BBA - Molecular Basis of Disease (v.1812, #8)
Editorial Board (i).
Preface: A special issue on nuclear receptors with a special view on the molecular basis of disease by Antonio Moschetta (807).
Discovery-driven research and bioinformatics in nuclear receptor and coregulator signaling by Neil J. McKenna (808-817).
Nuclear receptors (NRs) are a superfamily of ligand-regulated transcription factors that interact with coregulators and other transcription factors to direct tissue-specific programs of gene expression. Recent years have witnessed a rapid acceleration of the output of high-content data platforms in this field, generating discovery-driven datasets that have collectively described: the organization of the NR superfamily (phylogenomics); the expression patterns of NRs, coregulators and their target genes (transcriptomics); ligand- and tissue-specific functional NR and coregulator sites in DNA (cistromics); the organization of nuclear receptors and coregulators into higher order complexes (proteomics); and their downstream effects on homeostasis and metabolism (metabolomics). Significant bioinformatics challenges lie ahead both in the integration of this information into meaningful models of NR and coregulator biology, as well as in the archiving and communication of datasets to the global nuclear receptor signaling community. While holding great promise for the field, the ascendancy of discovery-driven research in this field brings with it a collective responsibility for researchers, publishers and funding agencies alike to ensure the effective archiving and management of these data. This review will discuss factors lying behind the increasing impact of discovery-driven research, examples of high-content datasets and their bioinformatic analysis, as well as a summary of currently curated web resources in this field. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► Nuclear receptors and coregulators regulate gene expression in physiology and disease. ► Transcriptomics and cistromics document their tissue-specific target gene networks. ► Affinity purification and mass spectrometry analysis define their proteomic interactions. ► Metabolomics sheds light on their role in maintaining metabolic control of cells. ► Bioinformatics and web development helps scientists manage and use these datasets.
Keywords: Nuclear receptors; Coregulators; Transcriptomics; Proteomics; Bioinformatics; Database;
Genome-wide interplay of nuclear receptors with the epigenome by Joost H.A. Martens; Nagesha A.S. Rao; Henk G. Stunnenberg (818-823).
The nuclear receptor superfamily consists of DNA binding transcription factors that are involved in regulating a wide variety of processes such as metabolism, development, reproduction, and immune responses. Upon binding, nuclear receptors modulate transcription through affecting the local chromatin environment via recruitment of various coregulatory proteins. The recent development of new high-throughput sequencing methods allowed for the first time the comprehensive examination of nuclear receptor action in the context of the epigenome. Here, we discuss how recent genome-wide analyses have provided important new insights on the interplay of nuclear receptors and the epigenome in health and disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► Advances in genome-wide profiling of nuclear receptors ► Nuclear receptor mediated chromatin modifications ► The role of the epigenome in determining nuclear receptor actions
Keywords: Nuclear receptor; Epigenome; Chromatin; Histone; Cancer;
Molecular basis for gene-specific transactivation by nuclear receptors by Mads M. Aagaard; Rasmus Siersbæk; Susanne Mandrup (824-835).
Nuclear receptors (NRs) are key transcriptional regulators of metazoan physiology and metabolism. Different NRs bind to similar or even identical core response elements; however, they regulate transcription in a highly receptor- and gene-specific manner. These differences in gene activation can most likely be accounted for by mechanisms involving receptor-specific interactions with DNA as well as receptor-specific interactions with protein complexes binding to adjacent and distant DNA sequences. Here, we review key molecular aspects of transactivation by NRs with special emphasis on the recent advances in the molecular mechanisms responsible for receptor- and gene-specific transcriptional activation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.►The non-conserved regions of NRs contribute to gene specificity. ►DNA looping is a key aspect of NR signaling. ►NRs associate dynamically with target sites in the chromatin template. ►TF crosstalk is important for gene-specific transcriptional regulation by NRs.
Keywords: Nuclear receptor specificity; Nuclear receptor structure; DNA binding; Chromatin; Co-factor interaction; DNA looping;
Proteomics for the discovery of nuclear bile acid receptor FXR targets by Cissi Gardmo; Antonio Tamburro; Salvatore Modica; Antonio Moschetta (836-841).
Nuclear receptors (NRs) are important pharmacological targets for a number of diseases, including cancer and metabolic disorders. To unmask the direct role of NR function it is fundamental to find the NR targets. During the last few years several NRs have been shown to affect microRNA expression, thereby modulating protein levels. The farnesoid X receptor (FXR), the main regulator of bile acid (BA) homeostasis, also regulates cholesterol, lipid and glucose metabolism. Here we used, for the first time, a proteomics approach on mice treated with a FXR ligand to find novel hepatic FXR targets. Nineteen spots with a more than two-fold difference in protein amounts were found by 2D-DIGE and 20 proteins were identified by MALDI-TOF MS as putative novel FXR targets. The most striking feature of the protein list was the great number of mitochondrial proteins, indicating a substantial impact of FXR activation on mitochondrial function in the liver. To examine if the differences found in the proteomics assay reflected differences at the mRNA level, a microarray assay was generated on hepatic samples from wild type and FXR−/− mice treated with a FXR ligand and compared to vehicle treatment. At least six proteins were shown to be regulated only at a post-transcriptional level. In conclusion, our study provides the impetus to include proteomic analysis for the identification of novel targets of transcription factors, such as NRs. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► Twenty proteins were identified as being potential novel hepatic FXR targets. ► Many of the potential FXR targets have a role in regulating mitochondrial function. ► Microarray analysis was made for a comparison of protein amounts with mRNA levels. ► Six of the proteins found by 2D-DIGE seem to be regulated only at the protein level.
