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The peroxisome is an organelle with essential roles in lipid metabolism, maintenance of reactive oxygen species homeostasis, and anaplerotic replenishment of tricarboxylic acid cycle intermediates destined for mitochondria. Peroxisomes constitute a dynamic endomembrane system. The homeostatic state of this system is upheld via two pathways for assembling and maintaining the diverse peroxisomal compartments constituting it; the relative contribution of each pathway to preserving such system may vary in different organisms and under various physiological conditions. One pathway begins with the targeting of certain peroxisomal membrane proteins to an endoplasmic reticulum template and their exit from the template via pre-peroxisomal carriers; these carriers mature into metabolically active peroxisomes containing the entire complement of membrane and matrix proteins. Another pathway operates via growth and maturation of pre-existing peroxisomal precursors that do not originate from the endoplasmic reticulum; mature peroxisomes proliferate by undergoing fission. Recent studies have uncovered new roles for the peroxisomal endomembrane system in orchestrating important developmental decisions and defining organismal longevity. This Frontiers Special Topic Issue is focused on the advances in our understanding of how evolutionarily distant organisms coordinate the formation, maturation, proliferation, maintenance, inheritance and quality control of the peroxisomal endomembrane system and how peroxisomal endomembranes communicate with other cellular compartments to orchestrate complex biological processes and various developmental programs from inside the cell.

peroxisomal endomembrane system --- development --- Reactive Oxygen Species --- Aging --- peroxisome --- Lipid Metabolism --- Endoplasmic Reticulum --- peroxisome biogenesis

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The present work is dedicated to the possible therapeutic effects of the PPAR agonists. PPARs (Peroxisome Proliferating-Activated Receptor) are nuclear receptors. They are subdivided into 3 main isotypes: PPARα, PPARγ and PPARβ/δ. These receptors are activated by endogenous hydrophobic molecules such as fatty acids or exogenous hydrophobic molecules like fibrates. PPAR are key receptors in the metabolic syndrome. lndeed, their activation allows among others a reduction of the glycemia (PPARγ) and a reduction of the triglycerides (PPARα). Currently, various PPAR agonists drugs are marketed in Belgium: they are fibrates (PPARα) and glitazones (PPARγ). A new family of dual PPARα/y agonists, the glitazars, has been developed; this one could perhaps become a new treatment for type 2 diabetes. Some glitazars successfuNy passed the prechnical development phase (muraglitazar, tesaglitazar). Despite everything, the clinical development of these glitazars was stopped in 2006, flot because of Iack of effectiveness, but due to serious unforeseen adverse effects (myocardial infarctions, transient ischemic attacks, increase in serum creatinin). However, the researchers do not give up PPARs: indeed they are also involved in the mechanism of the inflammation or cancer. Moreover the 3Id isotype PPARβ/δ could have a central role in the metabolic syndrome and in some cancer. This work reviews of the state of the question Le présent travail est consacré aux effets thérapeutiques possibles des agonistes PPAR. Les PPAR (Peroxisome Proliferating-Activated Receptor) sont des récepteurs nucléaires. Ils se subdivisent en 3 isotypes principaux PPARαγ, PPARγ et PPARβ/δ. Ces récepteurs sont activés par des molécules hydrophobes endogènes comme les acides gras ou exogènes, comme les fibrates. Les PPAR sont des récepteurs clés dans le syndrome métabolique. En effet, leur activation permet notamment une diminution de la glycémie (PPARγ) et une diminution des triglycérides (PPARα). Actuellement, divers médicaments agonistes PPAR sont commercialisés en Belgique : il s’agit des fibrates (PPARα) et des glitazones (PPARγ). Une nouvelle famille de molécules double agonistes PPARa/γ, les glitazars a été développée ; celle-ci pouvait peut-être devenir un nouveau traitement pour le diabète de type 2. Certains glitazars ont passé avec succès la phase de développement préclinique (muraglitazar, tésaglitazar). Malgré tout, le développement clinique de ces glitazars a été stoppé en 2006, non pas par manque d’efficacité de ces molécules, mais à cause d’effets indésirables graves imprévus (infarctus du myocarde, attaques ischémiques transitoires, augmentation de la créatinine sérique). Cependant, les chercheurs n’abandonnent pas les PPAR. En effet, ceux-ci sont également impliqués dans le mécanisme de l’inflammation ou du cancer. De plus, le 3e isotype, PPARβ/δ pourrait avoir un rôle central dans le syndrome métabolique et dans certains cancers. Ce travail propose une revue de l’état de la question.

PPAR beta --- PPAR delta --- PPAR alpha --- Peroxisome Proliferator-Activated Receptors

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At no other time in its history has humankind been as concerned about good health. Lifestyle habits are promoted as indispensable allies for the daily prevention against so-called metabolic diseases. Paradoxically, the world has never been so obese, while the beauty canons have never been so skinny! However, there is more to energy balance than alterations in body weight. In the 1990s, it was found that fatty acids not only function as fuel molecules only, but also serve as signaling molecules. They bind nuclear hormone receptors, the Peroxisome Proliferator-Activated Receptors, commonly referred to by the acronym PPARs. PPARs are transcription factors that directly control the expression of genes of metabolism, thereby impacting a multitude of pathways crucial for whole body physiology. PPARs are also activated by synthetic agonists, which are drugs used for lowering triglycerides and blood sugar. This book features articles that address tools for the identification of novel PPAR ligands, as well as the roles of the receptors in several organs, such as the brain, heart, liver, adipose tissue, gut, and muscle. As such, this book documents the multifaceted roles of these nuclear receptors that continue to attract significant attention, not least because of their still not fully realized potential to treat several health conditions.

