Jurnal Retinoid

Molecular and Cellular Endocrinology 491 (2019) 110436
Contents lists available at ScienceDirect
Molecular and Cellular Endocrinology

journal homepage: www.elsevier.com/locate/mce
Review
Alternative retinoid X receptor (RXR) ligands T

a,b,c,d,∗ e f
Wojciech Krężel , Ralph Rühl , Angel R. de Lera
a
Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
b
Centre National de la Recherche Scientifique, UMR 7104, Illkirch, France
c
Institut National de la Santé et de la Recherche Médicale, U 1258, Illkirch, France
d
Université de Strasbourg, Illkirch, France
e
Paprika Bioanalytics BT, Debrecen, Hungary
f
Departamento de Química Orgánica, Facultade de Química, Lagoas-Marcosende, 36310, Vigo, Spain
ARTICLE INFO ABSTRACT
Keywords: Retinoid X receptors (RXRs) control a wide variety of functions by virtue of their dimerization with other nuclear
Retinoid X receptor hormone receptors (NRs), contributing thereby to activities of different signaling pathways. We review known
Retinoids RXR ligands as transcriptional modulators of specific RXR-dimers and the associated biological processes. We
Polyunsaturated fatty acids also discuss the physiological relevance of such ligands, which remains frequently a matter of debate and which
DHA
at present is best met by member(s) of a novel family of retinoids, postulated as Vitamin A5. Through com-
Rexinoids
Evolution
parison with other natural, but also with synthetic ligands, we discuss high diversity in the modes of ligand
binding to RXRs resulting in agonistic or antagonistic profiles and selectivity towards specific subtypes of per-
missive heterodimers. Despite such diversity, direct ligand binding to the ligand binding pocket resulting in
agonistic activity was preferentially preserved in the course of animal evolution pointing to its functional re-
levance, and potential for existence of other, species-specific endogenous RXR ligands sharing the same mode of
function.
1. Introduction (Forman et al., 1995; Thompson et al., 1998), (ii) enhance activity in a
ligand-dependent manner of ligand-activated “conditional” partners
Retinoid X receptors discovered in the early 1990s (Leid et al., 1992; (RARs and in case of colon cancer or endothelial cells also VDR), here
Mangelsdorf et al., 1992) are nuclear hormone receptors (NRs) acting as not being able to induce NR/RXR activity on their own (Germain et al.,
transcription factors, which in mammals are represented by three iso- 2006a; Lin et al., 2016; Sanchez-Martinez et al., 2006), and (iii) induce
forms, RXRα, β, and γ (named also NR2B1, 2 and 3 (Germain et al., activity of “permissive” heterodimerization partners (PPARs, LXRs,
2006b). These are encoded by distinct genes (9q34.3, 6p21.1–3, 1q22- FXR, Nurr1, Nur77) upon binding of RXR ligand (Forman et al., 1995;
23, respectively) displaying different expression patterns (Dolle et al., Germain et al., 2006a; Giner et al., 2015). Importantly, RXR hetero-
1994; Krezel et al., 1999; Mori et al., 2001). RXRs are exceptional in the dimers with PPARs, LXRs, FXR can also be activated by respective li-
sense that they can act as homodimers, but also as obligatory hetero- gands of the RXR partner. On the other hand, RXR ligand remains the
dimerization partners for different types of NRs including: (i) classical only mean to activate heterodimers with orphan receptors or RXR
hormone receptors like thyroid receptors (TRα, β; NR1A1, 2), vitamin D homodimers (see Fig. 1). Such promiscuity of RXRs can be critical for
receptor (VDR; NR1I1) and retinoic acid receptors (RARα, β, γ; NR1B1, harmonized tuning of physiologic programs necessary for adaptive
2, 3), (ii) metabolite or drug sensor receptors such as peroxisome pro- process, but also re-adjustment of the transcriptional programs under
liferator activated receptors (PPARα, β/δ, γ; NR1C1, 2, 3), liver X re- pathological conditions, as reflected by clinical or experimental data for
ceptor (LXRα, β; NR1H2, 3), farnesoid X receptor (FXR; NR1H4), some RXR ligands discussed below. Knowledge on RXR architecture and
pregnane X receptor (PXR; N1I2) and (iii) orphan receptors like Nur77 its dynamics is essential for understanding of ligand binding mechan-
(NR4A1), Nurr1 (NR4A2) and constitutive androgen receptor (CAR; isms and their functional outcome. Here, we will first review RXR
NRI3). Hence RXRs bridge different signaling pathways whereby they structural data focusing much on those that are relevant for binding of
can: (i) act as “silent” partners of “non-permissive” NRs (TRs, VDR), different ligands. In contrast to previous reviews on RXRs and their
being insensitive to their own ligand in different biological settings ligands (named rexinoids) which focused much on structural biology,
∗
Corresponding author. Institut de Génétique et de Biologie Moléculaire et Cellulaire, 1 rue Laurent Fries, 67404, Illkirch Cedex, France.
E-mail address: krezel@igbmc.fr (W. Krężel).
https://doi.org/10.1016/j.mce.2019.04.016
Received 15 February 2019; Received in revised form 6 April 2019; Accepted 22 April 2019
Available online 23 April 2019
0303-7207/ © 2019 Elsevier B.V. All rights reserved.
W. Krężel, et al. Molecular and Cellular Endocrinology 491 (2019) 110436
modulators, which underlie pleiotropic activities of RXRs. Such mod-

ulators include ligands, which are the focus of this review, but also DNA
regulatory elements and post-translational modifications, as reviewed
elsewhere (Dawson and Xia, 2012), which determine recruitment of
cell-specific heterodimerization partners and co-regulators to control
the expression of the corresponding sets of target genes. In the absence
of the ligand, RXRs were reported to form tetramers (tRXR) (Kersten
et al., 1995). Whereas ligand or DNA binding was shown to dissociate
them (Chen et al., 1998), DNA-bound tetramers were also proposed to
antagonize transcriptional activation (Kersten et al., 1997). Analyses of
DNA binding patterns by RXRs in living cells suggested, however, that
in the absence of ligand stimulation, RXRs bind to DNA as homodimers
or heterodimers, possibly acting as inhibitors of transcription ready to
exchange their interaction partner upon ligand binding (Chatagnon
et al., 2015; Nielsen et al., 2008). Ligand binding induces a number of
conformational changes, which were first identified in isolated RXR
LBD. These initial crystallography studies revealed that the hydro-
phobic pocket formed by superposition of three helices (H3, H7, H11) is
connected through a hinge region with a hydrophobic channel formed
by H3 and H5 helices, forming the L-shaped LBD of RXRα (Egea et al.,
Fig. 1. RXR-ligand's ability to mediate transcriptional regulation of RXR-di- 2000) (Fig. 2).
mers. This structure of the ligand binding pocket is identical among all
three RXR isotypes (Egea et al., 2002). Importantly, ligand binding was
shown to induce repositioning of helix 12 next to helices H3/H5 to form
molecular functions and post-transcriptional modulation of RXR func-
the surface called activation function AF2, which by recruiting chro-
tions (Dawson and Xia, 2012), or modulation of metabolic receptors
matin modifiers, but also cofactors interacting directly with the tran-
(Hiebl et al., 2018), we will put particular emphasis on known en-
scriptional machinery, may either inhibit or activate transcription of
dogenous ligands and their metabolites. The physiological relevance of
target genes (Rosenfeld et al., 2006). AF2 formed by helices H3, H4,
such ligands will be discussed with its functional and nutritional per-
H11 and H12 (Fig. 2) of the ligand binding domain is thus the major
spectives. In particular, 9-cis-retinoic acid (9CRA), formerly widely
ligand-dependent activation domain in RXRs, whereas AF1, an addi-
accepted as the potential physiological RXR ligand, was found to be
tional activation function domain involved in recruitment of cofactors,
essentially undetectable under physiological conditions in vertebrates
is harbored by the N-terminal region which, due it is intrinsically un-
including human serum and tissue samples. We will review evidence
structured organization, is less prone to influences of conformational
indicating that 9-cis-13,14-dihydroretinoic acid (9CDHRA) meets
changes induced by ligand or DNA binding (reviewed in (Chambon,
probably best the criterion of a physiological ligand of RXRs. The
1996; Wurtz et al., 1996). Although AF1 is believed to act in an au-
physiological relevance of 9CDHRA is further supported by its central
tonomous manner in RXRs (Belorusova et al., 2016), it may also affect
role in the concept of vitamin A5, identified as a new class of vitamin A,
the efficiency and selectivity of gene expression as well as responses to
which may depend on a distinct set of nutritionally relevant precursors.
LBD-bound ligands in steroid NRs (Helsen and Claessens, 2014; Hilser
This does not exclude the possibility that other endogenous ligands
and Thompson, 2011; Yi et al., 2015). Thus, analyses of RXR structures
might also be physiologically and nutritionally relevant in specific cell
in the presence of AF1-interacting cofactors would be particularly in-
types or in some “challenging” conditions such as nutritional deficits of
teresting as such cofactors could not only locally structure the N-
specific micronutrients, as reviewed below. Characterization of the
terminal domain, but also make it sensitive to long-range structural
physiological relevance of any ligand remains both a conceptual and
technological challenge, which may require development of new ap-
proaches, as discussed below. Additional review of natural phyto-re-
xinoids, environmental pollutants and synthetic ligands highlights the
high diversity of their chemical structures, and thereby of possible
mechanisms of ligand binding and transcriptional regulatory activity.
Finally, despite such a diversity, studies of ancestral RXRs point to
particular evolutionary pressure to maintain ligand binding for these
receptors, and agonistic effect of such interaction. We will thus discuss
the potential physiological and nutritional relevance of endogenous
RXR ligand evolution. Characterization of such ligand(s), and their
genomic and functional effects, may help to define core, ancient RXR
functions and understand how ligand-dependent control of RXR func-
tions could provide evolutionary advantage.