Keywords: Nuclear receptor; FXR; Proteomic analysis; Expression profiling; Post-transcriptional modification; Mitochondrial;
Regulation of FXR transcriptional activity in health and disease: Emerging roles of FXR cofactors and post-translational modifications by Jongsook Kim Kemper (842-850).
Abnormally elevated lipid and glucose levels due to the disruption of metabolic homeostasis play causative roles in the development of metabolic diseases. A cluster of metabolic conditions, including dyslipidemia, abdominal obesity, and insulin resistance, is referred to as metabolic syndrome, which has been increasing globally at an alarming rate. The primary nuclear bile acid receptor, Farnesoid X Receptor (FXR, NR1H4), plays important roles in controlling lipid and glucose levels by regulating expression of target genes in response to bile acid signaling in enterohepatic tissues. In this review, I discuss how signal-dependent FXR transcriptional activity is dynamically regulated under normal physiological conditions and how it is dysregulated in metabolic disease states. I focus on the emerging roles of post-translational modifications (PTMs) and transcriptional cofactors in modulating FXR transcriptional activity and pathways. Dysregulation of nuclear receptor transcriptional signaling due to aberrant PTMs and cofactor interactions are key determinants in the development of metabolic diseases. Therefore, targeting such abnormal PTMs and transcriptional cofactors of FXR in disease states may provide a new molecular strategy for development of pharmacological agents to treat metabolic syndrome. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► FXR has important roles in controlling lipid and glucose levels. ► FXR activity is regulated by transcriptional cofactors, which catalyze PTMs of FXR as well as histones. ► Acetylation of FXR is normally dynamically regulated but is dysregulated in metabolic disease states. ► Aberrant FXR cofactors and PTMs may be targets for development of new therapeutic agents to treat metabolic disease.
Keywords: Bile acid; Cofactor; Post-translational modification; Acetylation; Phosphorylation; Chromatin; Metabolic syndrome;
Activation of bile salt nuclear receptor FXR is repressed by pro-inflammatory cytokines activating NF-κB signaling in the intestine by Raffaella M. Gadaleta; Bas Oldenburg; Ellen C.L. Willemsen; Maureen Spit; Stefania Murzilli; Lorena Salvatore; Leo W.J. Klomp; Peter D. Siersema; Karel J. van Erpecum; Saskia W.C. van Mil (851-858).
Hyperactivation of NF-κB is a key factor in the pathophysiology of inflammatory bowel disease (IBD). We previously showed that the bile salt nuclear Farnesoid X Receptor (FXR) counter-regulates intestinal inflammation, possibly via repression of NF-κB. Here, we examine whether mutual antagonism between NF-κB and FXR exists. FXR and its target genes IBABP and FGF15/19 expression were determined in HT29 colon carcinoma cells and ex vivo in intestinal specimens of wild type (WT) and Fxr-ko mice, treated with/without FXR ligands (GW4064/INT-747) and inflammatory stimuli (TNFα/IL-1β). In addition, FXR activation was studied in vivo in WT and Fxr-ko mice with DSS-colitis. The involvement of NF-κB in decreasing FXR activity was investigated by reporter assays and Glutathione S-transferase pulldown assays. FXR target gene expression was highly reduced by inflammatory stimuli in all model systems, while FXR mRNA expression was unaffected. In line with these results, reporter assays showed reduced FXR transcriptional activity upon TNFα/IL-1β stimulation. We show that this reduction in FXR activity is probably mediated by NF-κB, since overexpression of NF-κB subunits p50 and/or p65 also lead to inhibition of FXR activity. Finally, we report that p65 and p50 physically interact with FXR in vitro. Conclusions: Together, these results indicate that intestinal inflammation strongly reduces FXR activation, probably via NF-κB-dependent tethering of FXR. Therefore, FXR not only inhibits inflammation, but also is targeted by the inflammatory response itself. This could result in a vicious cycle where reduced FXR activity results in less repression of inflammation, contributing to development of chronic intestinal inflammation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► TNFα decreases FXR target gene expression in differentiated HT29 intestinal cells. ► TNFα and IL-1β decrease ileal FXR target gene expression ex vivo in WT mice. ► In the DSS model of murine colitis, FXR target gene expression is decreased. ► TNFα, IL-1β and overexpression of NF-κB subunits P50/P65 decrease FXR transcriptional activity. ► Intestinal inflammation inhibits FXR activation, probably via NF-κB-dependent tethering of FXR.
Keywords: Inflammatory bowel disease; Nuclear factor κB; Farnesoid X Receptor; Mutual inhibition;
Farnesoid X receptor activation improves erectile dysfunction in models of metabolic syndrome and diabetes by Annamaria Morelli; Linda Vignozzi; Mario Maggi; Luciano Adorini (859-866).
