scholarly journals The Role of PPARs in Disease

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2367
Author(s):  
Nicole Wagner ◽  
Kay-Dietrich Wagner
Keyword(s):  
Target Genes ◽  
Peroxisome Proliferator ◽  
Downstream Target ◽  
Novel Approach ◽  
Pparγ Agonists ◽  
Cell Type Specific ◽  
Peroxisome Proliferator Activated Receptors ◽  
Specific Regulation ◽  
X Receptors

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that function as ligand-activated transcription factors. They exist in three isoforms: PPARα, PPARβ/δ, and PPARγ. For all PPARs, lipids are endogenous ligands, linking them directly to metabolism. PPARs form heterodimers with retinoic X receptors, and upon ligand binding, they modulate the gene expression of downstream target genes, depending on the presence of co-repressors or co-activators. This results in a complex, cell type-specific regulation of proliferation, differentiation, and cell survival. PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPARβ/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases; however, this has been limited due to the highly controversial function of PPARβ/δ in cancer. This Special Issue of Cells brings together the most recent advances in understanding the various aspects of the action of PPARs, and it provides new insights into our understanding of PPARs, implying also the latest therapeutic perspectives for the utility of PPAR modulation in different disease settings.

scholarly journals Peroxisome Proliferator-Activated Receptor Subtype- and Cell-Type-Specific Activation of Genomic Target Genes upon Adenoviral Transgene Delivery

2006 ◽  
Vol 26 (15) ◽  
pp. 5698-5714 ◽  
Author(s):  
Ronni Nielsen ◽  
Lars Grøntved ◽  
Hendrik G. Stunnenberg ◽  
Susanne Mandrup
Keyword(s):  
Target Genes ◽  
Receptor Subtype ◽  
Peroxisome Proliferator ◽  
Cell Type ◽  
Peroxisome Proliferator Activated Receptor ◽  
Molecular Events ◽  
Adenoviral Delivery ◽  
Cell Type Specific ◽  
Peroxisome Proliferator Activated Receptors ◽  
The Individual

ABSTRACT Investigations of the molecular events involved in activation of genomic target genes by peroxisome proliferator-activated receptors (PPARs) have been hampered by the inability to establish a clean on/off state of the receptor in living cells. Here we show that the combination of adenoviral delivery and chromatin immunoprecipitation (ChIP) is ideal for dissecting these mechanisms. Adenoviral delivery of PPARs leads to a rapid and synchronous expression of the PPAR subtypes, establishment of transcriptional active complexes at genomic loci, and immediate activation of even silent target genes. We demonstrate that PPARγ2 possesses considerable ligand-dependent as well as independent transactivation potential and that agonists increase the occupancy of PPARγ2/retinoid X receptor at PPAR response elements. Intriguingly, by direct comparison of the PPARs (α, γ, and β/δ), we show that the subtypes have very different abilities to gain access to target sites and that in general the genomic occupancy correlates with the ability to activate the corresponding target gene. In addition, the specificity and potency of activation by PPAR subtypes are highly dependent on the cell type. Thus, PPAR subtype-specific activation of genomic target genes involves an intricate interplay between the properties of the subtype- and cell-type-specific settings at the individual target loci.

The metabolic coregulator RIP140: an update

2010 ◽  
Vol 299 (3) ◽  
pp. E335-E340 ◽  
Author(s):  
Asmaà Fritah ◽  
Mark Christian ◽  
Malcolm G. Parker
Keyword(s):  
Nuclear Receptors ◽  
Posttranslational Modifications ◽  
Energy Homeostasis ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Transcriptional Coregulator ◽  
Peroxisome Proliferator Activated Receptors ◽  
Direct Regulation

