ERRs and cancers: effects on metabolism and on proliferation and migration capacities

ERRs are orphan members of the nuclear receptor superfamily which, at least for ERRα and ERRγ display important roles in the control of various metabolic processes. On other hand, correlations have been found between the expression of ERRα and γ and diverse parameters of tumor progression in human cancers. Whereas it is tempting to speculate that ERR receptors act in tumors through the regulation of metabolism, recent data have suggested that they also may directly regulate tumor proliferation and progression independently of their effects on metabolism. The two aspects of tumoral functions of ERR receptors are the purpose of the present review.     

Retinoid-related orphan receptor alpha and the regulation of lipid homeostasis

Many nuclear hormone receptors (NRs) control lipid, glucose and energy homeostasis in an organ specific manner. Concordantly, dysfunctional NR signalling results in metabolic disease. The Retinoic acid receptor-related orphan receptor alpha (RORα), a member of the NR1F subgroup, is expressed in metabolic tissues. Previous studies identified the role of this NR in dyslipidemia, apo-lipoprotein metabolism and atherosclerosis. Recent data is underscoring the significant role of this orphan NR in the regulation of phase I/II metabolism (bile acids, xenobiotics, steroids etc.), adiposity, insulin signalling, and glucose tolerance. Moreover, oxygenated sterols, have been demonstrated to function as native ligands and inverse agonists. This review focuses on the rapidly emerging and evolving role of RORα in the control of lipid and glucose homeostasis in major mass metabolic tissues. Article from the special issue orphan receptors.     

Farnesyl pyrophosphate is a novel transcriptional activator for a subset of nuclear hormone receptors

In silico docking of a chemical library with the ligand-binding domain of thyroid hormone nuclear receptor-beta (TRbeta) suggested that farnesyl pyrophosphate (FPP), a key intermediate in cholesterol synthesis and protein farnesylation, might function as an agonist. Surprisingly, addition of FPP to cells activated TR as well as the classical steroid hormone receptors but not peroxisome proliferative-activating receptors, farnesoid X receptor, liver X receptor, or several orphan nuclear receptors the ligands of which are unknown. FPP enhanced receptor-coactivator binding in vitro and in vivo, and elevation of FPP levels in cells by squalene synthetase or farnesyl transferase inhibitors leads to activation. The FPP effect was blocked by selective receptor antagonists, and in silico docking with 143 nuclear receptor ligand-binding domain structures revealed that FPP only docked with the agonist conformation of those receptors activated by FPP. Our results suggest that certain nuclear receptors maintain a common structural feature that may reflect an action of FPP on an ancient nuclear receptor or that FPP could function as a ligand for one of the many orphan nuclear receptors the ligands of which have not yet been identified. This finding also has potential interesting implications that may, in part, explain the pleotropic effects of statins as well as certain actions of farnesylation inhibitors in cells.     

Recent advances in the TR2 and TR4 orphan receptors of the nuclear receptor superfamily

The human testicular receptor 2 (TR2) and TR4 orphan receptors are two evolutionarily related proteins belonging to the nuclear receptor superfamily. Numerous TR2 and TR4 variants and homologs have been identified from different species, including vertebrates (e.g. human, murine, rabbit, fish, and amphibian) and invertebrates (e.g. Drosophila, sea urchin, and nematode) since TR2 was initially isolated over a decade ago. Specific tissue distribution, genomic organization, and chromosomal assignment of both orphan receptors have been investigated. In order to reveal the physiological functions played by both TR2 and TR4, upstream modulators of TR2 and TR4 gene expression, their downstream target gene regulation, feedback mechanisms, and differential modulation mediated by the recruitment of other nuclear receptors and coregulators have been investigated. Studies summarized in the present report have provided unexpected insights into the TR2 and TR4 functions in a variety of biological processes. The essential and difficult tasks of identifying orphan receptor ligands, agonist/antagonist assignment, their physiological functions, and mechanisms of action will continue to challenge nuclear receptor researchers in the future.     

Nuclear receptors and inflammatory diseases

It is well known that the steroid hormone glucocorticoid and its nuclear receptor regulate the inflammatory process, a crucial component in the pathophysiological process related to human diseases that include atherosclerosis, obesity and type II diabetes, inflammatory bowel disease, Alzheimer's disease, multiple sclerosis, and liver tumors. Growing evidence demonstrates that orphan and adopted orphan nuclear receptors, such as peroxisome proliferator-activated receptors, liver x receptors, the farnesoid x receptor, NR4As, retinoid x receptors, and the pregnane x receptor, regulate the inflammatory and metabolic profiles in a ligand-dependent or -independent manner in human and animal models. This review summarizes the regulatory roles of these nuclear receptors in the inflammatory process and the underlying mechanisms.     

Spermatogenesis and testis development are normal in mice lacking testicular orphan nuclear receptor 2

Early in vitro cell culture studies suggested that testicular orphan nuclear receptor 2 (TR2), a member of the nuclear receptor superfamily, may play important roles in the control of several pathways including retinoic acids, vitamin D, thyroid hormones, and ciliary neurotrophic factor. Here we report the surprising results showing that mice lacking TR2 are viable and have no serious developmental defects. Male mice lacking TR2 have functional testes, including normal sperm number and motility, and both male and female mice lacking TR2 are fertile. In heterozygous TR2(+/-) male mice we found that beta-galactosidase, the indicator of TR2 protein expression, was first detected at the age of 3 weeks and its expression pattern was restricted mainly in the spermatocytes and round spermatids. These protein expression patterns were further confirmed with Northern blot analysis of TR2 mRNA expression. Together, results from TR2-knockout mice suggest that TR2 may not play essential roles in spermatogenesis and normal testis development, function, and maintenance. Alternatively, the roles of TR2 may be redundant and could be played by other close members of the nuclear receptor superfamily such as testicular orphan receptor 4 (TR4) or unidentified orphan receptors that share many similar functions with TR2. Further studies with double knockouts of both orphan nuclear receptors, TR2 and TR4, may reveal their real physiological roles.     