The metabolic syndrome (MetS) is an insulin-resistant state characterized by a cluster of cardiovascular risk factors, including abdominal obesity, hyperglycemia, elevated blood pressure and combined dyslipidemia. In this review, we discuss the potential of farnesoid X receptor (FXR) agonists in the treatment of erectile dysfunction (ED), a multifactorial disorder often comorbid with MetS. FXR not only regulates lipid and glucose homeostasis but also influences endothelial function and atherosclerosis, suggesting a regulatory role for this hormone nuclear receptor in the cardiovascular complications associated with the MetS, including ED. MetS induces ED via several mechanisms, and in particular through endothelial dysfunction in penile vessels. In a high-fat diet rabbit model of MetS, a 3-month treatment with the potent and selective FXR agonist INT-747 restores endothelium-dependent relaxation in isolated cavernous tissue, normalizing responsiveness to acetylcholine and to electrical field stimulation. Accordingly, eNOS expression in the penis is greatly up-regulated by INT-747 treatment. Experiments in a rat model of chemically-induced type 1 diabetes further demonstrate that INT-747 treatment preserves erectile function induced by electrical stimulation of the cavernous nerve. These results add a new facet to the pleiotropic activities mediated by FXR, and reveal novel beneficial effects of FXR activation with potential clinical relevance. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.►The metabolic syndrome is an insulin-resistant state characterized by a cluster of cardiovascular risk factors. ► Erectile dysfunction is a multifactorial disorder often comorbid with the metabolic syndrome. ► In this review, we discuss the potential of farnesoid X receptor (FXR) agonists in the treatment of erectile dysfunction associated with the metabolic syndrome.
Keywords: Farnesoid X receptor; Metabolic syndrome; Erectile dysfunction;
Role of nuclear receptors for bile acid metabolism, bile secretion, cholestasis, and gallstone disease by Thierry Claudel; Gernot Zollner; Martin Wagner; Michael Trauner (867-878).
Nuclear receptors (NRs) play a key role in the transcriptional control of critical steps of hepatobiliary transport and phase I/II metabolism of endo- and xenobiotics such as bile acids and drugs. Apart from these metabolic roles, NRs may also play a key role in the control of hepatic inflammation. Hereditary and acquired alterations of NRs contribute to our understanding of the pathogenesis of cholestasis and gallstone disease. Moreover, NRs may represent attractive drug targets for these disorders. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.►Nuclear receptors control hepatobiliary transport and phase I/II metabolism of bile acids and drugs. ►Nuclear receptors modulate hepatic inflammation. ►Hereditary and acquired alterations of NR help to understand cholestasis and gallstone disease pathogenesis. ►Nuclear receptors represent attractive drug targets for cholestasis and gallstone disease.
Keywords: Bile acids; Nuclear receptors; FXR; Cholestasis; Gallstone; Bile acid transport;
Nuclear receptor-driven alterations in bile acid and lipid metabolic pathways during gestation by Georgia Papacleovoulou; Shadi Abu-Hayyeh; Catherine Williamson (879-887).
Nuclear receptor signalling is essential for physiological processes such as metabolism, development, and reproduction. Alterations in the endocrine state that naturally occur during pregnancy result in maternal adaptations to support the feto-placental unit. A series of studies have shown that nuclear receptor signalling is involved in maternal adaptations of bile acid, cholesterol, and lipid homeostasis pathways to ensure maintenance of the nutritional demands of the fetus. We discuss regulation of hepatic nuclear receptors and their target genes in pregnancy and their impact on the development of disorders such as intrahepatic cholestasis of pregnancy and oestrogen-induced hepatotoxicity. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► Altered nuclear receptor signalling is part of the maternal hepatic adaptations that occur during pregnancy. ► Intrahepatic cholestasis and oestrogen-induced hepatotoxicity in pregnancy have been shown to be associated with reduced FXR and PPAR-α activity. ► Agonists of FXR and PPAR-α signalling pathways are of potential therapeutic benefit to treat metabolic pregnancy disorders.
Keywords: Metabolism; Pregnancy; Nuclear receptors; Bile acids; Oestrogens; Cholestasis;
Nuclear bile acid receptor FXR in the hepatic regeneration by Wei-Dong Chen; Yan-Dong Wang; Zhipeng Meng; Lisheng Zhang; Wendong Huang (888-892).
The liver can fully regenerate itself by a compensatory regrowth in response to partial hepatectomy or injury. This process consists of a variety of well-orchestrated phases and is mediated by many signals. Farnesoid X receptor (FXR) is a member of the nuclear hormone receptor superfamily of ligand-activated transcription factors. Bile acids are FXR physiological ligands. As a metabolic regulator, FXR plays key roles in regulating metabolism of bile acids, lipids and glucose. Recently, bile acid/FXR signaling pathway is shown to be required for normal liver regeneration. Furthermore, FXR promotes liver repair after injury and activation of FXR is able to alleviate age-related defective liver regeneration. These novel findings suggest that FXR-mediated bile acid signaling is an integrated component of normal liver regeneration machinery, and also highlight the potential use of FXR ligands to promote liver regeneration after segmental liver transplantation or resection of liver tumors. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► FXR mediates bile acid signaling in promoting liver regeneration. ► FXR promotes liver repair after injury. ► FXR promotes the regeneration of aged liver.
Keywords: FXR; Nuclear receptor; Bile acid; Liver regeneration; Liver repair;
Role of nuclear receptor SHP in metabolism and cancer by Yuxia Zhang; Curt H. Hagedorn; Li Wang (893-908).