RIP140 is a transcriptional coregulator highly expressed in metabolic tissues where it has important and diverse actions. RIP140-null mice show that it plays a crucial role in the control of lipid metabolism in adipose tissue, skeletal muscle, and the liver and is essential for female fertility. RIP140 has been shown to act as a ligand-dependent transcriptional corepressor for metabolic nuclear receptors such as estrogen-related receptors and peroxisome proliferator-activated receptors. The role of RIP140 as a corepressor has been strengthened by the characterization of RIP140-overexpressing mice, although it emerges through several studies that RIP140 can also behave as a coactivator. Nuclear localization of RIP140 is important for controlling transcription of target genes and is subject to regulation by posttranslational modifications. However, cytoplasmic RIP140 has been shown to play a role in the control of metabolism through direct regulation of glucose transport in adipocytes. In this review, we focus on recent advances highlighting the growing importance of RIP140 as a regulator of energy homeostasis.

scholarly journals Regulation of Peroxisome Proliferator-Activated Receptors by E6-Associated Protein

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-8 ◽  
Author(s):  
Lakshmi Gopinathan ◽  
Daniel B. Hannon ◽  
Russell W. Smith ◽  
Jeffrey M. Peters ◽  
John P. Vanden Heuvel
Keyword(s):  
Ubiquitin Ligase ◽  
Target Genes ◽  
Peroxisome Proliferator ◽  
Mrna Levels ◽  
Independent Manner ◽  
Coordinate Regulation ◽  
Protein Levels ◽  
Ubiquitin Ligase Activity ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors (NRs) that regulate genes involved in lipid and glucose metabolism. PPAR activity is regulated by interactions with cofactors and of interest are cofactors with ubiquitin ligase activity. The E6-associated protein (E6-AP) is an E3 ubiquitin ligase that affects the activity of other NRs, although its effects on PPARs have not been examined. E6-AP inhibited the ligand-independent transcriptional activity of PPARαand PPARβ, with marginal effects on PPARγ, and decreased basal mRNA levels of PPARαtarget genes. Inhibition of PPARαactivity required the ubiquitin ligase function of E6-AP, but occurred in a proteasome-independent manner. PPARαinteracted with E6-AP, and in mice treated with PPARαagonist clofibrate, mRNA and protein levels of E6-AP were increased in wildtype, but not in PPARαnull mice, indicating a PPARα-dependent regulation. These studies suggest coordinate regulation of E6-AP and PPARα, and contribute to our understanding of the role of PPARs in cellular metabolism.

scholarly journals PPARs Integrate the Mammalian Clock and Energy Metabolism

PPAR Research ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Lihong Chen ◽  
Guangrui Yang
Keyword(s):  
Energy Metabolism ◽  
Nuclear Receptors ◽  
Essential Role ◽  
Target Gene ◽  
Target Genes ◽  
Circadian Regulation ◽  
Peroxisome Proliferator ◽  
Mouse Tissues ◽  
Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptors that function as transcription factors regulating the expression of numerous target genes. PPARs play an essential role in various physiological and pathological processes, especially in energy metabolism. It has long been known that metabolism and circadian clocks are tightly intertwined. However, the mechanism of how they influence each other is not fully understood. Recently, all three PPAR isoforms were found to be rhythmically expressed in given mouse tissues. Among them, PPARαand PPARγare direct regulators of core clock components, Bmal1 and Rev-erbα, and, conversely, PPARαis also a direct Bmal1 target gene. More importantly, recent studies using knockout mice revealed that all PPARs exert given functions in a circadian manner. These findings demonstrated a novel role of PPARs as regulators in correlating circadian rhythm and metabolism. In this review, we summarize advances in our understanding of PPARs in circadian regulation.

scholarly journals Lysosome-Dependent LXR and PPARδ Activation Upon Efferocytosis in Human Macrophages

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana Carolina Mota ◽  
Monica Dominguez ◽  
Andreas Weigert ◽  
Ryan G. Snodgrass ◽  
Dmitry Namgaladze ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Target Genes ◽  
Inflammatory Responses ◽  
Regulatory Element ◽  
Peroxisome Proliferator ◽  
Liver X Receptors ◽  
Human Macrophages ◽  
Sterol Regulatory Element ◽  
Peroxisome Proliferator Activated Receptors ◽  
X Receptors

