LXRs are physiological regulators of cholesterol and

LXRs are physiological regulators of cholesterol and lipid metabolism and influence glucose metabolism. In addition, they have been shown to repress transcription of certain pro-inflammatory genes (Jakobsson et al., 2012; Ogawa et al., 2005; Terasaka et al., 2005). Thus, LXRs can either activate or repress gene expression (Joseph et al., 2003).
The farnesoid X receptor (FXR) FXR is a metabolic nuclear receptor mainly expressed in the liver, intestine, kidney and adrenal glands. The name “farnesoid X receptor” originates from its first identified ligand farnesol, an intermediate in the mevalonate biosynthetic pathway (Forman et al., 1995). Later on, the endogenous ligands for this receptor were identified to be bile acids, such as CDCA and CA, classifying FXR as nuclear bile Phusion high-fidelity DNA polymerase receptor (Makishima et al., 1999). There are two different FXR genes known, FXRα (NR1H4) and FXRβ (NR1H5), which exhibit a strong homology to each other. Both genes have been shown to encode for functional proteins in mice, rats, dogs and rabbits. In humans and primates, only FXRα encodes a functional protein, whereas FXRβ is a pseudogene. In mice, FXRβ is activated by lanosterol, an intermediate in cholesterol synthesis, and thought to be important in embryonal development and reproduction. Additionally, FXRβ seems to have overlapping functions with FXRα in mice (Otte et al., 2003). FXR is able to bind the response elements of target genes (FXRE) as monomer, homodimer or heterodimer with RXR as partner (Claudel et al., 2002). FXREs can contain an inverted repeat sequence (IR-1), direct repeats (DR-1) and everted repeats (ER-8) (Gadaleta et al., 2015). The FXR/RXR heterodimer is permissive, meaning it can be activated either by binding of an FXR ligand or an RXR ligand (Leblanc and Stunnenberg, 1995).
The retinoid X receptor (RXR) The nuclear receptor RXR is expressed in three different isoforms (NR2B1-3) (Auwerx et al., 1999). The genes of these isoforms are located on chromosome 9, 6 and 1 (bands q34.3, 21.3 and q22-q23, respectively) and are differentially expressed in different tissues (Almasan et al., 1994; Mangelsdorf et al., 1992). Interestingly, all RXR isoforms are mostly interchangeable in function and each cell expresses at least one isoform (Evans and Mangelsdorf, 2014). RXR forms heterodimers with other nuclear receptors, such as LXRα/β, FXR and PPARα/δ/γ but also with the thyroid hormone receptors (TRα/β) and the VDR. Although RXR as heterodimer partner of the thyroid hormone and vitamin D receptor remains silent (RXR ligands cannot activate these non-permissive receptors), RXR ligands can display a variety of biological functions by modulating permissive nuclear receptors, including LXR, FXR and the PPARs (Dawson and Xia, 2012; Evans and Mangelsdorf, 2014). Moreover, RXR is able to act as homodimer (Lefebvre et al., 2010) and to aggregate to homotetramers (Gilardi and Desvergne, 2014). The final expression pattern induced by an RXR ligand may vary depending on the protein abundance of RXR and respective heterodimer partners as well as coregulators in the respective tissue, the affinity of the heterodimer partner to RXR, the allosteric changes induced by the RXR ligand in the LBD and consequently the allosteric interaction with the heterodimer partner or coregulators, the promoter context, the target gene (Gilardi and Desvergne, 2014) and posttranslational modifications of the receptor (Dawson and Xia, 2012).
Conclusion and outlook Metabolic syndrome-related diseases, such as obesity and diabetes, have alarming prevalence worldwide and are therefore an important health concern (Levesque and Lamarche, 2008). Treatment options for patients suffering from such disorders have to be improved to combat this development. Natural products can either act as sources for new drugs on their own or as lead structures for drug discovery (Newman and Cragg, 2016). None of the natural products mentioned in this review are in clinical studies, but valuable pharmacological data are already available. To yield commercially relevant products, patentability is a crucial factor, which is often held against natural product research. However, improving the properties of promising natural products by chemical modification can overcome this hurdle. Interestingly, several of the mentioned natural products are food constituents, like taurine, quercetin, sesame oil, naringenin, xanthohumol, soy protein, phytanic acid, and oleanolic acid amongst others, and are therefore potential candidates for dietary interventions (Hernandez-Rodas et al., 2015). Moreover, nutrigenomics and precision nutrition is an emerging field, taking into account the genetic background and metabolic profile of patients and making dietary nuclear receptor ligands an interesting research field (Wang and Hu, 2018). One advantage of natural products, in particular plant extracts, as opposed to synthetic compounds is that they contain a variety of constituents that may complement each other and might therefore account for their broad spectrum efficacy. Moreover, in the context of nuclear receptors, some pure compounds might have the advantage to act – as their endogenous counterparts – as low affinity ligands and/or partial agonists as exemplified in this review. Thus, they might be an interesting source for the discovery of SNuRMs or act as part of the daily diet or phytopharmaceuticals as modulators of energy homeostasis and inflammation. It also has to be considered that, although several natural products show their effects on nuclear receptors in the mid to high μM range, these concentrations might be reachable locally e.g. in the gut after oral administration.