BBA - Molecular and Cell Biology of Lipids (v.1771, #8)

Peroxisome proliferator-activated receptors (PPARs) compose a family of nuclear receptors that mediate the effects of lipidic ligands at the transcriptional level. In this review, we highlight advances in the understanding of the PPAR ligand binding domain (LBD) structure at the atomic level. The overall structure of PPARs LBD is described, and important protein ligand interactions are presented. Structure–activity relationships between isotypes structures and ligand specificity are addressed. It is shown that the numerous experimental three-dimensional structures available, together with in silico simulations, help understanding the role played by the activating function-2 (AF-2) in PPARs activation and its underlying molecular mechanism. The relation between the PPARs constitutive activity and the intrinsic stability of the active conformation is discussed. Finally, the interactions of PPARs LBD with co-activators or co-repressors, as well as with the retinoid X receptor (RXR) are described and considered in relation to PPARs activation.
Keywords: Peroxisome proliferator-activated receptor; Structure; Activating Function-2; Regulators binding; Ligand specificity; Molecular switch;

PPARs and molecular mechanisms of transrepression by Mercedes Ricote; Christopher K. Glass (926-935).
In the last few years, PPARs have emerged as key regulators of inflammatory and immune responses. However, the mechanistic basis of the anti-inflammatory effects of peroxisome proliferator-activated receptors (PPARs) remains poorly understood. Accumulating evidence suggests that these effects result from inhibition of signal-dependent transcription factors that mediate inflammatory programs of gene activation. Several mechanisms underlying negative regulation of gene expression by PPARs have been described. Recent studies, using siRNA, microarray analysis and macrophage-specific knockout mice, have highlighted PPARs molecular transrepression mechanism in macrophages. Identification of their mechanism of action should help promote the understanding of the physiologic roles that PPARs play in immunity and contribute to the development of new therapeutic agents.
Keywords: Peroxisome proliferator-activated receptors; Inflammation; Macrophage; Transrepression; Coactivators; Corepressors;

Peroxisome proliferator-activated receptors (PPARs) regulate diverse biological processes such as development, differentiation, neoplastic conversion, inflammation and wound healing in addition to their critical roles in energy (lipid and carbohydrate) metabolism. Unliganded PPARs heterodimerize with retinoid X receptor α and repress transcription when bound to DNA by interacting with corepressor molecules. Upon canonical ligand binding, PPARs manifest conformational changes that facilitate the dissociation of corepressor molecules to enable a spatiotemporally orchestrated recruitment (association) of coactivators and coactivator-associated proteins to the liganded receptor. Functional significance for the existence of over 200 nuclear receptor cofactors is not readily evident, but emerging gene knockout mouse models show that some of the coactivators are essential for embryonic growth and survival and for controlling receptor specific target gene expression in a cell specific need based demands. Coactivators contain one or more highly conserved LXXLL amphiphatic α-helix motif, called nuclear receptor box, for direct interaction with the activation function 2 (AF-2) regions in nuclear receptors. PPARs interact with large multisubunit coactivator protein complexes, some exhibiting intrinsic histone acetyltransferase or methyltransferase activity, while others functioning as facilitators of ATP-dependent chromatin remodeling or as linkers to the basal transcription machinery. While the dynamic and coordinated changes in nuclear receptor expression and differences in the nature of their key target genes are important, it is becoming increasingly evident that perturbations in the expression of coactivators may affect the function of many nuclear receptors including PPARs. Tissue specific differences in coactivator expression add another dimension to the complexity of gene- and cell-specific transcriptional regulation. Identification of PPAR specific coactivators should further our understanding of the complexities of metabolic diseases associated with energy metabolism.
Keywords: PPARα,-β/δ or -γ; Transcriptional coactivator; PBP/TRAP220/MED1; Gene-knockout mouse model;