Efferocytosis is critical for tissue homeostasis, as its deregulation is associated with several autoimmune pathologies. While engulfing apoptotic cells, phagocytes activate transcription factors, such as peroxisome proliferator-activated receptors (PPAR) or liver X receptors (LXR) that orchestrate metabolic, phagocytic, and inflammatory responses towards the ingested material. Coordination of these transcription factors in efferocytotic human macrophages is not fully understood. In this study, we evaluated the transcriptional profile of macrophages following the uptake of apoptotic Jurkat T cells using RNA-seq analysis. Results indicated upregulation of PPAR and LXR pathways but downregulation of sterol regulatory element-binding proteins (SREBP) target genes. Pharmacological inhibition and RNA interference pointed to LXR and PPARδ as relevant transcriptional regulators, while PPARγ did not substantially contribute to gene regulation. Mechanistically, lysosomal digestion and lysosomal acid lipase (LIPA) were required for PPAR and LXR activation, while PPARδ activation also demanded an active lysosomal phospholipase A2 (PLA2G15). Pharmacological interference with LXR signaling attenuated ABCA1-dependent cholesterol efflux from efferocytotic macrophages, but suppression of inflammatory responses following efferocytosis occurred independently of LXR and PPARδ. These data provide mechanistic details on LXR and PPARδ activation in efferocytotic human macrophages.

scholarly journals Nutrigenomic Functions of PPARs in Obesogenic Environments

PPAR Research ◽  
2016 ◽  
Vol 2016 ◽  
pp. 1-17 ◽  
Author(s):  
Soonkyu Chung ◽  
Young Jun Kim ◽  
Soo Jin Yang ◽  
Yunkyoung Lee ◽  
Myoungsook Lee
Keyword(s):  
Target Genes ◽  
Current Knowledge ◽  
Critical Role ◽  
Bioactive Molecules ◽  
Metabolic Adaptation ◽  
Peroxisome Proliferator ◽  
Beige Adipocytes ◽  
Peroxisome Proliferator Activated Receptors ◽  
Obesogenic Environments

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that mediate the effects of several nutrients or drugs through transcriptional regulation of their target genes in obesogenic environments. This review consists of three parts. First, we summarize current knowledge regarding the role of PPARs in governing the development of white and brown/beige adipocytes from uncommitted progenitor cells. Next, we discuss the interactions of dietary bioactive molecules, such as fatty acids and phytochemicals, with PPARs for the modulation of PPAR-dependent transcriptional activities and metabolic consequences. Lastly, the effects of PPAR polymorphism on obesity and metabolic outcomes are discussed. In this review, we aim to highlight the critical role of PPARs in the modulation of adiposity and subsequent metabolic adaptation in response to dietary challenges and genetic modifications. Understanding the changes in obesogenic environments as a consequence of PPARs/nutrient interactions may help expand the field of individualized nutrition to prevent obesity and obesity-associated metabolic comorbidities.

Transcriptional regulation of macrophage cholesterol trafficking by PPARα and LXR

2006 ◽  
Vol 34 (6) ◽  
pp. 1128-1131 ◽  
Author(s):  
G. Chinetti ◽  
J.C. Fruchart ◽  
B. Staels
Keyword(s):  
Transcription Factors ◽  
Peroxisome Proliferator ◽  
Liver X Receptors ◽  
Cholesterol Trafficking ◽  
Peroxisome Proliferator Activated Receptors ◽  
Atherosclerosis Development ◽  
X Receptors ◽  
And Function ◽  
Atherosclerosis Research

PPARs (peroxisome-proliferator-activated receptors) and LXRs (liver X receptors) are ligand-activated transcription factors that control lipid and glucose metabolism, as well as the inflammatory response. Since the macrophage plays an important role in host defence and immuno-inflammatory pathologies, particular attention has been paid to the role of PPARs and LXRs in the control of macrophage gene expression and function. Altered macrophage functions contribute to the pathogenesis of many infectious, immunological and inflammatory disease processes, including atherosclerosis. Research over the last few years has revealed important roles for PPARs and LXRs in macrophage inflammation and cholesterol homoeostasis with consequences in atherosclerosis development. This review will discuss the role of these transcription factors in the control of cholesterol trafficking in macrophages.

