Nuclear receptors are a class of intracellular proteins that sense and respond to a variety of endogenous hormones, vitamins, and xenobiotic endocrine disruptors by modulating gene expression. These proteins have well-established roles in the regulation of energy balance and the skeletal system, and they are emerging as important players in other areas of human physiology and disease. Humans have 48 nuclear receptors that all possess an N-terminal transactivation domain, a highly conserved central region DNA-binding domain, and a C-terminal ligand-binding domain. Ligand binding results in the transactivation of specific genes within a given tissue. Notably, a number of nuclear receptors do not have a known endogenous ligand and structural studies indicate that they may not bind ligands at all, but instead recruit other nuclear receptors or chromatin modifiers to control gene expression. Nuclear receptor activity can be modulated through interactions with other nuclear receptors or transcriptional coactivator or corepressor proteins, as well as through modulation by numerous growth factor and cytokine signaling cascades that induce various posttranslational modifications. Reviews in this series examine the role of nuclear receptors in metabolic syndrome, cardiovascular disease, liver function, hormone-dependent cancers, responses to common therapeutic agents, genetic disorders, the effects of vitamin D, and parasitic disease.
Glucocorticoids (GCs; referred to clinically as corticosteroids) are steroid hormones with potent anti-inflammatory and immune modulatory profiles. Depending on the context, these hormones can also mediate pro-inflammatory activities, thereby serving as primers of the immune system. Their target receptor, the GC receptor (GR), is a multi-tasking transcription factor, changing its role and function depending on cellular and organismal needs. To get a clearer idea of how to improve the safety profile of GCs, recent studies have investigated the complex mechanisms underlying GR functions. One of the key findings includes both pro- and anti-inflammatory roles of GR, and a future challenge will be to understand how such paradoxical findings can be reconciled and how GR ultimately shifts the balance to a net anti-inflammatory profile. As such, there is consensus that GR deserves a second life as a drug target, with either refined classic GCs or a novel generation of nonsteroidal GR-targeting molecules, to meet the increasing clinical needs of today to treat inflammation and cancer.
Sofie J. Desmet, Karolien De Bosscher
The vitamin D receptor (VDR) is the single known regulatory mediator of hormonal 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] in higher vertebrates. It acts in the nucleus of vitamin D target cells to regulate the expression of genes whose products control diverse, cell type–specific biological functions that include mineral homeostasis. In this Review we describe progress that has been made in defining new cellular sites of action of this receptor, the mechanisms through which this mediator controls the expression of genes, the biology that ensues, and the translational impact of this receptor on human health and disease. We conclude with a brief discussion of what comes next in understanding vitamin D biology and the mechanisms that underlie its actions.
J. Wesley Pike, Mark B. Meyer, Seong-Min Lee, Melda Onal, Nancy A. Benkusky
The adult heart is uniquely designed and equipped to provide a continuous supply of energy in the form of ATP to support persistent contractile function. This high-capacity energy transduction system is the result of a remarkable surge in mitochondrial biogenesis and maturation during the fetal-to-adult transition in cardiac development. Substantial evidence indicates that nuclear receptor signaling is integral to dynamic changes in the cardiac mitochondrial phenotype in response to developmental cues, in response to diverse postnatal physiologic conditions, and in disease states such as heart failure. A subset of cardiac-enriched nuclear receptors serve to match mitochondrial fuel preferences and capacity for ATP production with changing energy demands of the heart. In this Review, we describe the role of specific nuclear receptors and their coregulators in the dynamic control of mitochondrial biogenesis and energy metabolism in the normal and diseased heart.
Rick B. Vega, Daniel P. Kelly
Parasitic worms infect billions of people worldwide. Current treatments rely on a small group of drugs that have been used for decades. A shortcoming of these drugs is their inability to target the intractable infectious stage of the parasite. As well-known therapeutic targets in mammals, nuclear receptors have begun to be studied in parasitic worms, where they are widely distributed and play key roles in governing metabolic and developmental transcriptional networks. One such nuclear receptor is DAF-12, which is required for normal nematode development, including the all-important infectious stage. Here we review the emerging literature that implicates DAF-12 and potentially other nuclear receptors as novel anthelmintic targets.
Zhu Wang, Nathaniel E. Schaffer, Steven A. Kliewer, David J. Mangelsdorf
Neural pathways, especially those in the hypothalamus, integrate multiple nutritional, hormonal, and neural signals, resulting in the coordinated control of body weight balance and glucose homeostasis. Nuclear receptors (NRs) sense changing levels of nutrients and hormones, and therefore play essential roles in the regulation of energy homeostasis. Understanding the role and the underlying mechanisms of NRs in the context of energy balance control may facilitate the identification of novel targets to treat obesity. Notably, NRs are abundantly expressed in the brain, and emerging evidence indicates that a number of these brain NRs regulate multiple aspects of energy balance, including feeding, energy expenditure and physical activity. In this Review we summarize some of the recent literature regarding effects of brain NRs on body weight regulation and discuss mechanisms underlying these effects.
Yong Xu, Bert W. O’Malley, Joel K. Elmquist
The nuclear receptors PPARα (encoded by
Geoffrey A. Preidis, Kang Ho Kim, David D. Moore