2. The structure of retinoid X receptors
Similarly to other nuclear receptors, RXRs display a domain-like

organization with a variable N-terminal domain (NTD) followed by a
highly conserved DNA binding domain (DBD) connected by a hinge
region with the C-terminal ligand binding (LBD) domain. Although Fig. 2. Structure of the RXRα ligand binding domain in holo (ligand-bound)
isolated domains display intrinsic activities, such as DNA binding for conformation with marked in yellow 9-cis-13,14-dihydroretinoic acid (left) and
DBD or ligand binding for LBD, their interactions within the entire re- in its apo (without ligand) conformation (right). The AF2 domain interacting
ceptor are highly dynamic and are under control of multiple allosteric with coactivator (CoA) is formed by the helices indicated in red.
2
Fig. 3. Free DHA with individual examples of protectins (Protectin D1), resolvins (Resolvin D1) and maresins (Maresin 1, MarR1). Note that those families of DHA
metabolites and their bioactive intermediates are detected in vertebrates at variable levels depending on age, nutritional or pathological condition, and can be higher
than those of their precursor – DHA (Mas et al., 2012; Serhan et al., 2015).
rearrangements triggered by ligand or DNA binding. Indeed, more re- pathway(s) and availability of nutritional precursors, as in the case of
cent studies of RXR LBD and AF2 in the context of the entire receptor small bioactive molecules like retinoids. Although several endogenous
alone or with its heterodimerization partners and cofactor peptides, ligands were proposed for RXRs, their physiological relevance is under
brought into light long-range structural modifications induced by li- debate, since the presence of the ligand in the right place, at the right
gand binding and their critical implications for permissiveness of some time and at sufficient concentration to activate RXRs is not always met
RXR heterodimers to be activated by ligands of either partner in the and, in most cases, is unknown. Importantly, manipulation of nutri-
RXR heterodimer (Fig. 1). Data reported by Kojetin et al. (2015) in- tional precursors, relevant metabolic pathways or natural ligands pro-
dicate that RXR agonist-induced repositioning of RXR H12 into the vides a method for regulation of ligand bioavailability ranging from
active conformation can be further stabilized by H12 of PPARγ when deficiency through maintenance of physiological levels relevant for
the agonist conformation of the latter is induced by full PPARγ agonist. organismal homeostasis to supraphysiological levels. In the latter cases,
In contrast, heterodimerization of RXR with non-permissive TRβ de- referred to as supra-physiological conditions or nutritional interven-
stabilizes RXR LBD by rotating helix H11 and twisting H5, deforming tion, exogenous ligands or endogenous substances not acting as en-
the RXR LBD and impeding efficient ligand binding by RXR. Similarly, dogenous ligands, may become relevant for the control of biological
RXR ligand binding was shown to synergize with FXR ligand binding to processes in an RXR-dependent manner.
induce conformational change of helix H11 in FXR, thus stabilizing FXR
coactivator binding surface and coactivator binding (Wang et al.,
3.1. Fatty acids as potential endogenous and nutritionally regulated RXR
2018c). Much of our understanding of the ligand-dependent mechanism
ligands
of NR activation stems from studies of synthetic RXR ligands, also re-
viewed in this article. For example, structural analyses of Nurr1/RXR
Docosahexaenoic acid (DHA) and other free fatty acids (FFAs).
heterodimers with synthetic derivatives of the natural RXR ligand
Using bio-guided fractionation of brain-conditioned medium, de
honokiol (discussed below) revealed that designed biaryl-ligands can
Urquiza and colleagues (de Urquiza et al., 2000) identified a series of
compact the LBD, thus allowing the mobility of helix H7 and H11,
FFAs capable of inducing RXR transcriptional activation with different
which may be necessary to accommodate helix H12 of Nurr1, thereby
efficiencies. Using sensitive reporter assays in JEG-3 or 293T cultured
favoring the formation of Nurr1/RXRα heterodimers instead of RXRα
cells, DHA (Fig. 3) displayed the best transactivation activities starting
homodimers (Scheepstra et al., 2017). Intriguing also are the opposing
already at 10 μM (EC50 = 50 μM), whereas docosatetraenoic, oleic and
transcriptional effects of the natural RXR ligand bigelovin (see below
arachidonic acids required higher 100–1000 μM (EC50 > 200 μM)
for description) on enhancing transcription of PPARγ/RXRα hetero-
concentrations. Although other studies (Calderon and Kim, 2007;
dimers and inhibiting LXRα/RXRα heterodimers. Crystallography
Goldstein et al., 2003) confirmed the requirement of such relatively
analyses point to alteration of the conformation of helix H10, the core
high concentrations of DHA to induce transcription by RXR, Lengqvist
of the dimerization interface, as a potential mechanism (Zhang et al.,
et al. reported an EC50 value of 5–10 μM, by using a different method of
2011b).
DHA application in cultured cells, as well as mass spectrometry evi-
dence for DHA attaching/binding to RXRα-LBD (Lengqvist et al., 2004).
3. Natural ligands of RXRs and their potential physiological Direct interaction of DHA with LBD was also documented by crystal-
relevance lography data using RXRα-LBD (Egea et al., 2002).
There is a substantial amount of data supporting the activity of DHA
Before discussing different types of ligands, we need first to define via RXRs under pharmacological conditions, i.e. after DHA treatment or
concepts of natural vs endogenous and physiological ligands, which are its nutritional supplementations, e.g. in fish oil. In in vitro experiments,
frequently misused. We will thus consider as natural ligands all sub- treatment with DHA (free acid form), similarly to synthetic RXR ago-
stances present in Nature that bind with high potency (optimally in the nists (LG100268 or BMS649), increased the number of surviving neu-
nanomolar range) their receptors leading to conformational changes in rons in primary culture cells and such effect was RXR dependent since it
the receptor structure, and induce relevant physiological functions. was prevented in the presence of the RXR antagonist LG100268
Excluded are all man-made compounds generated de novo, which will (Wallen-Mackenzie et al., 2003). Importantly, this effect was Nurr1-
be referred to as synthetic ligands. Endogenous ligands, although fre- dependent, pointing to the functional relevance of Nurr1/RXR hetero-
quently dependent on natural precursors found in nutrition, are unique dimerization and to the possibility of controlling Nurr1-dependent
in a sense that they are produced in the body and do not need to be signaling via ligand-dependent activation of its RXR heterodimerization
introduced into the organism from outside to be detected. Such en- partner. DHA-dependent RXR activation, using BSA-complexed free
dogenous production is therefore dependent on dedicated metabolic acid form, was also shown to be indispensable for survival of cultured
3
rat photoreceptors during early phases of primary cultures or in re- Yamamoto, 2008).
sponse to oxidative stress (German et al., 2013). Accordingly, treatment The relevance of DHA in modulating RXR signaling needs also to be
with 6.7 μM DHA mimicked the neuroprotective activities of different considered in a context of other RXR endogenous ligands due to po-
synthetic RXR agonists (HX630 or PA024), whereas its effect was tential competitions or cross-talk between metabolic pathways involved
abolished in the presence of RXR antagonists (HX531 or PA452). The in the production of such ligands. For example, in vitamin A-deficient
same authors also demonstrated that the availability of DHA in its free animals, enhanced DHA production was observed (Zhou et al., 2006).
acid form was essential for such RXR-mediated neuroprotective activ- Although the mechanism of this regulation is not known, it may in-
ities, since a phospholipase A2 inhibitor preventing DHA release from volve, in addition to transcriptional regulation of DHA metabolic en-
its phospholipid derivatives (the major form of DHA in cells) prevented zymes, competition for enzymes or binding proteins which might be
the neuroprotective effects of DHA treatment. In addition to neuro- shared in the biogenesis and metabolism of those fatty acids. For ex-
protection, RXR signaling is also critical for DHA cognitive and affective ample, some retinol-binding proteins may bind with different effi-
activities in vivo. Thus, the beneficial effect of DHA treatment (free acid ciencies also to DHA (Tachikawa et al., 2018). This could suggest that
form) on spatial working memory performance was abolished in mice FFA and retinoid signaling may cooperate in controlling RXR signaling
with a null mutation of RXRγ or in wild-type mice pre-treated with an and that such control may involve transcriptional control and sharing of
RXR antagonist (Wietrzych-Schindler et al., 2011). A similar experi- some proteins involved in ligand metabolism and traffic. Such co-
mental strategy was used to demonstrate the implication of RXRγ in operation could possibly become biased towards one of the ligands in
anti-despair effects of DHA in the forced swim task (Wietrzych- specifically challenging situations, like the deficiency of selected mi-
Schindler et al., 2011), which may have a direct relevance for anti- cronutrient(s).
depressant activities of DHA and other ω-3 polyunsaturated fatty acids, In summary, there is a strong link between DHA and RXR-mediated
as reviewed elsewhere (Larrieu and Laye, 2018). Finally, there are a signaling, although a clear picture of how it operates in vivo is still
number of other functions that are modulated by DHA treatment, but missing. Although available data does not provide evidence for the
the involvement of RXRs in such functions awaits documentation. For physiological significance of direct DHA control of RXR signaling, such
example, DHA enhancement of antibody phagocytosis by microglial control has nutritional and pharmacological relevance. Importantly, the
cells (Hjorth et al., 2013) could potentially be mediated by RXRs, and DHA-dependent control of RXRs needs also to take into account diverse
Yamanaka et al. have shown that this process could be enhanced by metabolites of DHA, but the area remains so far mostly unexplored.
bexarotene (LGD1069), a synthetic RXR ligand (see below), in an RXRα Phytanic acid. Using bio-guided fractionation, Kitareewan et al.
dependent manner, since it was prevented in the presence of relevant (1996) identified phytanic acid as a natural agonist of RXRs (Fig. 4).
siRNAs (Yamanaka et al., 2012). Using a CRBPII-CAT reporter system in an epithelial cell line transfected
The role of RXRs in mediating the diverse effects of DHA under with RXRα, these authors demonstrated the phytanic acid-dependent
supra-physiological conditions (i.e., after treatment or nutritional in- transactivation of RXRα activities at 10 μM. Although phytanic acid
tervention) and the capability of vertebrates to synthesize DHA from α- competed with [3H]-9CRA for RXRα binding with a Ki of 4 μM, it re-
linolenic acid as precursor of plant origin (Rajaram, 2014), may suggest mained a 200-fold less efficient ligand than 9CRA. Activation of RXRα,
that DHA can act as a physiological ligand. However, such a role is β and γ isotypes, with EC50 of 20 μM, was also confirmed in a Gal4
questionable due to the likely limited availability of the free acid form. reporter assay (Zomer et al., 2000). As an important metabolite of
Although the determination of free DHA levels is not evident because of chlorophyll, phytanic acid can be produced in ruminating animals by
the multiple forms of DHA, its levels were reported to range from their rumen bacteria. Humans do not efficiently absorb chlorophyll and
0.1 μM to 0.01 μM in animal and human serum or tissue samples cannot metabolize it; thus, levels of phytanic acid in the human body
(Elabdeen et al., 2013; Szklenar et al., 2013). Such endogenous levels of are entirely dependent on meat and milk products ingested in the diet.