Modulation of PPAR activity via phosphorylation by Katherine A. Burns; John P. Vanden Heuvel (952-960).
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of transcription factors that respond to specific ligands by altering gene expression in a cell-, developmental- and sex-specific manner. Three subtypes of this receptor have been discovered (PPARα, β and γ), each apparently evolving to fulfill different biological niches. PPARs control a variety of target genes involved in lipid homeostasis, diabetes and cancer. Similar to other nuclear receptors, the PPARs are phosphoproteins and their transcriptional activity is affected by cross-talk with kinases and phosphatases. Phosphorylation by the mitogen-activated protein kinases (ERK- and p38-MAPK), Protein Kinase A and C (PKA, PKC), AMP Kinase (AMPK) and glycogen synthase kinase-3 (GSK3) affect their activity in a ligand-dependent or -independent manner. The effects of phosphorylation depend on the cellular context, receptor subtype and residue metabolized which can be manifested at several steps in the PPAR activation sequence including ligand affinity, DNA binding, coactivator recruitment and proteasomal degradation. The review will summarize the known PPAR kinases that directly act on these receptors, the sites affected and the result of this modification on receptor activity.
Keywords: Peroxisome proliferator-activated receptor; Mitogen activated protein kinase; Glycogen synthase kinase-3; Protein kinase A; Protein kinase C; Protein phosphorylation; Gene expression; Transcriptional regulation; Nuclear receptor;

PPARα and dyslipidemia by Caroline Duval; Michael Müller; Sander Kersten (961-971).
Dyslipidemia is defined by abnormal levels of plasma lipoproteins. Several different types of dyslipidemia can be distinguished. An important group of drugs used in the treatment of dyslipidemia are the fibrates. Fibrates serve as agonists for the peroxisome proliferator-activated receptor alpha (PPARα), a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. By binding to response elements mostly present in the promoter of target genes, PPARα governs the expression of numerous genes involved in a variety of metabolic processes. Activation of PPARα results in a reduction of plasma TG levels, which is achieved by: (1) induction of genes that decrease the availability of TG for hepatic VLDL secretion, and (2) induction of genes that promote lipoprotein lipase-mediated lipolysis of TG-rich plasma lipoproteins. The stimulatory effect of PPARα on plasma HDL levels in humans, which is opposite to what is observed in mice, appears to be mainly mediated via increased production of APOA1 and APOA2, the apolipoprotein constituents of HDL. Apart from its major actions outlined above, PPARα modulates lipoprotein metabolism in several other ways, mostly via direct up-regulation of specific PPARα target genes. By taking into account novel insights into the metabolism of plasma lipoproteins and by considering the latest information on PPARα-dependent gene regulation, a fresh perspective on the molecular mechanisms underlying the plasma lipoprotein modulating effect of PPARα is presented.
Keywords: Dyslipidemia; Peroxisome Proliferator Activated Receptor; High Density Lipoprotein; Very Low Density Lipoprotein;

PPARα in atherosclerosis and inflammation by Fokko Zandbergen; Jorge Plutzky (972-982).
Peroxisome proliferator-activated receptor (PPAR)α is a nuclear receptor activated by natural ligands such as fatty acids as well as by synthetic ligands such as fibrates currently used to treat dyslipidemia. PPARα regulates the expression of genes encoding proteins that are involved in lipid metabolism, fatty acid oxidation, and glucose homeostasis, thereby improving markers for atherosclerosis and insulin resistance. In addition, PPARα exerts anti-inflammatory effects both in the vascular wall and the liver. Here we provide an overview of the mechanisms through which PPARα affects the initiation and progression of atherosclerosis, with emphasis on the modulation of atherosclerosis-associated inflammatory responses. PPARα activation interferes with early steps in atherosclerosis by reducing leukocyte adhesion to activated endothelial cells of the arterial vessel wall and inhibiting subsequent transendothelial leukocyte migration. In later stages of atherosclerosis, evidence suggests activation of PPARα inhibits the formation of macrophage foam cells by regulating expression of genes involved in reverse cholesterol transport, formation of reactive oxygen species (ROS), and associated lipoprotein oxidative modification among others. Furthermore, PPARα may increase the stability of atherosclerotic plaques and limit plaque thrombogenicity. These various effects may be linked to the generation of PPARα ligands by endogenous mechanisms of lipoprotein metabolism. In spite of this dataset, other reports implicate PPARα in responses such as hypertension and diabetic cardiomyopathy. Although some clinical trials data with fibrates suggest that fibrates may decrease cardiovascular events, other studies have been less clear, in terms of benefit. Independent of the clinical effects of currently used drugs purported to achieve PPARα, extensive data establish the importance of PPARα in the transcriptional regulation of lipid metabolism, atherosclerosis, and inflammation.
Keywords: PPARs; Atherosclerosis; Endothelium; Macrophage; Lipoproteins;

