查看更多>>摘要：Pregnancy is characterised by profound hormonal and metabolic changes in the mother. Both oestrogen and progesterone, along with their respective nuclear receptors, have an important role in maintaining a healthy pregnancy. Equally, other nuclear receptors such as LXR, FXR and the PPARs play important roles in the gradual alterations in metabolism that ensure survival of mother and fetus. Disruptions in nuclear receptor signalling can result in pregnancy disorders such as gestational diabetes mellitus, intrahepatic cholestasis of pregnancy, hypertensive disorders of pregnancy and preterm labour, all of which have both immediate and long-term implications for maternal and fetal health. By reviewing data from human studies and animal models, this chapter will describe the contribution of nuclear receptors to normal pregnancy, their role in gestational disorders and their potential as therapeutic targets.
查看更多>>摘要：Nuclear Receptors (NRs) are involved in a multitude of biological pathways and numerous disorders and diseases; it would be difficult to find another family of proteins in the human genome that has such a broad and critical role in both healthy and diseased contexts. Further, they constitute the archetypal proteins for studying some of the most fundamental processes of gene regulation and genomic organization. The first NR was cloned in the 1980s, and we now know that this family is comprised of 48 distinct proteins that share common structural properties. They play essential roles in the development of organs, as evidenced by phenotypic consequences following gene deletion. They are also frequently co-opted or altered in disease states, including cancer and metabolic disorders. One of the special features of the NR superfam-ily is the fact that they constitute the only class of readily druggable transcription factors. This makes them critical downstream effectors of numerous biological and cellular processes and also the targets of many treatments and therapies. Their vital role in both healthy and pathological contexts likely results from a relatively unique feature of this class of transcription factors: their ligand activated switchable states.
查看更多>>摘要：This book, entitled, Nuclear Receptors in Human Health and Disease, is designed as an update to an earlier book entitled Nuclear Receptors, Current Concepts and Future Challenges, which was published in 2010. As before, the chapters are written by leaders in the field, and are broadly intended to serve as an introduction to the field, to discuss the state-of-the-art, and also to speculate where the field is going to meet the challenges on the horizon.
查看更多>>摘要：The female reproductive system which consists of the ovaries, uterus (myometrium, endometrium), Fallopian tubes, cervix and vagina is exquisitely sensitive to the actions of steroid hormones. The ovaries play a key role in the synthesis of bioactive steroids (oestro-gens, androgens, progestins) that act both within the tissue (intracrine/paracrine) as well as on other reproductive organs following release into the blood stream (endocrine action). Sex steroid receptors encoded by the oestrogen (ESR1, ESR2), progesterone (PR) and androgen (AR) receptor genes, which are members of the superfamily of ligand activated transcription factors are widely expressed within these tissues. These receptors play critical role(s) in regulation of cell proliferation, ovulation, endometrial receptivity, myometrial cell function and inflammatory cell infiltration. Our understanding of their importance has been informed by studies on human tissues and cells, which have employed immunohistochemistry as well as a wide range of molecular and genetic methods to identify which processes are dependent steroid ligand activation. The development of mice with targeted deletions of each of these receptors has provided complementary data that has extended our appreciation of cell-cell interactions in the fine tuning of reproductive tissue function. This large body of work has formed the basis of new and improved therapeutics to treat conditions such as infertility.
查看更多>>摘要：The ovary undergoes cycles of hormone production that regulate physiological changes necessary for folliculogenesis, ovulation and luteinisation, ultimately contributing to female reproductive success. Crucial to these biological processes is stage-specific nuclear receptor signalling. While the transcriptional regulatory roles of steroid receptors in female fertility and especially ovarian functions have long been documented, non-steroid receptors also play an important part in regulating gene expression at various stages of ovarian development. The recent application of high-throughput genomic and transcriptomic technologies has begun to shed light on the molecular mechanisms underlying ovarian nuclear receptor actions and pointed to a complex interplay between highly specific transcription co-regulators as well as between nuclear receptors in mediating mutual as well as unique target genes. Interrelationships between nuclear receptors as well as the involvement of context-specific protein and non-protein co-regulators are likely keys to the precise and specific nuclear receptor action in the ovary. Leveraging such knowledge on the nuclear receptor network is especially valuable in the development of novel fertility treatments as well as female contraceptives.