Liver X receptors, lipids and their reproductive secrets in the male

Liver X receptor (LXR) α and LXRβ belong to the nuclear receptor superfamily. For many years, they have been called orphan receptors, as no natural ligand was identified. In the last decade, the LXR natural ligands have been shown to be oxysterols, molecules derived from cholesterol. While these nuclear receptors have been abundantly studied for their roles in the regulation of lipid metabolism, it appears that they also present crucial activities in reproductive organs such as testis and epididymis, as well as prostate. Phenotypic analyses of mice lacking LXRs (lxr−/−) pointed out their physiological activities in the various cells and organs regulating reproductive functions. This review summarizes the impact of LXR-deficiency in male reproduction, highlighting the novel information coming from the phenotypic analyses of lxrα−/−, lxrβ−/− and lxrα;β−/− mice. This article is part of a Special Issue entitled: Translating nuclear receptor from health to disease.     

Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease

Orphan nuclear receptors, in a manner comparable to classic steroid hormone receptors, regulate key developmental and physiological processes. However, the lack of appropriate pharmacological tools has often hindered the identification and study of their biological functions. In this review, we demonstrate that functional and physiological genomics are effective alternatives to discover biological functions associated with orphan nuclear receptors. Indeed, we document that these approaches have allowed for the unambiguous identification of the estrogen-related receptors (ERRs) α, β, and γ (NR3B1, 2, and 3) as global regulators of cellular energy metabolism. We further show that although the three ERR isoforms control analogous gene networks, each isoform performs unique biological functions in a tissue-specific manner in response to a variety of physiological stressors. Finally, we discuss how the activity of the three ERR isoforms contributes to the development and progression of metabolic diseases as well as to the adaptation of cancer cells to their unique bioenergetic requirement. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.     

The mammalian orphan nuclear receptors: orphans as cellular guardians

In classical endocrinology, receptors are molecules that bind a hormone or a ligand to transduce signal within a target cell. Later, however, many intracellular receptors have been discovered in mammals, which have not been shown to bind endogenous ligands and are now are referred as "orphan receptors." The orphan receptors share high degree of structural and functional homology with the classical nuclear receptors (NRs) and are now part of the NR superfamily and therefore referred as orphan nuclear receptors (ONRs). Interestingly, however, ONR members are not evolutionarily or functionally linked and they form a highly diverse group within the NR superfamily. In mammals, ONRs exhibit great functional diversity and majority of them are expressed in a tissue-specific fashion. In the past one decade, functional studies have revealed that they are mediators of multitude of crucial metabolic, developmental, reproductive, and immunological functions in mammals. Emerging studies also indicate the role of ONRs in the onset of several complex human diseases and hence they may be potential candidates for therapeutic drug targeting in the future.     

Induction of cell cycle arrest and morphological differentiation by Nurr1 and retinoids in dopamine MN9D cells.

Dopamine cells are generated in the ventral midbrain during embryonic development. The progressive degeneration of these cells in patients with Parkinson's disease, and the potential therapeutic benefit by transplantation of in vitro generated dopamine cells, has triggered intense interest in understanding the process whereby these cells develop. Nurr1 is an orphan nuclear receptor essential for the development of midbrain dopaminergic neurons. However, the mechanism by which Nurr1 promotes dopamine cell differentiation has remained unknown. In this study we have used a dopamine-synthesizing cell line (MN9D) with immature characteristics to analyze the function of Nurr1 in dopamine cell development. The results demonstrate that Nurr1 can induce cell cycle arrest and a highly differentiated cell morphology in these cells. These two functions were both mediated through a DNA binding-dependent mechanism that did not require Nurr1 interaction with the heterodimerization partner retinoid X receptor. However, retinoids can promote the differentiation of MN9D cells independently of Nurr1. Importantly, the closely related orphan receptors NGFI-B and Nor1 were also able to induce cell cycle arrest and differentiation. Thus, the growth inhibitory activities of the NGFI-B/Nurr1/Nor1 orphan receptors, along with their widespread expression patterns both during development and in the adult, suggest a more general role in control of cell proliferation in the developing embryo and in adult tissues.     

The mammalian orphan nuclear receptors: orphans as cellular guardians

In classical endocrinology, receptors are molecules that bind a hormone or a ligand to transduce signal within a target cell. Later, however, many intracellular receptors have been discovered in mammals, which have not been shown to bind endogenous ligands and are now are referred as “orphan receptors.” The orphan receptors share high degree of structural and functional homology with the classical nuclear receptors (NRs) and are now part of the NR superfamily and therefore referred as orphan nuclear receptors (ONRs). Interestingly, however, ONR members are not evolutionarily or functionally linked and they form a highly diverse group within the NR superfamily. In mammals, ONRs exhibit great functional diversity and majority of them are expressed in a tissue-specific fashion. In the past one decade, functional studies have revealed that they are mediators of multitude of crucial metabolic, developmental, reproductive, and immunological functions in mammals. Emerging studies also indicate the role of ONRs in the onset of several complex human diseases and hence they may be potential candidates for therapeutic drug targeting in the future.     

Is GPR39 the natural receptor of obestatin?

GPR39, an orphan receptor belonging to the family of G protein-coupled receptors, was originally reported to be the receptor of obestatin. However recently, numerous reports have questioned this conclusion. In mammals, GPR39 was reported to be involved in the regulation of gastrointestinal and the metabolic functions. In this article, a latest and brief review on the receptor family, structure, distribution and physiological functions of GPR39 has been reported.