The prevalence of metabolic disturbances, collectively known as metabolic syndrome, has reached an epidemic proportion in industrialized countries. Lifestyle interventions and pharmacological treatments of such pathologies are only partially efficient and new therapeutic approaches are urgently needed. This review focuses on the recent findings describing the regulatory functions of peroxisome proliferator-activated receptor beta (PPARβ) on lipid metabolism in several tissues and on the implications of such findings on the therapeutic usefulness of PPARβ agonists in the treatment of particular features of the metabolic syndrome, such as insulin resistance, obesity, dyslipidemia and cardiac dysfunctions.
Keywords: PPAR; Metabolic syndrome; Pharmacology; Skeletal muscle;

Peroxisome proliferator-activated receptors, PPARα, PPARβ/δ and PPARγ, are fatty acid activated transcription factors that belong to the nuclear hormone receptor family. While they are best known as transcriptional regulators of lipid and glucose metabolism, evidence has also accumulated for their importance in skin homeostasis. The three PPAR isotypes are expressed in rodent and human skin. Various cell culture and in vivo approaches suggest that PPARα contributes to fetal skin development, to epidermal barrier maturation and to sebocyte activity. PPARβ/δ regulates sebocyte differentiation, promotes hair follicle growth and has pro-differentiating effects in keratinocytes in normal and inflammatory conditions. In contrast, the role of PPARγ appears to be rather minor in keratinocytes, whereas its activity is required for sebaceous gland differentiation. Importantly, PPARα and β/δ are instrumental in skin repair after an injury, each of them playing specific roles. Due to their collective diverse functions in skin biology, PPARs represent a major research target for the understanding and treatment of many skin diseases, such as benign epidermal tumors, papillomas, acne vulgaris and psoriasis.
Keywords: Keratinocyte; Melanocyte; Sebaceous gland; Hair follicle; Wound-healing; Psoriasis; Skin cancer;

PPARγ in human and mouse physiology by Sami Heikkinen; Johan Auwerx; Carmen A. Argmann (999-1013).
The peroxisome proliferator activated receptor gamma (PPARγ) is a member in the nuclear receptor superfamily which mediates part of the regulatory effects of dietary fatty acids on gene expression. As PPARγ also coordinates adipocyte differentiation, it is an important component in storing the excess nutritional energy as fat. Our genes have evolved into maximizing energy storage, and PPARγ has a central role in the mismatch between our genes and our affluent western society which results in a broad range of metabolic disturbances, collectively known as the metabolic syndrome. A flurry of human and mouse studies has shed new light on the mechanisms how the commonly used insulin sensitizer drugs and PPARγ activators, thiazolidinediones, act, and which of their physiological effects are dependent of PPARγ. It is now evident that the full activation of PPARγ is less advantageous than targeted modulation of its activity. Furthermore, new roles for PPARγ signaling have been discovered in inflammation, bone morphogenesis, endothelial function, cancer, longevity, and atherosclerosis, to mention a few. Here we draw together and discuss these recent advances in the research into PPARγ biology.
Keywords: PPARγ; Mouse models; Human genetic variants; Longevity; Bone homeostasis; Metabolism;

PPARγ in immunity and inflammation: cell types and diseases by Lajos Széles; Dániel Töröcsik; László Nagy (1014-1030).
The lipid activated transcription factor, PPARγ appears to have multiple functions in the immune system. There are several cell types expressing the receptor, most prominently antigen presenting cells, such as macrophages and dendritic cells. The receptor's activation leads to primary transcriptional activation of many, mostly lipid metabolism-related genes. However, gene regulation also occurs on immunity and inflammation-related genes. Key questions are: in what way lipid metabolism and immune regulation are connected and how activation and/or repression of gene expression may modulate inflammatory and anti-inflammatory responses and in what way can these be utilized in therapy. Here we provide a cell type and disease centric review on the role of this lipid activated transcription factor in the various cells of the immune system it is expressed in, and in some major inflammatory diseases such as atherosclerosis, inflammatory bowel disease and rheumatoid arthritis.
Keywords: Peroxisome Proliferator-Activated Receptor gamma; Inflammation; Macrophage; Dendritic cell; Chronic inflammation; Atherosclerosis; Inflammatory bowel disease;