DHA would not be sufficient for transcriptional activation, which re- Consequently, phytanic acid cannot be considered as an endogenous
quires at best a concentration range of 5–10 μM (Lengqvist et al., 2004). ligand in humans, but may potentially act as such in ruminants. Fur-
Free DHA levels were not examined under conditions of nutritional or thermore, its low levels in human questions the physiological relevance
pharmacological interventions, and in particular no data are available
on its concentration in the nucleus; therefore, it is uncertain whether
such interventions really lead to sufficient increase of endogenous free
DHA levels to function as a ligand-dependent switch in the nucleus.
Moreover, central nervous system activities of DHA (including e.g.
promnemonic and antidepressant effects (see (Wietrzych-Schindler
et al., 2011) and references therein) might be also difficult to explain by
direct DHA-RXR interactions, since transfer of DHA through the blood-
brain-barrier is highly selective and of low efficacy for the free acid
form, whereas it might be easier for DHA metabolites or synthetic
acetyl derivatives (Lo Van et al., 2016; Picq et al., 2010). In this respect,
novel DHA metabolites that have been reported during recent years
might also be of interest. For example, a number of hydroxylated DHA
metabolites, including protectins, resolvins and maresins (Fig. 3), are
present endogenously in vertebrates including humans (Barden et al.,
2015, 2016; Mas et al., 2012). Different mechanisms have been pro-
posed to explain the numerous biological activities of these compounds,
though binding and transactivation of RXRs was rarely investigated
(Krishnamoorthy et al., 2010). Importantly, DHA metabolites display
anti-inflammatory and neuroprotective effects (Bazan, 2018; Serhan Fig. 4. 9-cis-retinoic acid and 9-cis-13,14 dihydroretinoic acid are shown for
et al., 2015), similar to those regulated by RXRs. Interestingly, protectin comparison with exogenous, nutritionally-relevant phytanic acid, which has
D1 (known also as neuroprotectin D1) down-regulated β-secretase-1 been drawn in a conformation that mimics a 9-cis-configuration, to underline its
(BACE1) with concomitant activation of the α-secretase ADAM1, which structural potential for RXR activation (A). Two apo-carotenoids acting as RXR
was attributed to activation of PPARγ (Zhao et al., 2011). Other po- antagonists are found mainly in processed food and can be detected in humans
tential DHA metabolites are also potent agonists of PPARγ (Itoh and (B).
4
of its activities as a nutritional RXR ligand. Thus, in human plasma 3.2.1. Retinoic acids
phytanic acid concentrations ranged around 1.6 μM, which was highly All-trans-retinoic acid (ATRA) is an undisputed endogenous and
dependent on dietary habits of healthy volunteers, with the highest physiological bona fide ligand of RARs (Allenby et al., 1993; Giguere
level (5.8 μM) found in meat eaters and the lowest in vegans (0.9 μM) et al., 1987). Indeed, it was shown to be produced in vertebrates from
(Al-Dirbashi et al., 2008; Allen et al., 2008). Phytanic acid levels ranged nutritional precursors and can be found in human and other vertebrates
around 1 μM in mouse plasma, but were approximatively 10–100 times at concentrations allowing efficient RAR binding and transactivation
lower in different tissues (Wanders et al., 2011). Such quantities were under physiological conditions (Allenby et al., 1993). Nutritional de-
increased to 10 μM levels under supplementation with high amounts of privation of ATRA precursors, which can be determined mainly as re-
phytol, a phytanic acid precursor (Wanders et al., 2011). Importantly, duced serum levels of ATRA/ATROL, lead to various abnormalities,
disruption of phytanol-CoA hydroxylase, the first enzyme in the α- which were observed in humans and extensively studied in rodents
oxidation in Refsum disease, leads to high accumulations of phytanic (Rhinn and Dolle, 2012; Wilson et al., 1953). Such abnormalities were
acid, which may reach up to 1000 times the level of a healthy person recapitulated by genetic inactivation of the two classes of retinoid re-
(Verhoeven and Jakobs, 2001), with highest levels found in the liver, ceptors, the RARs and the RXRs (Mark et al., 2009). In summary, ATRA
heart, adipose and peripheral nervous tissues, and much lower in the meets a global criterion of endogenous and physiological ligand of
brain (Cumings, 1971). Despite the wide range of symptoms, including RARs in vertebrates.
peripheral neuropathy, retinal degeneration and cerebellar ataxia (see The identification of the endogenous retinoid X receptor (RXR) li-
(Verhoeven and Jakobs, 2001) and references therein), no abnormal- gand was a bit more fragile, partly due to technical challenges in re-
ities relevant to general or even exacerbated RXR signaling were retinoid research (see below). Initially suggested as an endogenous ligand
ported like, for instance, decreased thyroid hormone T4 levels, elevated for RXRα (Heyman et al., 1992; Levin et al., 1992; Mangelsdorf et al.,
triglyceride levels or reduced food intake. This further questions the 1992), 9-cis-retinoic acid (9CRA, Fig. 4A) became quickly and widely
relevance of phytanic acid and potential phytanic acid metabolites as accepted as “the” natural RXR ligand (Desvergne, 2007; Evans and
RXR ligands. Implication of RXR activation in mediating effects of high Mangelsdorf, 2014; Kane, 2012; Kane et al., 2010). However, many
amounts of phytanic acid on glucose and lipid metabolism or adipocyte groups with expertise in the retinoid analysis area failed in detecting
differentiation (reviewed in (Roca-Saavedra et al., 2017)) is also not endogenous 9CRA in humans and other mammals (Blomhoff and
clear as such effects were not tested in competition with an RXR an- Blomhoff, 2006; Gundersen, 2006; Gundersen et al., 2007; Kane et al.,
tagonist or in mice/cells carrying null mutations for specific RXR iso- 2005, 2008, 2010; Rühl, 2006; Rühl et al., 2015; Schmidt et al., 2003;
types. Wongsiriroj et al., 2014) and partly questioned its endogenous ex-
In summary, RXR transactivation by phytanic acid starts at about istence as well as its physiological and nutritional significance (Kane
10 μM concentration, whereas physiological levels are on average et al., 2005, 2010; Rühl, 2006; Rühl et al., 2015). Just like in the ori-
around 1–6 μM concentration in plasma, which might be too low to ginal study (Heyman et al., 1992), 9CRA identification, secured only via
control RXR signaling under physiological conditions. With the excep- co-elution with a standard compound, was reported in animal models
tion of plasma, no data are available for human tissue levels. This led us only under supra-physiological conditions after administration of a high
to suggest that with the current knowledge, phytanic acid remains as a dosage of naturally-occurring retinoids (retinol or retinoic acids) or
nutritional RXR ligand candidate, but its physiological role in RXR after ingestion of food with high content of vitamin A derivatives
activation is uncertain. Further studies of its cell-type specificity and (Arnhold et al., 1996; Ulven et al., 2001). As a consequence, this led us
subcellular availability (including the nucleus), as well as potential to suggest that 9CRA is present in sufficient amounts for binding and
involvement of its metabolites in RXR-dependent signaling, should be activating the RXRs only after pharmacological or nutritional retinoid
encouraged. Finally, although its physiological role in humans is supplementation, but not under physiological conditions. Technological
questionable (or can be relevant under special conditions), it may play advances and use of highly sensitive MS-detectors made it possible to
an important role in ruminants where, in contrast to humans, phytanic detect low levels of 9CRA in the range of 0.03 to 0.003 nM (de Lera
acid may potentially act as an endogenous RXR ligand. This hypothesis et al., 2016; Kane et al., 2008), however such levels are not sufficient to
remains to be evaluated but, being the case, it could illustrate the modulate RXR signaling. Indeed, various transactivation assays in di-
variability in the type of endogenous RXR ligand as a function of nu- verse reporter cell lines showed that the minimal concentration of
tritional habitat, a determinant of available ligand precursors, which 9CRA required for RXR binding and initiation of transcriptional acti-
may differ between species (see also evolutionary considerations in this vation is in the range of 10–100 nM (Heyman et al., 1992; Levin et al.,
review). 1992; Rühl et al., 2015), thus excluding the possibility of 9CRA acting
as endogenous and physiological ligand (de Lera et al., 2016; Rühl
3.2. Retinoids and alternative carotenoid metabolites et al., 2015).
The difficulties in studying bioactive molecules, including retinoids,
Carotenoids, C40 isoprenoid pigments produced by plants or mi- may result not only from their low levels, but also from the type of
croorganisms, serve in animals as precursors for a number of bioactive equipment and the wide variety of additional molecules with similar
metabolites globally called apo-carotenoids (cleavage products of car- characteristics, which elute in the same area during chromatographic
otenoids). One of the best examples is apo-15′-carotenoic acid, better fractionation. Some of those may not even be detected by UV detectors,
known as all-trans-retinoic acid (ATRA) acting as “the” physiological often used in retinoid studies, due to the lack of conjugated double-
ligand of the RARs. In humans and other vertebrates it is formed by bond substructures. Use of highly sensitive MS detectors allows not only
central enzymatic cleavage of all-trans-β-carotene (ATBC, also called to detect weakly represented retinoids, but also to see those that cannot
pro-vitamin A1) originating from plants. ATRA, as well all-trans-retinol be sensed with UV detectors. This is especially true for 9CRA, as de-
(ATROL, known as vitamin A1), can be stored in the animal organism as scribed by one of our groups, with examples from an HPLC-MS-MS
esters (Blaner et al., 2016), which in turn can be a source of ready-to- methodology already in 2005 (Kane et al., 2010; Rühl, 2006; Rühl
use ATROL/ATRA once ingested in animals as food products. Recent et al., 2015). In particular, MS-MS detection allowed a better identifi-
published and unpublished data indicate the existence of other bioac- cation of other retinoids with similar structures, including 9-cis-13,14-
tive retinoids, including dihydroretinoids, some of which act as RXR dihydroretinoic acid (Fig. 4).
