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The nuclear receptors (NRs) are a family of transcription factors which bind and respond to certain steroids and other signaling molecules, such as thyroid hormone, vitamin D3, retinoids, vitamins A and D. The NR family can also encode metabolic sensors for other cholesterol-related and diet-derived lipids. Recently years, newly recognized and more diverse signaling molecules such as phospholipids and heme have been shown to be ligands for some members. The idea of a ‘‘Nuclear Receptor’’ that can directly translate simple chemical changes into distinct physiologic effects persisted for several decades. However, the fundamental nature of this receptor, its means for recognizing specific chemical ligands, mode of interaction with the genome and mechanism for control of gene transcription are all beyond the limits of classic biochemical analysis.
The discovery of NRs superfamily
The isolation of the first complete steroid receptor cDNAs, the glucocorticoid and estrogen receptors, is transformative (Figure 1). Comparison of the sequences revealed a conserved evolutionary template. Moreover, it also permitted the delineation of the structural and functional features which foreshadowed the emergence of a nuclear receptor superfamily. Importantly, access to the cDNAs enabled key experiments needed to test protein function, including mutagenesis of the receptor’s primary structure to evaluate the importance of specific amino acids and characterization of the nucleotide code within the target gene’s promoter which allows gene-specific expression. As a result of these early works, transcriptional regulation by hormone-receptor complexes was proved to be a fundamental process embedded in the circuitry of extracellular signal transduction through lipophilic endocrine hormones and vitamins. Because the associated small-molecule ligands were unknown, they garnered the name ‘‘orphan’’ receptors. Of further phylogenic significance, these orphan receptors were demonstrated to be conserved throughout metazoan evolution, although it should be noted that nuclear receptors are absent in protozoans, plants and fungi.
Figure 1. The discovery timeline of nuclear receptor
Transcriptional regulation by NRs
The spatial and temporal regulation of gene expression is an important way by which cells respond to physiological and environmental signals. DNA-binding transcription factors, non-DNA-binding coregulators, and the RNA polymerase II (Pol II) machinery are vital for mediating proper patterns of gene expression. NRs comprise a superfamily of ligand-regulated and DNA-binding transcription factors, which can both activate and repress gene expression. Transcriptional regulation through NRs is a multistep process including: (1) the association of NRs with regulatory sites in the genome in the context of chromatin, (2) the ligand-dependent recruitment and function of coregulators to modify chromatin and associated factors, (3) the regulation of Pol II binding and activity at target promoters, and (4) the attenuation or termination of NR-dependent signaling (Figure 2). The complexity of transcriptional regulation by NRs provides a lot of opportunities for exquisite regulatory control of signal-dependent transcriptional responses.
Figure 2. Transcriptional regulation by NRs.
NRs in physiology and therapeutics
• Steroid receptors
Through the action of two distinct estrogen receptor (ERs), ERα and ERβ, targeted ligands which compete with the natural estrogen 17β-estradiol (E2) exert a remarkable set of influences on the growth, differentiation, and maintenance of many reproductive tissues as well as the heart, liver and bone. As a result, ER targeting has been promising for therapeutic purposes such as treating breast cancer, cardiovascular disease, obesity, osteoporosis, as well as disorders of the central nervous system and immunity. Additional steroid receptors, such as the androgen receptor (AR), the glucocorticoid receptor (GR), the mineralocorticoid receptor (MR) and the progesterone receptor (PR), have also been intensely studied as drug targets.
Thyroid hormone receptor (TR), through a pair of endogenous ligands, triiodothyronine (T3) and thyronine (T4), regulates development and a wide variety of critical cellular functions including basal metabolic rate and metabolism of fat, protein and carbohydrate. The most common thyroid endocrine disorders include hyperthyroidism (e.g., Graves’s disease) and hypothyroidism (e.g., Hashimoto’s disease). More recent efforts at developing TR targeting have focused on lowering LDL levels, triglycerides and cholesterol from serum. As therapeutic molecules, TR agonists are potentially promising in promoting fat loss, preventing atherosclerosis and treating diabetes. However, a major goal of TR-targeting efforts is to minimize the undesired effects of thyroid hormone mimetics on the heart, muscle and bone.
Cholesterol is an essential component of living cells and its membrane is a necessary precursor for all steroid and bile acid production. But excessive levels of cholesterol also promote the development of atherosclerosis and other cardiovascular diseases. Transcriptional control of key cholesterol metabolic genes is mediated in part by two liver X receptor (LXR) isotypes, LXRα and LXRβ. The activation of LXRs by some ligands can lead to an altered reverse cholesterol transport and increase circulating high-density lipoprotein (HDL) levels, which are beneficial. And synthetic LXR agonists may prove promising for antiatherosclerotic effects, whereas the potentially adverse lipogenic effects could in theory be averted by receptor subtype selectivity.
Farnesoid X receptor (FXR) has emerged as a key modulator of many metabolic processes related to liver cholesterol and bile acid balance. Selective and potent FXR agonists, such as GW4064, 6-ECDCA and fexaramine, have been described. These compounds have allowed identification of a subset of FXR target genes implicated in cholesterol and bile acid homeostasis, suggesting an interrelationship between triglyceride metabolism, bile acid metabolism and insulin resistance. As such, FXR is a potential therapeutic target for diseases including liver and bile acid disorders, obesity and hyperlipidemia.
The family of PPARs is represented by the following three members: PPAR-α, PPAR-δ, and PPAR-γ. PPAR are involved in diverse independent and DNA-dependent molecular and enzymatic pathways in liver, adipose tissue and skeletal muscles. These pathways are affected by disease condition and lead to the metabolic energy imbalance. Therefore, the intervention of PPAR can provide therapeutic targets for plethora of diseases such as dyslipidemia, obesity, inflammation, diabetes, neurodegenerative disorder, and cancer. Evidence that PPARs may be interesting therapeutic targets to modulate obesity-induced inflammation has been reviewed.
An immediate implication that followed from the initial discovery of the receptors for the steroid and thyroid hormones and vitamins A and D was their potential as therapeutic targets. Indeed, drugs that target these receptors are among the most widely used and commercially successful. In fact, bexarotene and alitretinoin (RXRs), fibrates (PPARα), and thiazolidinediones (PPARγ) are already approved drugs for treating cancer, hyperlipidemia, and type 2 diabetes, respectively. Moreover, it is notable that FXR and LXR agonists are in development for treating nonalcoholic steatohepatitis and preventing atherosclerosis. Perhaps just as importantly, PXR is currently used routinely in the pharmaceutical industry to screen all new drug candidates for potentially dangerous drug-drug interactions.