PPARs in the brain by Michael T. Heneka; Gary E. Landreth (1031-1045).
The biology of peroxisome proliferator activated receptors (PPARs) in physiological and pathophysiological processes has been primarily studied in peripherial organs and tissues. Recently it became clear that PPARs play an important role for the pathogenesis of various disorders of the CNS. The finding that activation of PPARs, and in particular, the PPARγ isoform, suppresses inflammation in peripherial macrophages and in models of human autoimmune disease, instigated the experimental evaluation of these salutary actions for several CNS disorders that have an inflammatory component. Activation of all PPAR isoforms, but especially of PPARγ, has been found to be protective in murine in vitro and in vivo models of Multiple Sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARγ activation in Multiple Sclerosis patients. Likewise, Alzheimer’s disease has a prominent inflammatory component that arises in response to neurodegeneration and to extracellular deposition of β-amyloid peptides. The fact that non steroidal anti-inflammatory drugs (NSAIDs) delay the onset and reduce the risk to develop Alzheimer’s disease, while they also bind to and activate PPARγ, led to the hypothesis that one dimension of NSAID protection in AD may be mediated by PPARγ. Several lines of evidence from in vitro and in vivo studies have supported this hypothesis, using Alzheimer disease related transgenic cellular and animal models. The ability of PPAR agonists to elicit anti-amyloidogenic, anti-inflammatory and insulin sensitizing effects may account for the observed effects. A number of clinical trials employing PPAR agonists have yielded promising results and further trials are in preparation, which aim to delineate the exact mechanism of interaction. Animal models of other neurodegenerative diseases such as Parkinson’s and Amyotrophic lateral sclerosis, both associated with a considerable degree of CNS inflammation, have been studied with a positive outcome. Yet it is not clear whether reduction of inflammation or additional mechanisms account for the observed neuroprotection. Less is known about the physiological role of PPARs for brain development, maintenance and function. Lesions from transgenic mouse models, however, provide evidence that PPARs may play pivotal roles for CNS development and function.
Keywords: Neuroinflammation; Alzheimer’s disease; Multiple Sclerosis; Parkinson’s disease; Amyotrophic Lateral Sclerosis; Ischemic Stroke; Cerebral neoplasm;

Exploration of PPAR functions by microarray technology—A paradigm for nutrigenomics by Meike Bünger; Guido J.E.J. Hooiveld; Sander Kersten; Michael Müller (1046-1064).
Traditionally, nutritional science was mainly concentrated on nutrient deficiencies and their effects on health and disease. However, over the past few decades, research emphasis has gradually shifted to the link between (over)-nutrition and chronic diseases. Driven by the continuing and accelerating discoveries in omics technology, unique possibilities have emerged to investigate the genome-wide effects of nutrients at the molecular level. Nutrigenomics uses these techniques in combination with a range of models and molecular tools as a strategy to understand the mechanistic basis of nutrition. As a paradigm for this strategy microarray analysis of genes regulated by peroxisome proliferator-activated receptors (PPARs) can serve. PPARs are ligand-activated transcription factors mediating the effect of unsaturated fatty acids and certain drugs on gene expression. Physiologically they act as fatty acid sensors in metabolic active organs, regulating a wide range of metabolic and signaling pathways. This allows cells to modulate their function and metabolic capacity, for example according to diet/nutrient-related changes in ligand concentration. Although much is already known about PPARs, gaps in our knowledge remain. In so far as the biological role of a particular PPAR is directly coupled to the function of its target genes, probing PPAR-regulated genes via the application of genomics tools can greatly improve our understanding of PPAR function. In this review we summarize and discuss the application of transcriptomics to study PPAR function, and discuss some of the challenges inherent to the application of transcriptomics to nutrigenomics research.
Keywords: Peroxisome proliferator-activated receptor; PPAR; Nutrition; Nutrigenomics; Microarray; Functional genomics;