endogenous ligands, which are derived from different carotenoid pre-
cursors. In addition, alternative natural apo-carotenoids also display 3.2.2. The new hope - dihydroretinoids
activity in modulating the transcription of retinoid receptors (Harrison Recently our groups have identified the endogenous presence of 9-
and Quadro, 2018). cis-13,14-dihydroretinoic acid (9CDHRA, Fig. 4A) together with its all-
5
trans isomer, in several organs (liver, serum, brain) from mice through a activity by about 70%. Thus, the presence of β-apo-13-carotenone in
combined liquid chromatography–tandem mass spectrometry using UV human plasma at 3–5 nM concentrations could lead to active synergistic
analytical set-up and comparison with synthetic standard samples (Rühl suppression of RAR/RXR signaling by concomitant direct transcrip-
et al., 2015). The quantities measured in mouse serum (∼400 nM), tional inhibition of RARs and tetrameric sequestration of RXRα. Such
liver (∼450 nM) and brain (∼130 nM) were considered as sufficient for activity of β-apo-13-carotenone could be potentially deleterious; how-
direct interaction with RXRs and to maintain RXR-dependent activities. ever, it is not relevant for endogenous carotenoid signaling under
Accordingly, crystallography analyses revealed that 9CDHRA employs a physiological conditions, since β-apo-13-carotenone cannot be pro-
similar mode of binding to RXRα-LBD as 9CRA (Fig. 2), whereas the duced in mammals, and is instead generated by thermal degradation
affinity of such binding evaluated by fluorescence quenching assay was and oxidation of β-carotene during food processing, and otherwise is
90 ± 20 nM, which is very close to the Kd value of 20 ± 10 nM es- found only in few fresh fruits (Harrison and Quadro, 2018). Another
tablished for 9CRA (Chen et al., 1994). RXR transactivation activity study from the same group has also reported much lower (1 nM) levels
starting at about 100 nM was confirmed with a Gal4 reporter system in of β-apo-13-carotenone following chronic consumption of β-carotene-
Cos1 cells. Importantly, similarly to 9CRA or LG100268, 9CDHRA ac- enriched diets (Cooperstone et al., 2017). A similar scenario applies to
tivated transcription of several target genes of LXR/RXR, PPAR/RXR β-apo-14′-carotenal (Fig. 4B), another apo-carotenoid reported to act as
and RAR/RXR heterodimers in differentiating monocyte-derived a potential inhibitor of RXRα as well as of selected heterodimeric
human dendritic cells. The physiological relevance of 9CDHRA was partners (PPARα, PPARβ/δ, LXRα and LXRβ, but not RARs). This apo-
documented by deficits of spatial working memory associated with carotenoid can be found in several melons, but its detection in human
reduced levels of 9CDHRA in mice with a null mutation of Rbp1, a plasma was not consistent (Harrison and Quadro, 2018). It is therefore
protein potentially involved in the biogenesis of 9CDHRA. Importantly, unlikely that those apo-carotenoids are physiologically meaningful,
such deficits were rescued by 9CDHRA supplementation (Rühl et al., although in in vitro systems their inhibitory activities could explain the
2015). Additional functions of 9CDHRA related to RXR signaling are repression of Ap2/FABP4 and adiponectin transcription in 3T3-L1
currently under investigation. One of the key questions in such ongoing cultured adipocytes (Ziouzenkova et al., 2007).
studies is the nature and origin of metabolic precursors of 9CDHRA There is a high potential to identify additional bioactive apo-car-
(Rühl et al., 2018). It is not clear whether 9CDHRA is a new bioactive otenoids acting as RXR ligands, or maybe even as RAR ligands with
metabolite of ATROL (vitamin A1) and ATBC (pro-vitamin A1), or agonistic and/or antagonistic activity, considering the large diversity of
whether other dihydro-form(s) of retinol or carotenoids exist in vivo and the family of nutritionally-relevant carotenoids and the complex pat-
could play the role of such a precursor. Thus, if ATROL or ATBC act as tern of metabolic conversion in humans and animals (Bohn et al., 2017,
precursors of 9CDHRA, the latter could be considered as a new meta- 2019; Rodriguez-Concepcion et al., 2018). In this context, and based on
bolite of the vitamin A1 family. However, if 9CDHRA cannot be effi- the current knowledge, apo-carotenoic acids and apo-carotenals might
ciently generated from those precursors, being produced from other be of particular interest. Unfortunately, many pieces of the big picture
endogenous retinoid(s) like 9-cis-13,14-dihydroretinol and nu- are still missing to even draw limited conclusions. In addition, there are
tritionally relevant carotenoids like 9-cis-13,14-dihydro-β, β-carotene, several differences in carotenoid uptake and metabolism between
it could be considered as a founding member of a new class of vitamin mouse and human (Lee et al., 1999). Thus, whereas many studies have
A. In addition to vitamin A1 (ATROL) and vitamin A2 (3,4-didehy- focused on mice as an experimental model, just a limited number of
droretinol; for recent review see La Frano et al. (La Frano et al., 2018)) apo-carotenoids have been identified under physiological conditions
it would define a new class of vitamin A present in vertebrates meeting and after nutritional intervention in humans, whereas a limited number
a classical food-to-ligand concept of vitamins. Since the name of vi- of apo-carotenoids have been identified in the human food chain
tamin A3 was attributed to 3-hydroxyretinal present in arthropods (Eroglu et al., 2012; Harrison and Quadro, 2018; von Lintig, 2010). A
(Babino et al., 2016) and vitamin A4 to 4-hydroxyretinal found in clear picture of the functional cascade starting from food as source of
crustaceans (Goldsmith, 2013), we refer to this potential new class of carotenoids, the relevant concentrations of such carotenoids and their
vitamin A as vitamin A5. metabolites in human serum and tissues falling in the range for tran-
These studies highlight that documentation of the physiological scriptional RXR activation, is thus missing.
relevance of a ligand necessitates both the knowledge of RXR-related
functional markers and the availability of animal model(s) in which not 3.3. RXR ligands from traditional medical plants/products (phyto-
the receptor, but ligand availability, is compromised. Particularly pro- pharmacology)
mising for such studies are murine models with compromised activities
of enzymes or transport/chaperone proteins involved in ligand bio- Quite interestingly, a number of bioactive compounds isolated from
genesis or uptake. Thus, in order to further identify relevant metabolic traditional medicine sources were found to act as RXR ligands dis-
pathways and to understand whether 9CDHRA may act as ligand ful- playing different molecular and biological profiles.
filling the food-to-ligand concept, we hypothesized (Rühl et al., 2018) Honokiol (Fig. 5) was one of the first to be reported and probably
and are currently exploring the possibility of its endogenous synthesis the most extensively studied (Atanasov et al., 2013; Jung et al., 2010;
from nutritional precursors (Krezel et al., manuscript in preparation). Kotani et al., 2010, 2012). Using functional screens based on ABCA1
promoter-driven luciferase reporter, Jung et al. identified this natural
3.2.3. Alternative carotenoid metabolites product from an extract of Magnolia officinalis, as activator of ABCA1 in
A distinct ATBC derivative, β-apo-13-carotenone (Fig. 4B), has been glioma cells and of ABCA1, ABCG1 and apolipoprotein E (apoE) in THP-
recently demonstrated in model systems to compromise availability of 1 macrophages, and also of ABCA1 and ApoE in rat neuronal and as-
RXRα to form transcriptionally active dimers by stabilization of its trocyte primary cultures with EC50 ∼10 μM (Jung et al., 2010). Direct
tetrameric, inactive state (Sun et al., 2014b), leading as an end point to activation of LXR/RXRβ through RXRβ was proposed to mediate such
the inhibition of RXRα homodimer transcriptional activity on the DR1 transcriptional effects, based on the evidence of honokiol binding to
(“direct repeat 1” RA-response element)-containing RBP2 promoter RXRβ and the synergistic transcriptional activity of honokiol with pan-
(Eroglu et al., 2010). Its binding to RXRα was documented with a Ki of LXR agonist T0901317, but was independent from PPAR-signaling.
