Nuclear Receptors
Series edited by Stacie Bloom
This series focuses on the biologic roles of members of the nuclear receptor superfamily of ligand-dependent transcription factors involved in the regulation of lipid and carbohydrate metabolism, immunity, inflammation, and wound repair. The study of these receptors, including estrogen receptors, PPARs, and liver X receptors, has provided great insight into the pathogenesis of diseases including obesity, diabetes, and atherosclerosis, and has the potential to accelerate the development of new, safer treatment strategies.
Articles in series
Abstract
Estrogen receptors, PPARs, and liver X receptors are members of the nuclear receptor superfamily of ligand-dependent transcription factors that regulate diverse aspects of development and homeostasis. Recent studies of the biologic roles of these receptors and their mechanisms of action have significantly advanced our understanding of transcriptional programs that control lipid and carbohydrate metabolism, immunity and inflammation, and wound repair. These findings provide insights into the therapeutic actions of existing drugs that target nuclear receptors and raise new possibilities for development of safer, more effective drugs for the prevention and treatment of metabolic and cardiovascular diseases. In this introduction to this Review series, underlying mechanisms that enable nuclear receptors to positively and negatively regulate gene expression are presented as background to the focused reviews on estrogen receptors, PPARs, liver X receptors, and the PPARγ coactivator-1 (PGC-1) family of coactivators.
Authors
Christopher K. Glass
Abstract
Estrogens influence many physiological processes in mammals, including but not limited to reproduction, cardiovascular health, bone integrity, cognition, and behavior. Given this widespread role for estrogen in human physiology, it is not surprising that estrogen is also implicated in the development or progression of numerous diseases, which include but are not limited to various types of cancer (breast, ovarian, colorectal, prostate, endometrial), osteoporosis, neurodegenerative diseases, cardiovascular disease, insulin resistance, lupus erythematosus, endometriosis, and obesity. In many of these diseases, estrogen mediates its effects through the estrogen receptor (ER), which serves as the basis for many therapeutic interventions. This Review will describe diseases in which estrogen, through the ER, plays a role in the development or severity of disease.
Authors
Bonnie J. Deroo, Kenneth S. Korach
Abstract
PPARα is a nuclear receptor that regulates liver and skeletal muscle lipid metabolism as well as glucose homeostasis. Acting as a molecular sensor of endogenous fatty acids (FAs) and their derivatives, this ligand-activated transcription factor regulates the expression of genes encoding enzymes and transport proteins controlling lipid homeostasis, thereby stimulating FA oxidation and improving lipoprotein metabolism. PPARα also exerts pleiotropic antiinflammatory and antiproliferative effects and prevents the proatherogenic effects of cholesterol accumulation in macrophages by stimulating cholesterol efflux. Cellular and animal models of PPARα help explain the clinical actions of fibrates, synthetic PPARα agonists used to treat dyslipidemia and reduce cardiovascular disease and its complications in patients with the metabolic syndrome. Although these preclinical studies cannot predict all of the effects of PPARα in humans, recent findings have revealed potential adverse effects of PPARα action, underlining the need for further study. This Review will focus on the mechanisms of action of PPARα in metabolic diseases and their associated vascular pathologies.
Authors
Philippe Lefebvre, Giulia Chinetti, Jean-Charles Fruchart, Bart Staels
Abstract
The nuclear receptor family of PPARs was named for the ability of the original member to induce hepatic peroxisome proliferation in mice in response to xenobiotic stimuli. However, studies on the action and structure of the 3 human PPAR isotypes (PPARα, PPARδ, and PPARγ) suggest that these moieties are intimately involved in nutrient sensing and the regulation of carbohydrate and lipid metabolism. PPARα and PPARδ appear primarily to stimulate oxidative lipid metabolism, while PPARγ is principally involved in the cellular assimilation of lipids via anabolic pathways. Our understanding of the functions of PPARγ in humans has been increased by the clinical use of potent agonists and by the discovery of both rare and severely deleterious dominant-negative mutations leading to a stereotyped syndrome of partial lipodystrophy and severe insulin resistance, as well as more common sequence variants with a much smaller impact on receptor function. These may nevertheless have much greater significance for the public health burden of metabolic disease. This Review will focus on the role of PPARγ in human physiology, with specific reference to clinical pharmacological studies, and analysis of PPARG gene variants in the abnormal lipid and carbohydrate metabolism of the metabolic syndrome.
Authors
Robert K. Semple, V. Krishna K. Chatterjee, Stephen O’Rahilly
Abstract
Obesity is a growing threat to global health by virtue of its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X. The nuclear receptors PPARα and PPARγ are therapeutic targets for hypertriglyceridemia and insulin resistance, respectively, and drugs that modulate these receptors are currently in clinical use. More recent work on the less-described PPAR isotype PPARδ has uncovered a dual benefit for both hypertriglyceridemia and insulin resistance, highlighting the broad potential of PPARδ in the treatment of metabolic disease. PPARδ enhances fatty acid catabolism and energy uncoupling in adipose tissue and muscle, and it suppresses macrophage-derived inflammation. Its combined activities in these and other tissues make it a multifaceted therapeutic target for the metabolic syndrome with the potential to control weight gain, enhance physical endurance, improve insulin sensitivity, and ameliorate atherosclerosis.
Authors
Grant D. Barish, Vihang A. Narkar, Ronald M. Evans
Abstract
Tissue damage resulting from chemical, mechanical, and biological injury, or from interrupted blood flow and reperfusion, is often life threatening. The subsequent tissue response involves an intricate series of events including inflammation, oxidative stress, immune cell recruitment, and cell survival, proliferation, migration, and differentiation. In addition, fibrotic repair characterized by myofibroblast transdifferentiation and the deposition of ECM proteins is activated. Failure to initiate, maintain, or stop this repair program has dramatic consequences, such as cell death and associated tissue necrosis or carcinogenesis. In this sense, inflammation and oxidative stress, which are beneficial defense processes, can become harmful if they do not resolve in time. This repair program is largely based on rapid and specific changes in gene expression controlled by transcription factors that sense injury. PPARs are such factors and are activated by lipid mediators produced after wounding. Here we highlight advances in our understanding of PPAR action during tissue repair and discuss the potential for these nuclear receptors as therapeutic targets for tissue injury.
Authors
Liliane Michalik, Walter Wahli
Abstract
The liver X receptors (LXRs) are nuclear receptors that play central roles in the transcriptional control of lipid metabolism. LXRs function as nuclear cholesterol sensors that are activated in response to elevated intracellular cholesterol levels in multiple cell types. Once activated, LXRs induce the expression of an array of genes involved in cholesterol absorption, efflux, transport, and excretion. In addition to their function in lipid metabolism, LXRs have also been found to modulate immune and inflammatory responses in macrophages. Synthetic LXR agonists promote cholesterol efflux and inhibit inflammation in vivo and inhibit the development of atherosclerosis in animal models. The ability of LXRs to integrate metabolic and inflammatory signaling makes them particularly attractive targets for intervention in human metabolic disease.
Authors
Noam Zelcer, Peter Tontonoz
Abstract
Members of the PPARγ coactivator-1 (PGC-1) family of transcriptional coactivators serve as inducible coregulators of nuclear receptors in the control of cellular energy metabolic pathways. This Review focuses on the biologic and physiologic functions of the PGC-1 coactivators, with particular emphasis on striated muscle, liver, and other organ systems relevant to common diseases such as diabetes and heart failure.
Authors
Brian N. Finck, Daniel P. Kelly
Copyright © 2019 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)