Ligand identification --- Peroxisome Proliferator-Activated Receptors (PPARs) --- Energy homeostasis --- Metabolic diseases --- Metabolic regulations --- Tumor development

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This reprint combines recent original manuscripts and reviews covering the multiple functions of peroxisome proliferator-activated receptors in physiology and pathophysiology. Potential applications and limitations of PPAR agonists and antagonists are discussed. All original contributions were published in Cells.

peroxisome-proliferator activated receptors --- tumor angiogenesis --- tumor progression --- metastasis formation --- endothelial cells --- RNA sequencing --- PPARs --- toxicology --- pharmacology --- ligand --- vascular --- coronary artery --- lipidomics --- eicosanoids --- inflammation --- CYP450 --- peroxisome proliferator-activated receptor --- angiogenesis --- proliferation --- metastasis --- immortality --- resistance to cell death --- growth suppressors --- immune system --- cellular metabolism --- PPAR --- nuclear receptors --- addiction --- alcohol --- nicotine --- opioids --- psychostimulants --- animal models --- human studies --- Alzheimer’s --- risk factors --- PPARα --- lipids --- fatty acids --- modulators --- cognition --- sex --- therapy --- hypertrophic adipocytes --- PPARG isoforms --- PPARG splicing --- dominant-negative isoform --- in vitro adipocytes --- adipogenesis --- hypertrophic obesity --- insulin-resistance --- peroxisome proliferator-activated receptors (PPARs) --- synthetic agonists --- non-alcoholic fatty liver disease (NAFLD) --- non-alcoholic steatohepatitis (NASH) --- fibrosis --- Sirtuin1 --- peroxisome proliferator-activated receptor-γ coactivator-1α --- peroxisome proliferator activated receptors --- obesity --- metabolic syndrome --- vitamin B12 --- folate --- fetal programming --- inherited metabolic disorders --- PGC-1α, disease --- kidney --- cancer --- AKI --- CKD --- nephron --- PKD --- cilia --- cystogenesis --- ligands --- Alzheimer’s disease (AD)

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Mounting evidence suggests a bidirectional relationship between metabolism and inflammation. Molecular crosstalk between these processes occurs at different levels with the participation of nuclear receptors, including peroxisome proliferator-activated receptors (PPARs). There are three PPAR isotypes, α, β/δ, and γ, which modulate metabolic and inflammatory pathways, making them key for the control of cellular, organ, and systemic processes. PPAR activity is governed by fatty acids and fatty acid derivatives, and by drugs used in clinics (glitazones and fibrates). The study of PPAR action, also modulated by post-translational modifications, has enabled extraordinary advances in the understanding of the multifaceted roles of these receptors in metabolism, energy homeostasis, and inflammation both in health and disease. This Special Issue of IJMS includes a broad range of basic and translational article, both original research and reviews, focused on the latest developments in the regulation of metabolic and/or inflammatory processes by PPARs in all organs and the microbiomes of different vertebrate species.

Research & information: general --- Biology, life sciences --- Biochemistry --- nuclear receptor --- gene transcription --- inflammation --- molecular docking --- PPARβ/δ --- lung --- pulmonary artery --- GW0742 --- GSK3787 --- docking --- lipopolysaccharide (LPS) --- PPARγ ligand --- coumarin --- fluorescent ligand --- screening --- crystal structure --- PPAR --- atopic dermatitis --- psoriasis --- metabolic reprograming --- glucose --- fatty acids --- mycobacteria --- M. tuberculosis --- M. leprae --- PPARs --- lipid droplets --- metabolic alterations --- hepatic damage --- nuclear factors --- pharmacological targets --- AMPK --- GDF15 --- insulin resistance --- type 2 diabetes mellitus --- peroxisome proliferator-activated receptor gamma (PPARγ) --- real-time PCR --- ELISA --- immunohistochemistry --- signaling pathway --- PPAR gamma --- brain --- neural stem cells --- infection --- neuroinflammation --- HIV --- Zika --- cytomegalovirus --- neurogenesis --- microglia --- liver damage --- toll-like receptor 4 --- P2Y2 receptor --- metabolic syndrome --- resveratrol --- quercetin --- PPARα --- peroxisome --- β-oxidation --- PPRE --- ligand --- coregulator --- micronutrients --- PPARα knockout --- adipose tissue --- browning --- lipid metabolism --- depression --- PPARg --- neuropathology --- corticotropin releasing hormone --- norepinephrine --- subgenual prefrontal cortex --- amygdala --- nucleus accumbens --- common carotid artery occlusion --- electroretinography --- fibroblast growth factor 21 --- pemafibrate --- peroxisome proliferator-activated receptor alpha --- retinal ischemia --- skeletal muscle --- substrate metabolism --- nonalcoholic fatty liver disease (NAFLD) --- sex dimorphism --- lipidomics --- hepatic sex-biased gene expression --- PPARγ --- pulmonary arterial hypertension --- TGFβ --- vascular injury --- proliferation --- kidney fibrosis --- pattern-recognition receptors --- phagocytosis --- nitric oxide synthase --- fenofibrate --- oleoylethanolamide --- palmitoylethanolamide --- cancer --- immunity --- obesity --- diabetes --- miRNA --- DNA methylation --- histone modification --- peroxisome-proliferator-activated receptor --- fatty acid oxidation --- doping control --- regulatory T cells --- exercise --- nuclear receptors --- nutrigenomics --- energy homeostasis --- dairy animals --- non-alcoholic fatty liver disease (NAFLD) --- non-alcoholic steatohepatitis (NASH) --- peroxisome proliferator-activated receptors (PPAR) --- bezafibrate --- fenofibric acid --- peroxisome proliferator-activated receptor --- dual/pan agonist --- X-ray crystallography --- n/a