), referred to as lymphoid tissue inducer (LTi) cells [7,10,47]. Retinoic acid (RA) was found to control LTi cell maturation by directly regulating RORγt expression through the recruitment of RA receptors (RARs) to the promoter region of RORγt [87]. RORγt also regulates different subsets of ILC3s in the intestine [20,69]. Moreover, RORγt is essential for the differentiation of naïve T cells into Th17 cells, which have an important role in fighting bacterial and fungal infections and are implicated in several autoimmune diseases [8,24,29,55,95,97]. RORγt was shown to directly regulate the transcription of several Th17 marker genes, including Ilf17a, Il17f, Irf4, and Il23r [23,97-98,100]. Loss of RORγt expression in mice abolished the expression of many Th17 cytokines and protects against the development of several experimental autoimmune diseases as well as allergen-induced lung inflammation [24,84,97]. Inversely, overexpression of RORγt in mice induced a steroid-insensitive neutrophilic inflammation [3]. RORγ has also been reported to directly regulate the transcription of the L-phenylalanine oxidase IL41, which is involved in the control of TCR signaling [62].


RORα Immune Functions

RORα has a small role in Th17 differentiation [29,97], but is essential for the development and function of type 2 ILCs, which are implicated in immune defense and allergy-induced inflammation [18,61,90,94]. A role for RORα in the control of allergy-induced inflammation is supported by studies showing an association of RORA SNPs with increased susceptibility to asthma [49,51,60] and reduced Th2 cytokine production, airway hyper-reactivity, and allergic skin inflammation in RORα-deficient mice [18,27,61]. RORα has also been reported to regulate the diurnal expression of several pathogen recognition receptors, including Nod2 and the Toll-like receptors, TLR1-5 and TLR9, in the intestinal epithelium where it also directly regulates the diurnal expression of interleukin-1 receptor-associated kinase 1 (IRAK1) and Toll-interleukin 1 receptor domain containing adaptor protein (TIRAP), and several clock genes [53].


RORα/β Functions in Brain and Retina

Loss of RORα in Purkinje cells results in impairment of the hedgehog signaling pathway and cerebellar degeneration that leads to the development of a staggerer phenotype [19,77]. RORα has also been implicated in several neuropsychiatric disorders, including autism spectrum disorder [2,6,12,44,50,54]. Several genes directly regulated by RORα were found to be repressed in individuals with ASD [64-66]. It has been suggested that protecting brain cells from the damaging effects of injury and stress might be relevant to several brain disorders [32].

RORβ has a role in the regulation of circadian, motor and visual functions [30,68] and controls the cytoarchitectural patterning of neocortical neurons during mouse development [26]. GWAS studies observed a correlation between RORβ and verbal intelligence [11]. RORβ1 is critical for the differentiation of retinal progenitors into amacrine and horizontal interneurons [43]. This involves direct transcriptional regulation of Ptf1a by RORβ1. Both RORβ1 and -β2 directly regulate neural retina leucine zipper factor (NRL) [15]. In turn, NRL enhances the transcription of RORβ2. NRL and RORβ form two positive feedback loops that synergistically promote the commitment to a rod cell lineage.


ROR Functions in Metabolism

Both RORα and RORγ have been implicated in the regulation of metabolism and energy homeostasis [14,30,35,41-42,58-59,81-83,93]. RORα-deficient mice are less sensitive to developing metabolic syndrome when fed a high fat diet (HFD) as indicated by a reduced adiposity, inflammation, and hepatic steatosis, and improved insulin sensitivity [36,41]. RORα regulates Glut4 expression in skeletal muscle [14,41] and the hepatic expression of several genes involved in triglyceride synthesis, cholesterol metabolism, glucose and lipid homeostasis and inflammation [35-36,56-57,86,89,93]. ChIP and promoter analysis demonstrated that several of these genes are directly regulated by RORα. An RORα SNP was found to be associated with an increased risk for type 2 diabetes [16].

RORγ as well has a role in the regulation of glucose and lipid metabolism and insulin sensitivity [35,48,56,56,59,79,82-83,85]. Genome-wide cistromic profiling showed that in liver RORγ directly regulates the diurnal expression of a number of metabolic genes critical in the control of glycolysis and gluconeogenesis pathways, and lipid metabolism [82]. A role for RORγ in glucose homeostasis was supported by findings showing a positive correlation between the level of RORγ expression and insulin resistance [48,85].


RORs and Circadian Rhythm

Earlier studies provided evidence for a role of RORs in the regulation of circadian rhythm and clock gene expression [1,5,9,28,30,46,67,74,80-81]. RORγ exhibits a robust circadian pattern of expression that is under the direct control of the circadian clock [52,80]. RORγ regulates the diurnal expression of several glucose and lipid metabolic genes and insulin sensitivity downstream of the clock machinery [35,57,80,82-83]. Recently, RORγt was found to play also a role in the diurnal regulation of Th17 differentiation and TLR signaling [53,99].

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