8 nM in a 9CRA competitive displacement assay, although in silico li- Such activities, confirmed by a parallel study, were functionally re-
gand docking analyses with RXRα-LBD suggested different modes of levant as honokiol reduced cholesterol efflux from macrophages (Kotani
binding (Sun et al., 2014b). Importantly, the same apo-carotenoid also et al., 2010). These effects may be highly cell-type and/or dose specific,
acts as a competitive inhibitor of RARs with a Ki of 4 nM (Eroglu et al., since in 3T3-L1 cells honokiol displayed only little or no transcriptional
2012). At equimolar concentration it reduces ATRA-RAR-mediated effect on similar transcriptional targets alone, but efficiently synergized
6
Fig. 5. Naturally-occurring RXR ligands from plants with phyto-pharmacological relevance.
with LXR selective ligands (Kotani et al., 2012). In contrast, it activated and rhein (Fig. 5), isolated from Chinese rhubarb Rheum palmatum,
in the same cells PPARγ/RXR signaling, with evidence of direct binding were reported to antagonize 9CRA in RXRα-LBD, Gal4-luciferase
and transcriptional activation of PPARγ as well as induction of glucose transactivation assays at relatively low concentrations, with IC50 values
uptake at low concentrations (1–10 μM) (Atanasov et al., 2013). of 10 and 70 μM, respectively (Zhang et al., 2011a, 2011d). Crystal-
Whereas the effects of honokiol on ApoE/ABCA1 expression and cho- lography studies revealed that through direct interactions with LBD,
lesterol metabolism and trafficking, and its anti-inflammatory activities leading to exacerbated displacement of H12 helix, antraquinones in-
(Rickert et al., 2018) might be of interest for the prevention of ather- duce the recruitment of SMRT (silencing mediator for retinoid and
osclerosis and Alzheimer's disease, the effects on glucose metabolism thyroid hormone receptors) corepressor and stabilize an inactive, tet-
were shown to be relevant for reduction of glucose levels and body rameric form of RXR making it inaccessible for formation of tran-
weight in a genetic mouse model of diabetes (Atanasov et al., 2013). It scriptionally functional homo- or heterodimers. As a consequence,
remains to be investigated whether anti-inflammatory, neuroprotective danthron and rhein inhibit RXR-mediated transactivation through RXR-
or antitumor activities of honokiol demonstrated more recently in an- homodimers, but also through heterodimers with FXR, LXR or PPARγ.
imal models of Alzheimer's or Parkinson's disease may also involve Although those ligands were suggested as potentially useful for the
direct RXR activation in addition to the proposed stimulation of PPARγ treatment of diabetes due to improvement of insulin tolerance in mouse
signaling (Chen et al., 2018; Wang et al., 2018b). Similar attention was models (Wang et al., 2018d; Zhang et al., 2011a, 2011d), the direct
paid to magnolol (Fig. 5), isolated from another extract from Magnolia involvement of RXRs in those activities is unlikely. In support of this
officinalis, which through crystallization and binding studies was shown assumption, respective treatments induced activation of some RXR
to bind RXRα and PPARγ with EC50 ∼40 μM and EC50 ∼2 μM, re- target genes like ABCA1 and ABCG1, which is opposite to what could be
spectively. The data might explain its preference for activation of expected from an RXR antagonist. An alternative mechanism, proposed
PPARγ/RXR transcription at EC50 ∼10 μM (Zhang et al., 2011c). to involve the action on AMPK signaling for danthron (Zhou et al.,
Drupanin (Fig. 5) was isolated from Brazilian green propolis (bee 2013) or the modulation of microbiota for rhein (Wang et al., 2018d),
glue), a resinous mixture that honey bees produce by mixing saliva and might be thus more relevant.
beeswax with additional exudates from Baccharis dracunculifolia (as Bigelovin (Fig. 5) is a sesquiterpene lactone isolated from the
aster family plant), here produced by Africanized honey-bees (Apis flowers of Inula helianthus-aquatica or Inula hupehensis, which are used
mellifera). It is a natural compound with selective, dual PPARγ/RXR in folk medicine for their anti-cancer virtues as confirmed also by some
agonistic profile in transactivation and binding assays (no binding to experimental studies (see for example anti-colon cancer (Li et al., 2018)
RARs, LXRs, VDR was observed) (Nakashima et al., 2014). This profile and anti-liver cancer (Wang et al., 2018a)). Although bigelovin binds to
was similar to that reported for magnolol, with the exception that RXRα-LBD (no binding was identified for LXRα, FXR or PPARγ), it
drupanin can bind with higher efficacy to all RXR isotypes displays very peculiar transcriptional activities since it transactivates
(EC50 = 2–7 μM) than to PPARγ (EC50 ∼15 μM). Consistent with the PPARγ/RXRα heterodimers, but fails to transactivate FXR/RXRα het-
activation of the PPARγ/RXR pathway, drupanin increased Ap2/FABP4 erodimers and suppresses RXR-homodimers or LXR/RXRα hetero-
expression and accelerated lipid accumulation in differentiated 3T3-L1 dimers on their respective response elements in the 1–10 μM con-
cells. centration range (Zhang et al., 2011b). Although the relevance of such
Prenylated flavonones. RXR agonistic activity was also identified specific transcriptional activities is not clear, crystallographic studies
for two prenylated flavonones (Fig. 5) isolated from Sophora tonkinensis indicated a specific mode of action of bigelovin binding to RXR-LBD,
(Inoue et al., 2014), a herb used in traditional Chinese medicine. They revealing that by ligand-mediated remodeling of LBD structure it may
could both bind similarly to all three RXR isotypes, at the nanomolar discriminate not only between RXR-homodimer and heterodimer in-
range, and did not bind or activate RARα, LXRα or PPARα, β/δ or γ. teractions, but also induce opposing activities of specific RXR hetero-
Transcriptional profiling for selected target transcripts revealed par- dimers.
tially overlapping to synthetic RXR-agonist bexarotene (LDG1069), but Valerenic acid. Recently, the screen of the Dictionary of Natural
also the necessity of at least one range higher concentration to induce Products based on isofunctional mimetics of structures of natural RXR
such activities. Importantly, either one or the other, or both flavonones, modulators allowed to identify valerenic acid (Fig. 5) as a novel RXR
induced expression of several transcripts known to be direct targets of agonist (Merk et al., 2018b). This sesquiterpenoid, isolated from Va-
RXR heterodimers with LXR, PPARβ/δ, PPARγ, but differentially or not leriana officinalis (a flowering plant mainly present in Europe and Asia),
at all induced by bexarotene. Involvement of such genes in lipogenesis showed agonistic activity in the micromolar range, which was reflected
(e.g. lipoprotein lipase), counteracting inflammation and being anti- in the efficient induction of the RXR transcription target genes ABCA1
oxidant (heme oxygenase-1) points to a different transcriptional spe- and ApoE. The Gal4-based reporter assays performed in HEK293T cells
cificity of prenylated flavonones and bexarotene, which highlights the revealed intriguing partial selectivity for RXRβ, since valerenic acid
potential biomedical interest of those flavonones. showed better EC50 (5 μM) and about 10-times higher transactivation of
Danthron and rhein. RXR antagonistic activity was observed for RXRβ as compared to RXRα (EC50 = 27 μM), and RXRγ
several naturally-occurring compounds. The anthraquinones danthron (EC50 = 43 μM). In addition, no activation of RARs, PPARs, LXRs, FXR,
7
CAR, VDR and PXR was observed. Molecular modeling studies sug- of 9-cis-retinoic acid. Compound LG100754 (Canan Koch et al., 1996) is
gested similar binding modes to RXRα and RXRβ as classical rexinoids transcriptionally neutral by itself, and functions as a competitive RXR
(Merk et al., 2018b). This first-in-class ligand with RXR-isotype se- antagonist in RXR homodimers, and as an agonist for PPARα/RXR
lectivity has stimulated further development of synthetic ligands (see heterodimers, but does not activate LXR/RXR, FXR/RXR, or Nurr77/
below). RXR heterodimers (Canan Koch et al., 1996). It inhibited transactiva-
tion in a concentration-dependent manner at low concentrations (IC50
4. Synthetic ligands 20 nM) and also antagonized transactivation of RXR homodimers by
rexinoid agonists LG100268 (Fig. 7A) or 9-cis-retinoic acid. Moreover,
The design of synthetic ligands was much instructed by the chemical LG100754 binding to RXRα did not affect the binding of the SRC-1 NR2
structures of endogenous ligands, the structure of RXR LBD and data on peptide to the RARα apo form (Sato et al., 2010b). Crystallography
ligand – LBD interactions. Inversely, challenging RXR LBD with such studies confirmed that LG100754 binding leads to stabilization of H12
ligands and millions of molecules in silico and in functional screens in an unfolded position typical for inactive RXR (Sato et al., 2010a,
followed by determination of their structure-activity relationship 2010b).
(SAR), and sometimes even crystal structure, was highly informative 9cUAB30 (Muccio et al., 1998) showed induction of apoptosis, re-
about: (i) flexibility of LBD in binding different compounds, (ii) how duction of proliferation and prevention of mammary cancer in rodent
such flexibility affects specificity of RXR dimerization with other nu- models, similarly to 9-cis-retinoic acid (Atigadda et al., 2003; Grubbs
clear receptors, and (iii) alternative modes of binding to RXRs. et al., 2006). National Cancer Institute clinical trials of 9cUAB30 as
Importantly, whereas some compounds like organotins can bind effi- cancer chemopreventive agent revealed no significant toxicity (Kolesar
ciently RXR LBD despite their small size and thanks to covalent bonds, et al., 2010), although hepatomegaly was observed in animal studies at
other compounds can bind in the proximity of LBD or at cofactor high doses (Kapetanovic et al., 2010).
binding hydrophobic surface of AF2. Collectively, such diverse modes AGN194204 appears to be the most potent and specific agonist re-
of interactions suggest a possibility of existence of alternative natural or ported (Vuligonda et al., 1996) with EC50 values ranging from 0.08 nM
endogenous ligands with such novel or yet unknown modes of inter- (RXRγ) to 0.8 nM (RXRβ). It also showed a potent hypoglycemic effect
action. in the db/db mouse model (genetically defective in leptin signaling),
perhaps due to the activation of the PPARγ/RXR or other hetero-
4.1. “Classical” ligands generated by mimetics of endogenous ligands dimeric-dependent pathways.