Small heterodimer partner (SHP, NR0B2) is a unique member of the nuclear receptor (NR) superfamily that contains the dimerization and ligand-binding domain found in other family members, but lacks the conserved DNA-binding domain. The ability of SHP to bind directly to multiple NRs is crucial for its physiological function as a transcriptional inhibitor of gene expression. A wide variety of interacting partners for SHP have been identified, indicating the potential for SHP to regulate an array of genes in different biological pathways. In this review, we summarize studies concerning the structure and target genes of SHP and discuss recent progress in understanding the function of SHP in bile acid, cholesterol, triglyceride, glucose, and drug metabolism. In addition, we review the regulatory role of SHP in microRNA (miRNA) regulation, liver fibrosis and cancer progression. The fact that SHP controls a complex set of genes in multiple metabolic pathways suggests the intriguing possibility of developing new therapeutics for metabolic diseases, including fatty liver, dyslipidemia and obesity, by regulating SHP with small molecules. To achieve this goal, more progress regarding SHP ligands and protein structure will be required. Besides its metabolic regulatory function, studies by us and other groups provide strong evidence that SHP plays a critical role in the development of cancer, particularly liver and breast cancer. An increased understanding of the fundamental mechanisms by which SHP regulates the development of cancers will be critical in applying knowledge of SHP in diagnostic, therapeutic or preventive strategies for specific cancers. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► SHP generally functions as a transcriptional repressor. ► SHP interacts with a wide variety of nuclear receptors and transcription factors. ► SHP regulates the development of fatty liver, obesity, diabetes and cancer. ► SHP is a critical regulator of miRNA gene transcription.
Keywords: Nuclear receptors; Small heterodimer partner; Metabolic regulation; Metabolic syndrome; Cancer;
Transcriptional control of metabolic and inflammatory pathways by nuclear receptor SUMOylation by Eckardt Treuter; Nicolas Venteclef (909-918).
Nuclear receptors (NRs) exert crucial functions in controlling metabolism and inflammation by both positively and negatively regulating gene expression. Recent evidence suggests that the transcriptional activities of many NRs can be modulated and even re-directed through post-translational modification by small ubiquitin-related modifiers (SUMO). SUMOylation triggers a plethora of diverse molecular events that can alter both the fate and function of modified NRs at the nongenomic, genomic, and epigenomic level. However, it is the intriguing link of SUMOylation to transcriptional repression, and in particular to transrepression, that has emerged as a common underlying mechanism that impacts on biological processes controlled by NRs. It further appears that the cell-type-specific SUMOylation status of NRs can be regulated by ligands and by signal-dependent crosstalk of post-translational modifications. Given the causal role of altered NR signaling in the development and pathogenesis of human diseases, it is likely that aberrant SUMO conjugation, deconjugation, or interpretation contributes to these alterations. Here, we review the current progress made in both the study and understanding of the molecular mechanisms and consequences of NR SUMOylation and also discuss the physiological and pharmacological implications with a particular focus on transrepression pathways that link metabolism and inflammation. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.►SUMOylation is a fundamental modification reported for more than 20 NRs to date. ►SUMOylation inhibits transcriptional NR functions, mostly via repression. ►SUMOylation of metabolic NRs triggers anti-inflammatory transrepression pathways. ►SUMO recognition by corepressors is necessary for signal interpretation. ►Selective NR–SUMO modulation by novel ligands may lead to therapeutic applications.
Keywords: Nuclear receptor; Post-translational modification; SUMO; Metabolism; Inflammation; Acute phase response; Transrepression; LXR; PPAR; LRH-1; N-CoR; SMRT; GPS2;
Role of nuclear receptor corepressor RIP140 in metabolic syndrome by Meritxell Rosell; Marius C. Jones; Malcolm G. Parker (919-928).
Obesity and its associated complications, which can lead to the development of metabolic syndrome, are a worldwide major public health concern especially in developed countries where they have a very high prevalence. RIP140 is a nuclear coregulator with a pivotal role in controlling lipid and glucose metabolism. Genetically manipulated mice devoid of RIP140 are lean with increased oxygen consumption and are resistant to high-fat diet-induced obesity and hepatic steatosis with improved insulin sensitivity. Moreover, white adipocytes with targeted disruption of RIP140 express genes characteristic of brown fat including CIDEA and UCP1 while skeletal muscles show a shift in fibre type composition enriched in more oxidative fibres. Thus, RIP140 is a potential therapeutic target in metabolic disorders. In this article we will review the role of RIP140 in tissues relevant to the appearance and progression of the metabolic syndrome and discuss how the manipulation of RIP140 levels or activity might represent a therapeutic approach to combat obesity and associated metabolic disorders. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► RIP140 regulates energy expenditure and storage in adipose tissue. ► RIP140 modulates muscle fiber type. ► RIP140 affects inflammatory responses. ► RIP140 is a promising target for treatment of metabolic disorders.
Keywords: Metabolic syndrome; RIP140; White adipose tissue; Inflammation;
Role of thyroid receptor β in lipid metabolism by Camilla Pramfalk; Matteo Pedrelli; Paolo Parini (929-937).