查看更多>>摘要：Nuclear receptors are master regulators of energy metabolism through the conversion of extracellular signals into gene expression signatures. The function of the respective nuclear receptor is tissue specific, signal and co-factor dependent. While normal nuclear receptor function is central to metabolic physiology, aberrant nuclear receptor signaling is linked to various metabolic diseases such as type 2 diabetes mellitus, obesity, or hepatic steatosis. Thus, the tissue specific manipulation of nuclear receptors is a major field in biomedical research and represents a treatment approach for metabolic syndrome. This chapter focuses on key nuclear receptors involved in regulating the metabolic function of liver, adipose tissue, skeletal muscle, and pancreatic β-cells. It also addresses the importance of nuclear co-factors for fine-tuning of nuclear receptor function. The mode of action, role in energy metabolism, and therapeutic potential of prominent nuclear receptors is outlined.
查看更多>>摘要：Fluctuations in concentration of diverse lipid classes occur in response to diet and metabolism. These changes are managed and mediated by a cell network of enzymes, pumps, and carriers under the control of the lipid responsive nuclear receptors. The understanding of how dysregulation of lipid metabolism are causes and indicators of disease beyond the cardiovascular system has developed in the last decade. A particular emphasis on the role of lipids and lipid-sensing nuclear receptors has emerged in the fields of cancer and the immune system's interaction with cancer.The range of known lipid-based ligands has also expanded. Lipids are not just signalling molecules, but also play structural roles in cells and tissues, for example as major constituents of the lipid bilayer - positioning them as integrators and mediators of signaling. This chapter will discuss the major groups of lipid-sensing nuclear receptors focusing on the liver x receptors, farnesoid x receptor, and the peroxi-some proliferator-activated receptors. Initially the reader is presented with information on how these receptors behave and function at the molecular biology level, the range of selective modulation of function by endogenous ligands, and examples of how activity is fine-tuned by mechanisms such as miRNA regulation and post-translational modification of the proteins. We then explore the advances in understanding that have positioned these receptors as therapeutic targets in cancer and immuno-oncology. Finally, the chapter explains the gaps in understanding and experimental challenges that should be prioritized in the coming decade.
Jessica R. IvyGillian A. GrayMegan C. HolmesMartin A. Denvir...
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查看更多>>摘要：Nuclear receptors play a central role in both energy metabolism and cardiomyocyte death and survival in the heart. Recent evidence suggests they may also influence cardiomyocyte endowment. Although several members of the nuclear receptor family play key roles in heart maturation (including thyroid hormone receptors) and cardiac metabolism, here, the focus will be on the corticosteroid receptors, the glucocorticoid receptor (GR) and mineralo-corticoid receptor (MR). The heart is an important target for the actions of corticoste-roids, yet the homeostatic role of GR and MR in the healthy heart has been elusive. However, MR antagonists are important in the treatment of heart failure, a condition associated with mitochondrial dysfunction and energy failure in cardiomyocytes leading to mitochondria-initiated cardiomyocyte death (Ingwall and Weiss, Circ Res 95:135-145, 2014; Ingwall , Cardiovasc Res 81:412-419, 2009; Zhou and Tian , J Clin Invest 128:3716-3726, 2018). In contrast, animal studies suggest GR activation in cardiomyocytes has a cardioprotective role, including in heart failure.
查看更多>>摘要：Nuclear receptors (NRs) are transcription factors that modulate gene expression in a ligand-dependent manner. The ubiquitously expressed glucocorticoid receptor (GR) and peroxisome proliferator-activated receptor gamma (PPARy) represent steroid (type I) and non-steroid (type II) classes of NRs, respectively. The diverse transcriptional and physiological outcomes of their activation are highly tissue-specific. For example, in subsets of immune cells, such as macrophages, the signaling of GR and PPARγ converges to elicit an anti-inflammatory phenotype; in contrast, in the adipose tissue, their signaling can lead to reciprocal metabolic outcomes. This review explores the cooperative and divergent outcomes of GR and PPARγ functions in different cell types and tissues, including immune cells, adipose tissue and the liver. Understanding the coordinated control of these NR pathways should advance studies in the field and potentially pave the way for developing new therapeutic approaches to exploit the GR:PPARγ crosstalk.
查看更多>>摘要：All life of Earth has evolved mechanisms to track time. This permits anticipation of predictable changes in light/dark, and in most cases also directs fed/fasted cycles, and sleep/ wake. The nuclear receptors enjoy a close relationship with the molecular machinery of the clock. Some play a core role within the circadian machinery, other respond to ligands which oscillate in concentration, and physical cross-talk between clock transcription factors, eg cryptochromes, and multiple nuclear receptors also enable coupling of nuclear receptor function to time of day. Essential processes including inflammation, and energy metabolism are strongly regulated by both the circadian machinery, and rhythmic behaviour, and also by multiple members of the nuclear receptor family. An emerging theme is reciprocal regulation of key processes by different members of the nuclear receptor family, for example NR1D1/2, and NR1F1, in regulation of the core circadian clock transcription factor BMAL1.
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