LG101506 was identified as a heterodimer-selective RXR modulator
Crystal structures of RXR-ligand complexes (Huang et al., 2014) (Leibowitz et al., 2006) that binds RXR with high affinity (Ki values of
have shown that RXR ligands hold or adopt frequently a bent structure 3.0 ± 0.8; 9.0 ± 1.7; 11.0 ± 3.6 nM for RXRα, β, and γ, respectively)
including a twisted polyene side-chain in order to bind to the L-shaped and was also characterized as a RXR homodimer partial agonist.
ligand-binding pocket of RXR (Egea et al., 2000). Thus, conformational LG101506 selectively activated PPARγ/RXR and PPARα/RXR (Haffner
flexibility and modular structure of 9CRA and 9CDHRA, and also cer- et al., 2004; Leibowitz et al., 2006), but not RARα/RXR, LXRα/RXR,
tain unsaturated fatty acids, allows them to bind both RAR and RXR by LXRβ/RXR or FXRα/RXR heterodimers (Michellys et al., 2003). When
optimal adaptation to (and filling of) the LBP. Rationally-designed re- administered daily at 30 mg/kg body weight to db/db mice, a model of
xinoid scaffolds making reference to these natural ligands, and called type 2 diabetes, this compound induced lowering of glucose levels.
therefore “classical”, usually contain three structural modules: the Preclinical studies have shown that LG101506 caused beneficial me-
carboxylic acid, a linker fragment allowing to achieve permanent or tabolic effects without inducing undesired hypertriglyceridemia or
induced skeletal twist and the hydrophobic carbo- or heterocyclic thyroid suppression and did not induce weight gain in rodents
terminal ring (see respectively red, blue and green domain in Fig. 6). (Leibowitz et al., 2006).
The linking unit is quite amenable to modifications, which ac-
cording to their chemical nature and functional groups can be divided 4.1.2. Group B. Benzoic acids with geminal diarylethene groups and
(Fig. 6) into 5 groups: A) polyenoic acids including 9-cis-locked com- analogues (Fig. 7B)
pounds, B) aryl rings connected by trigonal (Csp2) or tetrahedral (Csp3) LGD1069 (bexarotene, Targretin®) was found to bind RXR with high
carbon, C) biphenyl rings with ortho substituents, D) diarylamines, and affinity (Kd values of 14 ± 3; 21 ± 4; 29 ± 7 nM) and showed poor
E) fully condensed rings, such as dibenzodiazepines (Dominguez et al., binding affinity for the RAR isotypes (Kd > 1000 nM)(Boehm et al.,
2017). Comparison of these structures points to the high adaptability 1994, 1995; Lehmann et al., 1992). It has been approved for the
exhibited by the RXR LBD, which is also supported by the ligand-bound treatment of cutaneous T-cell lymphoma (CTCL) (Tanaka and De Luca,
crystal structure complexes (Huang et al., 2014). On line with the above 2009), although as observed with other rexinoids, the drawbacks as-
structural considerations, RXR antagonists usually contain certain sociated to the use of LGD1069 are the induction of hypothyroidism due
substituents attached to the central linker region (see arrows in Fig. 6) to antagonism of the TR receptor with ligand-activated RXR (Sherman
which, depending upon their overall size, fully or partially disrupt the et al., 1999), and hyperlipidemia and cutaneous toxicity as a result of
hydrophobic interactions that stabilize the agonist conformation of H12 residual RAR agonism. Bexarotene was found to activate Nurr1/RXR
(Egea et al., 2000). The functional transition from agonists to partial heterodimers, rescue dopamine neurons and restore behavioral func-
agonists/antagonists within a family of rexinoids by changes on the tions in a rat model of Parkinson's disease (McFarland et al., 2013).
length or bulk of these substituents is usually observed. The structural analogue LG100268 (Fig. 7B) was found to be even
Recent revisions and arbitrary classifications of the most important more RXR-specific (Kd of 3 nM for RXR subtypes; Kd > 1000 nM for
rexinoid scaffolds, for which comprehensive structural and functional RARs), with a binding affinity somewhat higher than LGD1069. This
information has been provided, can be consulted (Dominguez et al., compound gave 50% maximal activation at a concentration at least 10-
2017; Mendoza-Parra et al., 2015; Su et al., 2017; Wagner et al., 2017). fold lower than that of 9-cis-retinoic acid (Boehm et al., 1995). By ac-
Only an overview of the most potent and selective rexinoids will be tivation of RXR homodimers (Szeles et al., 2010) as indicated by tran-
described, with a particular emphasis on their structural diversity, scriptome profiling, LG100268 was able to induce a number of target
mode of binding to RXR, and activity on specific RXR homodimers and genes during differentiation of monocytes to dendritic cells or during
NR/RXR permissive heterodimers. osteoclast differentiation (Menendez-Gutierrez et al., 2015). LG100268
strongly activates the LXR/RXR (Faul et al., 2001) and the PPARγ/RXR
4.1.1. Group A. Polyenyl carboxylic acids (Fig. 7A) heterodimers (Cesario et al., 2001; Forman, 2002).
This group of rexinoids maintains part of the acyclic polyene chain Rexinoid LG101305 (Fig. 7B) was shown to suppress the
8
Fig. 6. Structures of the rationally-designed rexinoid classes organized in series collecting their structural diversity as the combination of building blocks with
hydrophobic features (green), linkers (blue) and polar motifs (red). Antagonist feature groups attached to the arrowed positions are shown.
transactivation of androgen receptor (AR) in a reporter gene assay (LBP) in two different conformations leading to the formation of hRXRα
(Chuang et al., 2005). tetramers that consist of activated (H12 in folded conformation) and
repressed (H12 in opened conformation) forms of hRXRα, thus ex-
4.1.3. Group C. o,o'-Disubstituted biaryl cinnamic acids (Fig. 7C) plaining potentially partial agonistic activity (Miyashita et al., 2019).
Sterically hindered compounds such as CD3254 were characterized PA024 was found to activate PPARγ/RXR and LXR/RXR hetero-
as selective RXR agonists (Pérez-Santín et al., 2009). The incorporation dimers, whereas alkoxy derivatives modified at the lipophilic region as
of O-alkyl substituents led to antagonist UVI3003 (Nahoum et al., in analogue 1 (Fig. 7D) led to selective activation of PPARγ/RXRα vs
2007), which showed no effect on the tetrameric state (Sun et al., LXRα/RXRα heterodimers (Ohsawa et al., 2010).
2014a). Analogs with shorter alkoxy side chains were found to act as XCT0135908 compound (discovered after screening of a chemical
partial agonists, and their crystal structures when bound to RXRα LBD library) selectively activated the Nurr1/RXR heterodimers in African
and co-activator peptide TIF2 NR2 revealed the structural reasons for green monkey CV-1 cells (Wallen-Mackenzie et al., 2003). As indicated
their activity (Nahoum et al., 2007; Pérez-Santín et al., 2009). above, Nurr1/RXR specific rexinoids might be of interest for the
treatment of neurodegenerative diseases (Parkinson's disease) (Wallen-
Mackenzie et al., 2003).
4.1.4. Group D. Benzoic acids substituted with N-aryl groups at C4
(Fig. 7D)
These analogues (Fig. 7D) were found to display a full range of re- 4.1.5. Group E. Benzofused locked poly(hetero)cyclic benzoic acids
xinoid ligand functions, including the differential modulation of RXR (Fig. 7E)
heterodimers (Takamatsu et al., 2008a, 2008b). NEt-4IB HX600 was shown to play a dual function in the regulation of re-
(EC50 = 169 nM), which showed a 50–60% efficacy towards all RXR tinoid receptor activities, acting as a RXR synergyst (rexinoid) or as a
subtypes in a luciferase reporter gene assay (Kawata et al., 2015), was RAR antagonist at low and high concentrations, respectively (Umemiya
characterized as a RXR partial agonist (Ohsawa et al., 2013) since it et al., 1997). Modeling studies indicated that HX600 occupied the
recruited both coactivators (CoA) and corepressors (CoR). Oral ad- RXRα LBP and maximized the cavity occupancy when anchored simi-
ministration of NEt-4IB to mice resulted in antidiabetic effects without larly to 9-cis-retinoic acid (Egea et al., 2000). Albeit a weak RXR ago-
the undesired side effects of full agonists. nist, HX600 was able to selectively activate NGFI-B/RXR (via an al-
CBt-PMN (Kakuta et al., 2012; Ohsawa et al., 2013) is a re- losteric effect) and Nurr1/RXR heterodimers (Morita et al., 2005).
presentative member of a class of ligands having reduced conforma- Modifications of the skeleton generated RXR antagonists (Kagechika
tional flexibility. In vitro, CBt-PMN activated selectively the PPARγ/ and Shudo, 2005), such as the nitroderivative HX531, which inhibited
RXRα and LXRα/RXRα heterodimers as a partial agonist both RXR transactivation and HL-60 cell differentiation mediated by
(EC50 = 143 nM, Emax = 75%), whereas in vivo (EC50 = 15 nM, RAR/RXR heterodimers, and transactivation of RARs induced by an
Emax = 67%) it showed beneficial effects (potent glucose-lowering, RAR agonist (Ebisawa et al., 1999). It also antagonized PPARγ/RXR,
improvement in insulin secretion and glucose tolerance) in type 2 but not the PPARα/RXR heterodimer. Thus, even in the case of per-
diabetes mice models (Kakuta et al., 2012). Interestingly, X-Ray struc- missive RXR heterodimers, some rexinoids appear to adopt formal
tures revealed that CBt-PMN could bind hRXRα ligand-binding pocket agonistic and antagonistic structures, depending upon the partner and/
9
Fig. 7. Structure of polyenyl rexinoids (A), rexinoids with geminal diarylethene units (B), rexinoids with biaryl cinnamic acid substructures (C), rexinoids with p-N-
aryl benzoic acids (D), and benzofused poly(hetero)cyclic rexinoids (E).
or related cofactors (Shulman et al., 2004). structural diversity and revealing novel modes of ligand-LBP interac-
Other rexinoids have been developed to also function as Nurr1/RXR tions. In this regard, computational search of a collection of commer-
heterodimer activators, with sterically constrained enantiomer 2 being cially available compounds (3.38 million) aimed to discover new RXR
the most potent of the series (Sundén et al., 2016). ligands revealed the agonistic activity of structurally novel RXR ligands,
such as 3, which showed micromolar potency and some moderate RXRβ
and RXRγ selectivity (Merk et al., 2018a).