Thyroid hormones (THs) exert their actions by binding to thyroid hormone receptors (TRs) and thereby affect tissue differentiation, development, and metabolism in most tissues. TH-deficiency creates a less favorable lipid profile (e.g. increased plasma cholesterol levels), whereas TH-excess is associated with both positive (e.g. reduced plasma cholesterol levels) and negative (e.g. increased heart rate) effects. TRs are encoded by two genes, THRA and THRB, which, by alternative splicing, generate several isoforms (e.g. TRα1, TRα2, TRβ1, and TRβ2). TRα, the major TR in the heart, is crucial for heart rate and for cardiac contractility and relaxation, whereas TRβ1, the major TR in the liver, is important for lipid metabolism. Selective modulation of TRβ1 is thus considered as a potential therapeutic target to treat dyslipidemia without cardiac side effects. Several selective TH analogs have been tested in preclinical studies with promising results, but only a few of these compounds have so far been tested in clinical studies. This review focuses on the role of THs, TRs, and selective and non-selective TH analogs in lipid metabolism. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.►Thyroid hormones exert their actions by binding to thyroid hormone receptors (TRs). ►TRs are encoded by two genes, THRA and THRB. ►TRβ1, the major TR in the liver, is important for lipid metabolism. ►In preclinical studies, several TRβ1 selective TH analogs prove to improve lipid profile and decrease atherosclerosis. ►Only a few of these compounds have so far been tested in clinical studies providing promising results.
Keywords: Thyroid receptor; Thyroid hormone; Cholesterol; Triglyceride; Atherosclerosis; Reverse cholesterol transport;
The thyroid hormones and their nuclear receptors in the gut: From developmental biology to cancer by Maria Sirakov; Michelina Plateroti (938-946).
The thyroid hormones control the development and the homeostasis of several organs in vertebrates. Their actions depend, for the most part, on nuclear receptors, the TRs, which are transcription factors whose activity is modulated by the hormone T3. The gastrointestinal tract is a well characterized target of thyroid hormones and TRs, as extensively described in the literature. In fact, its remodeling in amphibians during thyroid hormone-dependent metamorphosis is well characterized at the cellular and the molecular levels. However, whereas a great attention has been paid to the nervous system and to cardiac development and physiology, the function of thyroid hormones and TRs in the mammalian gastrointestinal tract has been, until recently, underestimated. Several studies have described an important conservation of this hormonal signal during intestinal development and have suggested that it may play a role in stem cell physiology in both amphibians and mammals. These findings show the importance of the thyroid hormones and TRs, whose homologous actions are maintained across species. In the present review, we summarize the most recent data on this issue, starting from work that has been conducted on amphibian metamorphosis to results on postnatal development, homeostasis, and tumorigenesis in mammals. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.►The intestine is an organ target of the thyroid hormone and its nuclear receptor TRα1. ►This hormone controls gut progenitor proliferation in both amphibians and mammals. ►The gut-specific over-activation of this signal in the mouse results in tumor induction. ►New data also describe their involvement in gut epithelial stem cell physiology.
Keywords: Intestinal development; Intestinal tumor; Thyroid hormone; Thyroid hormone receptor TR; Stem cells;
Emerging actions of the nuclear receptor LRH-1 in the gut by Pablo J. Fernandez-Marcos; Johan Auwerx; Kristina Schoonjans (947-955).
Liver receptor homolog-1 (NR5A2) is a nuclear receptor originally identified in the liver and mostly known for its regulatory role in cholesterol and bile acid homeostasis. More recently, liver receptor homolog-1 has emerged as a key regulator of intestinal function, coordinating unanticipated actions, such as cell renewal and local immune function with important implications to common intestinal diseases, including colorectal cancer and inflammatory bowel disease. Unlike most of the other nuclear receptors, liver receptor homolog-1 acts as a constitutively active transcription factor to drive the transcription of its target genes. Liver receptor homolog-1 activity however is to a major extent regulated by different corepressors and posttranslational modifications, which may account for its tissue-specific functions. This review will provide an update on the molecular aspects of liver receptor homolog-1 action and focus on some emerging aspects of its function in normal and diseased gut. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► This review highlights the role of nuclear receptors in normal and diseased gut with a particular focus on the nuclear receptor LRH-1. ► We summarize the general molecular and physiological actions of LRH-1. ► We comment on the relevance of LRH-1 in development. ► We discuss the most recent findings on LRH-1 in intestinal renewal and cancer. ► Finally, we review the role of LRH-1 in gut inflammation and inflammatory bowel disease.
Keywords: NR5A2; Cell renewal; Steroidogenesis; Inflammation; Inflammatory bowel disease; Cancer;
Nuclear receptor PXR, transcriptional circuits and metabolic relevance by Chibueze A. Ihunnah; Mengxi Jiang; Wen Xie (956-963).