New trends in the pharmacological intervention of PPARs in obesity: Role of natural and synthetic compounds_

2020 ◽  
Vol 28 ◽  
Author(s):  
Seyed Mohammad Nabavi ◽  
Kasi Pandima Devi ◽  
Sethuraman Sathya ◽  
Ana Sanches-Silva ◽  
Listos Joanna ◽  
...  
Keyword(s):  
Tissue Expression ◽  
Health Concern ◽  
Pharmacological Intervention ◽  
Peroxisome Proliferator ◽  
Expression Of Genes ◽  
Ppar Agonists ◽  
Prevalence Of Obesity ◽  
Peroxisome Proliferator Activated Receptors ◽  
Natural And Synthetic

: Obesity is a major health concern for a growing fraction of the population, with the prevalence of obesity and its related metabolic disorders not being fully understood. Over the last decade, many attempts have been undertaken to understand the mechanisms at the basis of this condition, in which the accumulation of fat occurring in adipose tissue, leads to the pathogenesis of obesity related disorders. Among the most recent studies, those on Peroxisome Proliferator Activated Receptors (PPARs) revealed that these nuclear receptor proteins acting as transcription factors, among others, regulate the expression of genes involved in energy, lipid, and glucose metabolisms, and chronic inflammation. The three different isotypes of PPARs, with different tissue expression and ligand binding specificity, exert similar or overlapping functions directly or indirectly linked to obesity. In this study, we reviewed the available scientific reports concerning the PPARs structure and functions, especially in obesity, considering both natural and synthetic ligands and their role in the therapy of obesity and obesity-associated disorders. In the whole, the collected data show that there are both natural and synthetic compounds that show beneficial promising activity as PPAR agonists in chronic diseases related to obesity.

scholarly journals Molecular Mechanisms of Obesity-Linked Cardiac Dysfunction: An Up-Date on Current Knowledge

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 629
Author(s):  
Jorge Gutiérrez-Cuevas ◽  
Ana Sandoval-Rodriguez ◽  
Alejandra Meza-Rios ◽  
Hugo Christian Monroy-Ramírez ◽  
Marina Galicia-Moreno ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Dysfunction ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Peroxisome Proliferator ◽  
White Adipocyte ◽  
Peroxisome Proliferator Activated Receptors ◽  
And Oxidative Stress

Obesity is defined as excessive body fat accumulation, and worldwide obesity has nearly tripled since 1975. Excess of free fatty acids (FFAs) and triglycerides in obese individuals promote ectopic lipid accumulation in the liver, skeletal muscle tissue, and heart, among others, inducing insulin resistance, hypertension, metabolic syndrome, type 2 diabetes (T2D), atherosclerosis, and cardiovascular disease (CVD). These diseases are promoted by visceral white adipocyte tissue (WAT) dysfunction through an increase in pro-inflammatory adipokines, oxidative stress, activation of the renin-angiotensin-aldosterone system (RAAS), and adverse changes in the gut microbiome. In the heart, obesity and T2D induce changes in substrate utilization, tissue metabolism, oxidative stress, and inflammation, leading to myocardial fibrosis and ultimately cardiac dysfunction. Peroxisome proliferator-activated receptors (PPARs) are involved in the regulation of carbohydrate and lipid metabolism, also improve insulin sensitivity, triglyceride levels, inflammation, and oxidative stress. The purpose of this review is to provide an update on the molecular mechanisms involved in obesity-linked CVD pathophysiology, considering pro-inflammatory cytokines, adipokines, and hormones, as well as the role of oxidative stress, inflammation, and PPARs. In addition, cell lines and animal models, biomarkers, gut microbiota dysbiosis, epigenetic modifications, and current therapeutic treatments in CVD associated with obesity are outlined in this paper.

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