Safety issues and prospects for future generations of PPAR modulators by Anne Rubenstrunk; Rémy Hanf; Dean W. Hum; Jean-Charles Fruchart; Bart Staels (1065-1081).
Because of their wide range of actions on glucose homeostasis, lipid metabolism and vascular inflammation, peroxisome proliferator-activated receptors (PPARs) are promising targets for the development of new drugs for the treatment of metabolic disorders such as diabetes, dyslipidemia and atherosclerosis. In clinical practice, PPARα agonists, such as the already available fibrates, improve dyslipidemia, while PPARγ agonists, such as thiazolidinediones, improve insulin resistance and diabetes. The complementary action of simultaneous activation of each PPAR in patients suffering from metabolic syndrome and type 2 diabetes has led to new pharmacological strategies focused on the development of agonists targeting more than one receptor such as the dual PPARα/γ agonists. However, despite the proven benefits of targeting PPARs, safety concerns have recently led to late stage development failures of various PPAR agonists including novel specific PPARγ agonists and dual PPARα/γ agonists. These safety concerns include potential carcinogenicity in rodents, signs of myopathy and rhabdomyolysis, increase in plasma creatinine and homocysteine, weight gain, fluid retention, peripheral edema and potential increased risk of cardiac failure. Although the discontinued compounds shared common side effects, the reason for discontinuation was always compound specific and the toxicological or adverse effects which have motivated the discontinuation could be either due to the activation of PPARγ, PPARα or both (class effect) or due to a PPAR unrelated effect. Thus, the risk evaluation of each adverse effect should be viewed on a case by case basis considering both the PPAR profile of the drug, its absorption/distribution profile, the nature of the side effect and the putative PPAR-related mechanism of action. This review mainly focuses on the preclinical and clinical adverse events of PPAR agonists that could be of concern when considering the development of new PPAR agonists. The selective modulation of PPAR activities is a promising approach to develop new drugs with preserved efficacy but diminished adverse effects.
Keywords: PPAR agonists; Safety issues; Side effects; Fluid retention; Edema; Congestive heart failure; Carcinogenesis; Myopathy; Rhabdomyolysis; Homocysteine; Creatinine; SPPARM;

The next generation of PPAR drugs: Do we have the tools to find them? by Barry G. Shearer; Andrew N. Billin (1082-1093).
Agonists of PPARα and PPARγ are currently approved for use in treating, respectively, dyslipidemia and type 2 diabetes. Agonists of PPARβ/δ are currently in development by several pharmaceutical companies. Despite their therapeutic importance, there are dose limiting side effects associated with PPAR drug treatments, thus a new generation of safer PPAR drugs are being actively sought after. In this review we will discuss the side effects associated the PPARs, how the current drugs in clinical development were discovered and new concepts in how to screen for PPAR drugs.
Keywords: PPAR; Safety; Drug discovery; TZD;

Molecular basis of selective PPARγ modulation for the treatment of Type 2 diabetes by Laurent Gelman; Jérôme N. Feige; Béatrice Desvergne (1094-1107).
Peroxisome proliferator-activated receptors (PPARs) (α, β/δ and γ) are lipid sensors capable of adapting gene expression to integrate various lipid signals. As such, PPARs are also very important pharmaceutical targets, and specific synthetic ligands exist for the different isotypes and are either currently used or hold promises in the treatment of major metabolic disorders. In particular, compounds of the class of the thiazolinediones (TZDs) are PPARγ agonists and potent insulin-sensitizers. The specific but still broad expression patterns of PPARγ, as well as its implication in numerous pathways, constitutes also a disadvantage regarding drug administration, since this potentially increases the chance to generate side-effects through the activation of the receptor in tissues or cells not affected by the disease. Actually, numerous side effects associated with the administration of TZDs have been reported. Today, a new generation of PPARγ modulators is being actively developed to activate the receptor more specifically, in a cell and time-dependent manner, in order to induce a specific subset of target genes only and modulate a restricted number of metabolic pathways. We will discuss here why and how the development of such selective PPARγ modulators is possible, and summarize the results obtained with the published molecules.
Keywords: PPAR; Selective modulator; Type 2 diabetes; tzd; Transcription;

The PPAR resource page by John P. Vanden Heuvel (1108-1112).
Keywords: PPAR resource page; Steroid; Thyroid receptor; Nuclear receptor;