The pregnane X receptor (PXR, NR1I2) is a ligand activated transcription factor that belongs to the nuclear hormone receptor (NR) superfamily. PXR is highly expressed in the liver and intestine, but low levels of expression have also been found in many other tissues. PXR plays an integral role in xenobiotic and endobiotic metabolism by regulating the expression of drug-metabolizing enzymes and transporters, as well as genes implicated in the metabolism of endobiotics. PXR exerts its transcriptional regulation by binding to its DNA response elements as a heterodimer with the retinoid X receptor (RXR) and recruitment of a host of coactivators. The biological and physiological implications of PXR activation are broad, ranging from drug metabolism and drug–drug interactions to the homeostasis of numerous endobiotics, such as glucose, lipids, steroids, bile acids, bilirubin, retinoic acid, and bone minerals. The purpose of this article is to provide an overview on the transcriptional circuits and metabolic relevance controlled by PXR. This article is part of a Special Issue entitled: Translating Nuclear Receptors from Health to Disease.► PXR was initially cloned as a xenobiotic receptor regulating drug metabolism. ► Accumulating evidence has suggested broader transcriptional circuits controlled by this receptor. ► Moreover, the perceived function of PXR has been extended to a sensor that dictates the homeostasis of both xenobiotics and endobiotics.
Keywords: Nuclear receptor; Gene regulation; Xenobiotic receptor; Xenobiotics; Endobiotics;
Sex differences in nuclear receptor-regulated liver metabolic pathways by Gianpaolo Rando; Walter Wahli (964-973).
Liver metabolism is markedly sex-dimorphic; accordingly, the prevalence of liver diseases is different between sexes. The superfamily of nuclear receptors (NRs) governs the proper expression of key liver metabolism genes by sensing lipid-soluble hormones and dietary lipids. When the expression of those genes is deregulated, disease development is favored. However, we lack a comprehensive picture of the differences between NR actions in males and females. Here, we reviewed explorative studies that assessed NR functions in both sexes, and we propose a first map of sex-dimorphic NR expression in the liver. Our analysis suggested that NRs in the female liver exhibited cross-talk with more liver-protective potential than NRs in male liver. This study provides empirical support to the hypothesis that women are more resilient to some liver diseases than men, based on a more compensative NR network. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► We review explorative studies that assessed nuclear receptor functions in both sexes. ► Sexual dimorphism is a major physiological characteristic of the liver. ► Nuclear receptors fine-tune gender-specific metabolic pathways. ► Women are more resilient to some liver diseases than men.
Keywords: Nuclear receptors; Liver sex dimorphism; Gender dimorphism; Sexual differences; Nuclear receptor crosstalk;
Liver X receptors, lipids and their reproductive secrets in the male by Fatim-Zorah El-Hajjaji; Abdelkader Oumeddour; Aurélien J.C. Pommier; Aurélia Ouvrier; Emilie Viennois; Julie Dufour; Françoise Caira; Joël R. Drevet; David H. Volle; Silvère Baron; Fabrice Saez; Jean-Marc A. Lobaccaro (974-981).
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.►LXRs are activated by oxysterols presented in the male reproductive tract. ►LXRs are necessary for testicular physiology. ►LXR-deficient mice present abnormal features of the epididymis. ►LXR agonist modifies the apoptosis–proliferation balance in prostate cancer cells. ►LXRs are promising pharmacological targets in human disease.
Keywords: Testis; Epididymis; Prostate; LXR; Lipids;
Liver X receptors as regulators of macrophage inflammatory and metabolic pathways by Noelia A-González; Antonio Castrillo (982-994).
The liver X receptors (LXRα and LXRβ) are members of the nuclear receptor family of transcription factors that play essential roles in the transcriptional control of lipid metabolism. LXRs are endogenously activated by modified forms of cholesterol known as oxysterols and control the expression of genes important for cholesterol uptake, efflux, transport, and excretion in multiple tissues. In addition to their role as cholesterol sensors, a number of studies have implicated LXRs in the modulation of innate and adaptive immune responses. Both through activation and repression mechanisms, LXRs regulate diverse aspects of inflammatory gene expression in macrophages. The ability of LXRs to coordinate metabolic and immune responses constitutes an attractive therapeutic target for the treatment of chronic inflammatory disorders. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► The liver X receptors are transcription factors that play essential roles in the transcriptional control of lipid metabolism. ► LXRs are also involved in the modulation of innate and adaptive immune responses. ► LXRs regulate diverse aspects of inflammatory gene expression in macrophages, through activation and repression mechanisms. ► The ability of LXRs to coordinate metabolic and immune responses consitutes an attractive therapeutic target for the treatment of chronic inflammatory disorders.
Keywords: Liver X receptors; Macrophage; Cholesterol; Innate immunity; Phagocytosis; Autoimmunity;
Cross-regulation of hepatic glucose metabolism via ChREBP and nuclear receptors by Audrey Poupeau; Catherine Postic (995-1006).