4.1.6. Group F. Novel LBP-binding ligands (Fig. 8) In addition, screening the Dictionary of Natural Products based on
Structurally novel ligands have emerged from computer-aided isomimetics of natural RXR ligands led to identification of valerenic
screens (Katsila et al., 2016; Sliwoski et al., 2014), increasing the
10
Fig. 8. RXR modulators from virtual ligand screening and computational-based drug discovery (A), non-canonical RXR modulators (B), and ligands of environmental
relevance (C).
acid as new natural RXR ligand (Merk et al., 2018b) (see section on 2013).
natural ligands for detailed description). De novo design based on this Although the discovery of some of these new RXR ligands resulted
natural product afforded analogue 4, which showed 3-times enhanced from the evaluation of structurally diverse collections of natural pro-
activation of RXR as compared with valerenic acid and retaining some ducts and their metabolites, as well as commercial libraries, their re-
selectivity to RXRβ activation (Merk et al., 2018a). latively small structural diversity, easy adaptation to the LBP and, in
Structure-based virtual screening of RXRα LBP using a collection of most of the cases, their smaller size result in suboptimal occupancy of
1280 drugs approved by the FDA in different conformations into the the ligand binding cavity of RXR. However, some of the existing
LBP of the agonist- and antagonist-bound structures of RXRα afforded structural differences (see Fig. 8) are just an indication of the con-
several potential ligands. Statin drugs (which are inhibitors of sterol formational adaptability of RXR LBP to bind compounds with a variety
biosynthesis) were predicted to be RXRα antagonists, including pita- of skeletons (Dominguez et al., 2017). Synthetic and medicinal chemists
vastatin (and its bis-dihydrated derivative), fluvastatin and analogues are now capable of further developing these scaffolds in order to im-
(Xu et al., 2017). Rosiglitazone (as maleate) and domperidone behaved prove potency and selectivity.
as agonists only in the presence of 9-cis-retinoic acid, and therefore
enhanced the effect of the latter. Surface plasmon resonance experi- 4.2. Non-canonical modulators of RXR
ments indicated binding of these compounds to the purified RXRα-LBP
protein although Molecular Dynamics simulations suggested that pita- Other RXR modulators lack the carboxylic acid, such as the natural
vastatin and fluvastatin bind to the LBP, with very fast rates of asso- product honokiol (Fig. 5), and the positional isomer magnolol (Fig. 8B),
ciation and dissociation, and the hydroxyl groups do not make any which induced the transactivation of the PPARγ/RXRα heterodimer,
contact with residues of the LBD (Xu et al., 2017). but not that of the RXRα/RXRα homodimer (Park et al., 2011). The
Compound 5 (Fig. 8A) was discovered as a selective RXRα agonist crystal structure of the ligand-bound RXRα LBD revealed that the p-allyl
after a screening campaign of a 5000 compound library. It was found to phenol moiety of honokiol occupies the L-shaped arms of the LBD and
induce apoptosis of MCF-7 breast cancer cells and inhibit proliferation one of the phenol hydroxyl groups forms a hydrogen bond with Asn306
of HL-60 cells (Park et al., 2011). Although subsequent comprehensive on N-terminal helix H5. More recent Molecular Modeling and NMR
SAR studies carried out after docking of the lead structure suggested spectroscopy studies concluded that honokiol targets RXR at both sides
structural modification to improve binding efficiency (among them, the of the interface, acting on the coactivator side of the dynamic activation
presence of a carboxylic acid side chain), they did not reveal the function (AF2) or alternatively switches from one to the other side of
structural basis of the interaction with RXR (Conda-Sheridan et al., the interface. Rational design allowed to split the dual-binding
11
properties of the natural product honokiol, and led to compound 6 in cultured rat astrocytes, leading to cholesterol efflux (Chen et al.,
(Fig. 8B), a first-in-class modulator reported to inhibit co-activator 2011).
binding at the solvent-exposed side of AF2 (as confirmed by the X-Ray Organotins constitute a large group of tin compounds that are widely
structure) (Scheepstra et al., 2014). present in the environment since the 1960's due to their application in
Compound 7 is representative of a new RXR scaffold (Dawson et al., many agricultural and industrial processes like antifouling paints for
2009) that did not activate RARs or PPARγ. Docking experiments pro- ships and fishing nets (Appel, 2004; Fent, 1996). Tributyltin chloride
posed the stabilization of the complex by formation of the salt bridge of (Fig. 8C, TBT) is among the best-documented organotins for its action
the carboxylic acid of 7 with Arg316, and interactions of the indole on RXRs. Crystallography analyses revealed a very particular mode of
rings with Cys269 and Cys432, and the N-methyl group with hydro- binding to RXRα LBD. Despite the fact of its much smaller size than any
phobic residues (Dawson et al., 2009). other RXR ligand, but also absence of a carboxylate group with long
A VLS campaign using the coactivator binding site of the crystal aliphatic chain, it could bind RXRα-LBP with high, nanomolar affinity
structure of RXRα-CD3254-CoA peptide led to the discovery of the new through limited number of molecular interactions including covalent S-
antagonist 8 (Chen et al., 2014a), which offered some selectivity for Sn binding with C432 of helix H11 (Hiromori et al., 2015; le Maire
RXRα over other NRs, as well as for the RXR heterodimers (Chen et al., et al., 2009). Accordingly, tributyltin chloride induced transcriptional
2014a). Competition experiments with tritiated 9-cis-retinoic acid al- activity of PPARγ/RXR as well as LXR/RXR and NURR1/RXR hetero-
lowed to discard compound binding to the LBP and supported binding dimers (Germain et al., 2006b; Grun and Blumberg, 2006; Hiromori
of 8 to the coregulator binding site. Compound 8 inhibited AKT-de- et al., 2015). Such transcriptional activities were shown to be relevant
pendent activation in several cancer cell lines in the absence or pre- for control of aromatase gene expression (Nakanishi et al., 2005) and
sence of TNFα, and this effect might be related to its ability to induce were found to promote adipocyte differentiation at nanomolar con-
apoptosis through inhibition of the interaction of tRXRα with p85α centrations (Grun and Blumberg, 2006; Kanayama et al., 2005), and to
(Chen et al., 2014a). More recent studies have proven that the com- cause pseudohermaphroditic transformation in some gastropode fe-
pound sits in a coactivator-binding groove (Xu et al., 2016). males known as “imposex” leading to reproduction failure (Urushitani
Sulindac analogs with increased affinity for tRXRα have been de- et al., 2018).
signed (Zhou et al., 2010), in particular K-8012 (Fig. 8B). K-8012 Further analyses of environmental pollutants may lead to the
showed improved activity in the inhibition of the tRXRα-mediated PIK/ identification of additional RXR ligands as suggested by recent in silico
AKT signaling pathway. It was characterized as antagonist of RXRα in analyses of molecular interactions, which predict strong binding of
co-transfection assays, and in cell-based assays it was more potent than easily absorbed bisphenol PH to hPPARα, β, γ and hRXRα (Sharma
Sulindac in the induction of apoptosis and inhibition of the binding of et al., 2018). It is worrying that some of the most toxic bisphenol
tRXRα to the p85α regulatory subunit of PI3K (Chen et al., 2014b). analogues, bisphenol M and bisphenol AF, were also predicted to
Strikingly, it failed to displace tritiated 9-cis-retinoic acid from its strongly bind to hRXRβ and hRXRγ.