There is a worldwide epidemic of obesity and type 2 diabetes, two major public health concerns associated with alterations in both insulin and glucose signaling pathways. Glucose is not only an energy source but also controls the expression of key genes involved in energetic metabolism, through the glucose-signaling transcription factor, Carbohydrate Responsive Element Binding Protein (ChREBP). ChREBP has emerged as a central regulator of de novo fatty acid synthesis (lipogenesis) in response to glucose under both physiological and physiopathological conditions. Glucose activates ChREBP by regulating its entry from the cytosol to the nucleus, thereby promoting its binding to carbohydrate responsive element (ChoRE) in the promoter regions of glycolytic (L-PK) and lipogenic genes (ACC and FAS). We have previously reported that the inhibition of ChREBP in liver of obese ob/ob mice improves the metabolic alterations linked to obesity, fatty liver and insulin-resistance. Therefore, regulating ChREBP activity could be an attractive target for lipid-lowering therapies in obesity and diabetes. However, before this is possible, a better understanding of the mechanism(s) regulating its activity is needed. In this review, we summarize recent findings on the role and regulation of ChREBP and particularly emphasize on the cross-regulations that may exist between key nuclear receptors (LXR, TR, HNF4α) and ChREBP for the control of hepatic glucose metabolism. These novel molecular cross-talks may open the way to new pharmacological opportunities. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► ChREBP is a central transcriptional regulator of hepatic de novo fatty acid synthesis. ► ChREBP inhibition in liver of obese ob/ob mice improves hepatic steatosis and insulin-resistance. ► ChREBP represents an attractive target for lipid-lowering therapies in obesity and diabetes. ► Cross-regulations exist between ChREBP and liver nuclear receptors for the control of hepatic glucose and lipid metabolism. ► Identification of novel molecular cross-talks between ChREBP and nuclear receptors may open the way to new pharmacological opportunities.
Keywords: ChREBP; Nuclear receptors; Glucose metabolism; Lipogenesis; Steatosis;
PPARs are a unique set of fatty acid regulated transcription factors controlling both lipid metabolism and inflammation by Tamas Varga; Zsolt Czimmerer; Laszlo Nagy (1007-1022).
Cells are constantly exposed to a large variety of lipids. Traditionally, these molecules were thought to serve as simple energy storing molecules. More recently it has been realized that they can also initiate and regulate signaling events that will decisively influence development, cellular differentiation, metabolism and related functions through the regulation of gene expression. Multicellular organisms dedicate a large family of nuclear receptors to these tasks. These proteins combine the defining features of both transcription factors and receptor molecules, and therefore have the unique ability of being able to bind lipid signaling molecules and transduce the appropriate signals derived from lipid environment to the level of gene expression. Intriguingly, the members of a subfamily of the nuclear receptors, the peroxisome proliferator-activated receptors (PPARs) are able to sense and interpret fatty acid signals derived from dietary lipids, pathogenic lipoproteins or essential fatty acid metabolites. Not surprisingly, Peroxisome proliferator-activated receptors were found to be key regulators of lipid and carbohydrate metabolism. Unexpectedly, later studies revealed that Peroxisome proliferator-activated receptors are also able to modulate inflammatory responses. Here we summarize our understanding on how these transcription factors/receptors connect lipid metabolism to inflammation and some of the novel regulatory mechanisms by which they contribute to homeostasis and certain pathological conditions. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► PPARs and lipid environment form a regulatory circuit. ► Fatty acid derived molecules can regulate inflammation through PPARs. ► PPARs have anti-inflammatory roles in a number of inflammatory diseases. ► A number of outstanding questions about the biology of PPARs are still unanswered.
Keywords: PPAR; Inflammation; Lipid metabolism; Transcriptional regulation;
The molecular physiology of nuclear retinoic acid receptors. From health to disease by Vanessa Duong; Cécile Rochette-Egly (1023-1031).
The nuclear retinoic acid (RA) receptors (RARα, β and γ) are transcriptional transregulators, which control the expression of specific gene subsets subsequently to ligand binding and to strictly controlled phosphorylation processes. Consequently RARs maintain homeostasis through the control of cell proliferation and differentiation. Today, it is admitted that, analogous to the paradigm established by the hematopoietic system, most adult tissues depict a differentiation hierarchy starting from rare stem cells. Here we highlight that the integrity of RARs is absolutely required for homeostasis in adults. Indeed, strictly controlled levels of RARs are necessary for the correct balance between self-renewal and differentiation of tissue stem cells. In addition, loss, accumulation, mutations or aberrant modifications of a specific RAR lead to uncontrolled proliferation and/or to differentiation block and thereby to cancer. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► Advances in RAR functions. ► RARs control cell proliferation and differentiation. ► RAR integrity is required for homeostasis. ► RAR deregulation leads to cancer.
Keywords: Nuclear retinoic acid receptors; Transcription; Homeostasis; Cancer;
Functional and physiological genomics of estrogen-related receptors (ERRs) in health and disease by Geneviève Deblois; Vincent Giguère (1032-1040).
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.►Estrogen-related receptors (ERRs) regulate development and physiological homeostasis. ►The ERRs mediate their biological functions via the activation of vast gene networks. ►Functional genomics has uncovered ERR-specific gene networks. ►Physiological genomics has identified ERR-dependent physiological response pathways
Keywords: Breast cancer; Chromatin immunoprecipitation; Energy metabolism; Mitochondrion; Nuclear receptor; PGC-1;
Mitochondrial defect and PGC-1α dysfunction in parkin-associated familial Parkinson's disease by Consiglia Pacelli; Domenico De Rasmo; Anna Signorile; Ignazio Grattagliano; Giuseppe di Tullio; Andria D'Orazio; Beatrice Nico; Giacomo Pietro Comi; Dario Ronchi; Ermanno Ferranini; Domenico Pirolo; Peter Seibel; Susanna Schubert; Antonio Gaballo; Gaetano Villani; Tiziana Cocco (1041-1053).