binding site, thus discarding the possibility of binding to the canonical
LBP. A time-resolved FRET RXRα coactivator peptide competition assay 5. Evolutionary considerations
showed that unlike 9-cis-retinoic acid, and similarly to Sulindac, K-8012
targets the hydrophobic receptor surface region near the entry and the To better understand the origins but also the functional relevance of
edge of the cognate LBP (Chen et al., 2014a), resulting in stabilization ligand-dependent regulation of RXRs in vertebrates, we need to travel
of the tetrameric conformation of RXRα with two homodimers packed in time a billion years backwards and look into the evolution of RXRs,
in a bottom-to-bottom manner. This might explain why K-8012 fails to their ligands and their functions. Phylogenetic analyses identified an
compete with the binding of 9-cis-retinoic acid but can still inhibit RXR ancestral gene in Placozoans (Baker, 2008; Srivastava et al., 2008)
cancer cell growth (Zhang et al., 2011d). and Cnidarians (Fuchs et al., 2014; Kostrouch et al., 1998), the simplest
multicellular organisms and most ancient animal lineages. In particular,
4.3. Environmentally relevant synthetic ligands Trichoplax adhaerens (an ameboid-like multicellular organism, a
member of Placozoans present in seawater) is the first organism in the
Discussing RXR ligands to which human and multiple animal spe- animal lineage to have a well-documented RXR orthologue, the TaRXR
cies are exposed in daily life, it is necessary to mention environmental (Baker, 2008; Srivastava et al., 2008). This RXR prototype was recently
pollutants. The group of compounds which may modulate RXR activ- shown to share a number of important structural and functional simi-
ities include phthalates, plasticizers, certain herbicides, organotins, larities with mammalian RXRs. First, it displayed high degree of
biocides, and pharmaceuticals. These have been extensively reviewed homology with RXRs from several species, which for human hRXRα
elsewhere (Rogers et al., 2013; Delfosse et al., 2014, 2015). In this re- attains 81% of homology for the DBD and 70% for the LBD (Novotny
view we will focus only on those that have been well documented to et al., 2017; Reitzel et al., 2018). This homology is functionally relevant
bind RXRs and modulate their activities (Fig. 8C). as DNA-binding motif specificity as revealed by protein binding mi-
Methoprene acid (MPA) is one of the very widely used pesticides for croarrays was conserved up to 85% as compared to hRXRα (Reitzel
mosquito control. It is a synthetic analogue of the juvenile hormone, et al., 2018). Similarly to human RXRs, TaRXR also bound with high
acting as its mimetic. It was originally identified as a transcriptional affinity 9CRA which modulated its transcriptional activity (Novotny
activator of RXR in a screen of synthetic and natural isoprenoid com- et al., 2017; Reitzel et al., 2018). Importantly, the possibility of ligand-
pounds (Harmon et al., 1995). MPA acts as a RXR-selective agonist, dependent TaRXR-mediated induction of an orthologue of vertebrate L-
without activation or binding to other nuclear receptors. The mode of malate-NADP+ oxidoreductase places this receptor and its ligand(s) as
MPA action involves direct binding of L-shaped LBD thanks to the key modulators of an ancestral Krebs cycle, a cornerstone of the evo-
flexibility of its polyene chain. It was documented by competition with lution of cellular metabolism and central regulator of different meta-
9CRA, but also Gal4-RXRα reporter assay and ultimately by crystal bolic pathways. Such an important function necessitates a high level of
structure of apo-RXRα-LBD with MPA (Svensson et al., 2003). It was precision in the control of TaRXR activities and might have exercised an
shown to induce transcription at RXR-specific CRBPII promoter through evolutionary pressure to limit the number of endogenous and/or phy-
all three isoptypes of RXRs with EC50 of 2 μM in insect and 20 μM in siological RXR ligands. Thus, ancestral TaRXR could have acted as the
mammalian cell lines. Whereas some preference for RXRγ over RXRα first high-affinity receptor for a limited number of ligand(s), with the
and RXRβ was observed in insect Schneider cells, only RXRβ responded main function to enhance global metabolic activity in environmentally
weakly in CV1 mammalian cell line (Harmon et al., 1995). Methopren, favorable conditions to produce energy (e.g. to ensure reproduction), or
a parent molecule of MPA, was reported to upregulate Abca1 and Abcg1 reduce energy production in unfavorable conditions (e.g. to avoid
12
exhaustion). Several arguments favor this hypothesis. Firstly, in con- particular, recent identification of ligands with novel modes of binding
trast to several other NRs acting as metabolic sensors and capable of outside the conventional ligand binding pocket should revive synthetic
binding different types of ligands (individually or even simultaneously) ligand-design studies. Although such data will have biomedical im-
in a large (> 1000 Å3) ligand binding pocket (Holzer et al., 2017), the plications, the question of the endogenous RXR ligand remains open as
RXR across different species has relatively well conserved small ligand 9CRA, widely accepted as endogenous and physiological ligand, is de-
binding pocket of about 400 Å3 in volume (Egea et al., 2000; Tocchini- tected in vertebrates only after pharmacological treatment or after
Valentini et al., 2009). Such small volume favors interactions with only nutritional intervention with high doses of retinoids, whereas in phy-
limited number of ligands, like 9CRA, which fills about 60% of this siological conditions 9CRA is either not detected or is found at very low
space assuring thereby a tight fit and specificity. Secondly, in addition levels, 10–100 fold below its range for RXR transactivation.
to conservation of the structure of the RXR LBD across a vast evolu- Free fatty acids, and in particular DHA, were proposed as en-
tionary distance (Tocchini-Valentini et al., 2009), its capacity to bind dogenous ligands of RXRs. However, here again an involvement of DHA
9CRA was conserved from the earliest metazoans (Reitzel et al., 2018), in control of RXR signaling under physiological conditions is still not
through mollusks (de Groot et al., 2005) or chordate-like amphioxus clear, since the endogenous concentration of DHA as free acid available
(Tocchini-Valentini et al., 2009), to Homo sapiens, documenting the for transcriptional activation of RXRs in the nucleus is unknown, and in
strong evolutionary pressure to conserve high-precision in binding the few reported cases of plasma levels in human or tissue levels in rodents,
same type of ligand(s). The exception would mostly be insect RXR or- such concentration is below the transactivation range. Data on tissue
thologues like ultraspiracle (USP) from Mecopterida (winged insects) levels in humans under basal conditions and after dietary stimuli are
and non-Mecopterida, which do not bind and are not activated by RXR not available. In turn, a larger array of fatty acid metabolites, including
ligands (Iwema et al., 2007) and can act as silent, non-permissive those from DHA, were reported to be present endogenously but again,
partners of the ecdysone receptor. The loss of ligand binding capacity not much knowledge is available on the potential overlap between RXR
emerged, however, relatively late during insect evolution as RXR or- transactivation properties and endogenous/nutritionally relevant
thologues from some primitive insects like Tribolium (beetles) (Iwema ranges.
et al., 2007) or Locusta migratoria (a grasshopper species) (Nowickyj In this context, identification of 9CDHRA as an endogenous and
et al., 2008; Palli et al., 2005) preserved potential to bind 9CRA. The physiologically relevant ligand of RXRs was an important step in un-
fact that TaRXR shows DNA-binding specificity mostly to a single half derstanding RXR signaling in vivo. Accordingly, this retinoid is present
site rather than to repeated sequences (Reitzel et al., 2018) also in- in mice and human at sufficient concentrations to activate RXR tran-
dicates that in Trichoplax adhaerens RXR was most probably acting as a scription and its absence in mice induces cognitive deficits associated
monomer, avoiding thus the influence of other signaling pathways in with deficient RXR signaling. Although at present 9CDHRA fulfills the
the control of global metabolic activity. best criteria for an endogenous ligand, there are still many questions to
The remaining question is, what is this mysterious ancestral ligand? be addressed, relating to its nutritional precursor(s), metabolic pathway
Was it produced in Trichoplax adhaerens from nutritional precursor(s) to (s), the biological functions it may control, and more generally its
act as endogenous ligand, or was it originally a nutritional ligand and bioavailability in health and disease. Importantly, determination of
organisms adopted it as “endogenous” through evolution of dedicated whether ATROL and ATBC are precursors of 9CDHRA or whether there
metabolic pathway(s)? Whereas 9CRA was certainly a very valuable are other precursors, will clarify the link with the known “canonical”
experimental ligand to document conservation and high-affinity vitamin A1 pathway. Addressing such questions may be useful for
binding properties of RXR ligand binding pocket across evolution, it better understanding the physiopathology of RXR-related diseases, and
does not seem to be a physiologically relevant ligand as it was detected to identify novel biomarkers and/or design pharmacological or nutri-
at moderate levels only in arthropod Locusta migratoria (Nowickyj et al., tional treatments and disease-prevention schemes.
2008; Palli et al., 2005), but not in other phyla or species. Thus, it is Among the unresolved challenges in RXR-ligand research is the
tempting to hypothesize that 9CDHRA, a physiological RXR ligand in physiological relevance for co-existence of alternative RXR ligands, like
vertebrates (Rühl et al., 2015), could be an ancestral retinoid and 9CDHRA, DHA and its metabolites or the nutritionally acquired phy-
prototypic ligand for RXRs. This possibility is supported by the identi- tanic acid. As discussed above, the relevance of one ligand may po-
fication of dihydroretinoids or their precursors in non-vertebrates tentially become evident in the absence of the other, as in case of
(Foster et al., 1993) and vertebrates (Aydemir et al., 2013; Moise et al., raising levels of DHA in vitamin A-deficient conditions. What is the
2004, 2007). Understanding the metabolic origin of 9CDHRA and its physiological meaning of it? Are the alternative ligands functionally
nutritional precursors will be the focus of future research, as they could redundant (at least as far as RXR signaling is concerned) or will they
be directly relevant to the diet of Trichoplax adhaerens. To address this activate different physiological programs that are best adapted to
theory, studies of representatives of ancestral organisms in the context homeostatic conditions or adaptation to environmental challenges?
of their endogenous habitats and food chain are necessary. The ob- Furthermore, such mutual regulations would imply a crosstalk between
tained data should provide insights into the interplay between genetic metabolic pathways involved in the biogenesis of such ligands.
and environmental constraints shaping ligand-receptor interactions Although such mechanisms may potentially involve transcriptional
with RXR as model NR. Of particular interest for such investigations, regulation and sharing of some transport proteins, this area of research
but also for the identification of new nutritionally or pharmacologic remains essentially unexplored and will require more holistic nutri-
valuable RXR ligands, might be the studies of micronutrient diversity in tional and analytical studies.
the oceans, the cradle of animal life (Markov et al., 2018). Finally, the difficulty in understanding the physiological relevance
of individual RXR endogenous ligands, but also their crosstalk, comes
6. Conclusions and future directions from the lack of cellular resolution in RXR-ligand studies. Similarly to a
high degree of cell-type specificity of transcriptomic profiles revealed
Since the initial identification of 9CRA as an agonist of RXR and the by single-cell genomic analyses, we could expect to dissect intra-vs
demonstration that RXR homo- and heterodimers can be modulated by intercellular diversity in ligand specificity and functions. This calls for
RXR ligands, much research has been performed to dissect their phy- development of new approaches that will allow to combine single-cell
siological and biological relevance, and the molecular mechanisms of metabolomics or nuclear identification of the ligand with single-cell
ligand-dependent RXR control. Investigation of natural and synthetic transcriptomic profiles.
RXR ligands have been very fruitful in revealing the high diversity of The biomedical relevance of RXR ligands was emphasized in many
ligand binding modes and the possibility of specific/selective activation studies on metabolic diseases, as several of the permissive RXR het-
of certain NR/RXR heterodimers to control biological functions. In erodimerization partners act as metabolic sensors. However, in recent
13
years the nervous system appears to be a promising but little explored N., 2016. Solution behavior of the intrinsically disordered N-terminal domain of re-
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Molecular and Cellular Endocrinology 491 (2019) 110436

Contents lists available at ScienceDirect

Molecular and Cellular Endocrinology

Alternative retinoid X receptor (RXR) ligands T

ARTICLE INFO ABSTRACT

modulators, which underlie pleiotropic activities of RXRs. Such mod-

2. The structure of retinoid X receptors

Similarly to other nuclear receptors, RXRs display a domain-like

Fig. 5. Naturally-occurring RXR ligands from plants with phyto-pharmacological relevance.

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