Mutations in the parkin gene are expected to play an essential role in autosomal recessive Parkinson's disease. Recent studies have established an impact of parkin mutations on mitochondrial function and autophagy. In primary skin fibroblasts from two patients affected by an early onset Parkinson's disease, we identified a hitherto unreported compound heterozygous mutation del exon2-3/del exon3 in the parkin gene, leading to the complete loss of the full-length protein. In both patients, but not in their heterozygous parental control, we observed severe ultrastructural abnormalities, mainly in mitochondria. This was associated with impaired energy metabolism, deregulated reactive oxygen species (ROS) production, resulting in lipid oxidation, and peroxisomal alteration. In view of the involvement of parkin in the mitochondrial quality control system, we have investigated upstream events in the organelles' biogenesis. The expression of the peroxisome proliferator-activated receptor gamma-coactivator 1-alpha (PGC-1α), a strong stimulator of mitochondrial biogenesis, was remarkably upregulated in both patients. However, the function of PGC-1α was blocked, as revealed by the lack of its downstream target gene induction. In conclusion, our data confirm the role of parkin in mitochondrial homeostasis and suggest a potential involvement of the PGC-1α pathway in the pathogenesis of Parkinson's disease. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► Report and phenotypic impact of a novel parkin mutation in early familial PD. ► Ultrastructural organellar abnormalities and mitochondrial bioenergetic dysfunctions. ► Increased ROS production, catalase deficiency and oxidative stress. ► Upregulation of PGC-1α expression but lack of target genes.
Keywords: Parkinson's disease; Parkin; Mitochondria; Oxidative stress; Peroxisome; PGC-1α;
Liganded and unliganded activation of estrogen receptor and hormone replacement therapies by Adriana Maggi (1054-1060).
Over the past two decades, our understanding of estrogen receptor physiology in mammals widened considerably as we acquired a deeper appreciation of the roles of estrogen receptor alpha and beta (ERα and ERβ) in reproduction as well as in bone and metabolic homeostasis, depression, vascular disorders, neurodegenerative diseases and cancer. In addition, our insights on ER transcriptional functions in cells increased considerably with the demonstration that ER activity is not strictly dependent on ligand availability. Indeed, unliganded ERs may be transcriptionally active and post-translational modifications play a major role in this context. The finding that several intracellular transduction molecules may regulate ER transcriptional programs indicates that ERs may act as a hub where several molecular pathways converge: this allows to maintain ER transcriptional activity in tune with all cell functions. Likely, the biological relevant role of ER was favored by evolution as a mean of integration between reproductive and metabolic functions. We here review the post-translational modifications modulating ER transcriptional activity in the presence or in the absence of estrogens and underline their potential role for ER tissue-specific activities. In our opinion, a better comprehension of the variety of molecular events that control ER activity in reproductive and non-reproductive organs is the foundation for the design of safer and more efficacious hormone-based therapies, particularly for menopause. This article is part of a Special Issue entitled: Translating Nuclear receptors from health to disease.► We describe the modalities of estrogen receptor transcriptional activation. ► Estrogen receptor may be activated in the presence and absence of ligands. ► Post-translational modification are important for unliganded estrogen receptor activation. ► The mechanisms of estrogen receptor activation are important to define new therapeutic strategies. ► Tissue-specific oscillatory activity of estrogen receptors.
Keywords: Estrogen receptor; Hormone replacement therapy; Transcriptinal oscillation; Estrogen receptor pharmacology;
Nuclear receptors in renal disease by Moshe Levi (1061-1067).
Diabetes is the leading cause of end-stage renal disease in developed countries. In spite of excellent glucose and blood pressure control, including administration of angiotensin converting enzyme inhibitors and/or angiotensin II receptor blockers, diabetic nephropathy still develops and progresses. The development of additional protective therapeutic interventions is, therefore, a major priority. Nuclear hormone receptors regulate carbohydrate metabolism, lipid metabolism, the immune response, and inflammation. These receptors also modulate the development of fibrosis. As a result of their diverse biological effects, nuclear hormone receptors have become major pharmaceutical targets for the treatment of metabolic diseases. The increasing prevalence of diabetic nephropathy has led intense investigation into the role that nuclear hormone receptors may have in slowing or preventing the progression of renal disease. This role of nuclear hormone receptors would be associated with improvements in metabolism, the immune response, and inflammation. Several nuclear receptor activating ligands (agonists) have been shown to have a renal protective effect in the context of diabetic nephropathy. This review will discuss the evidence regarding the beneficial effects of the activation of several nuclear, especially the vitamin D receptor (VDR), farnesoid X receptor (FXR), and peroxisome-proliferator-associated receptors (PPARs) in preventing the progression of diabetic nephropathy and describe how the discovery and development of compounds that modulate the activity of nuclear hormone receptors may provide potential additional therapeutic approaches in the management of diabetic nephropathy. This article is part of a Special Issue entitled: Translating nuclear receptors from health to disease.► Several nuclear receptors are highly expressed in the kidney. ► Animal studies using activating ligands, knockout mice, or transgenic mice have shown that FXR, VDR, and PPARs play an important role in modulation of kidney disease. ► Several human trials are essentially in agreement with the animal studies. ► Activation of VDR, FXR, and PPARs modulates kidney disease by regulating lipid metabolism, inflammation, oxidative stress, and fibrosis. ► There are several additional nuclear receptors whose function in the kidney remain unknown.
Keywords: Diabetes; Nuclear hormone receptors; Renal disease; VDR; FXR; PPAR;