New Insights into the Role of Peroxisome Proliferator-Activated Receptors in Regulating the Inflammatory Response after Tissue Injury

Major trauma results in a strong inflammatory response in injured tissue. This posttraumatic hyperinflammation has been implied in the adverse events leading to a breakdown of host defense mechanisms and ultimately to delayed organ failure. Ligands to peroxisome proliferator-activated receptors (PPARs) have recently been identified as potent modulators of inflammation in various acute and chronic inflammatory conditions. The main mechanism of action mediated by ligand binding to PPARs is the inhibition of the nuclear transcription factor NF-κB, leading to downregulation of downstream gene transcription, such as for genes encoding proinflammatory cytokines. Pharmacological PPAR agonists exert strong anti-inflammatory properties in various animal models of tissue injury, including central nervous system trauma, ischemia/reperfusion injury, sepsis, and shock. In addition, PPAR agonists have been shown to induce wound healing process after tissue trauma. The present review was designed to provide an up-to-date overview on the current understanding of the role of PPARs in the pathophysiology of the inflammatory response after major trauma. Therapeutic options for using recombinant PPAR agonists as pharmacological agents in the management of posttraumatic inflammation will be discussed.

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

Current Medicinal Chemistry ◽

10.2174/1570162x18666201123114934 ◽

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.

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Nuclear Control of the Inflammatory Response in Mammals by Peroxisome Proliferator-Activated Receptors

PPAR Research ◽

10.1155/2013/613864 ◽

2013 ◽

Vol 2013 ◽

pp. 1-23 ◽

Cited By ~ 51

Author(s):

Stéphane Mandard ◽

David Patsouris

Keyword(s):

Inflammatory Response ◽

Protective Role ◽

Peroxisome Proliferator ◽

Nuclear Control ◽

Inflammatory Bowel ◽

Peroxisome Proliferator Activated Receptors ◽

Ppar Ligands ◽

The Impact

Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that play pivotal roles in the regulation of a very large number of biological processes including inflammation. Using specific examples, this paper focuses on the interplay between PPARs and innate immunity/inflammation and, when possible, compares it among species. We focus on recent discoveries establishing how inflammation and PPARs interact in the context of obesity-induced inflammation and type 2 diabetes, mostly in mouse and humans. We illustrate that PPARγability to alleviate obesity-associated inflammation raises an interesting pharmacologic potential. In the light of recent findings, the protective role of PPARαand PPARβ/δagainst the hepatic inflammatory response is also addressed. While PPARs agonists are well-established agents that can treat numerous inflammatory issues in rodents and humans, surprisingly very little has been described in other species. We therefore also review the implication of PPARs in inflammatory bowel disease; acute-phase response; and central, cardiac, and endothelial inflammation and compare it along different species (mainly mouse, rat, human, and pig). In the light of the data available in the literature, there is no doubt that more studies concerning the impact of PPAR ligands in livestock should be undertaken because it may finally raise unconsidered health and sanitary benefits.

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Enhanced Hepatocarcinogenicity Due to Agonists of Peroxisome Proliferator-Activated Receptors in Senescent Rats: Role of Peroxisome Proliferation, Cell Proliferation, and Apoptosis

The Scientific World JOURNAL ◽

10.1100/tsw.2002.352 ◽

2002 ◽

Vol 2 ◽

pp. 1491-1500 ◽

Cited By ~ 9

Author(s):

Jihan Youssef ◽

Mostafa Badr

Keyword(s):

Cell Proliferation ◽

Peroxisome Proliferator ◽

Carcinogenic Effect ◽

Peroxisome Proliferator Activated Receptor ◽

New Findings ◽

Proliferation And Apoptosis ◽

Ppar Agonists ◽

Old Rats ◽

Peroxisome Proliferator Activated Receptors

Exposure to agonists of peroxisome proliferator-activated receptor alpha (PPARα) causes liver cancer in rodents, with aged animals being more susceptible than their younger counterparts to this effect. Treatment with these chemicals produced a five- to sevenfold higher yield of grossly visible hepatic tumors in old rats compared to young animals. The enhanced susceptibility of the aged livers to the carcinogenic effect of PPAR agonists could not be explained by differences in levels of peroxisomal and/or cell proliferation between young and old animals, as neither of these responses was exaggerated with aging. Reported studies have shown that activating PPARa results in the suppression of hepatic apoptosis. This effect is expected to diminish the ability of the liver to purge itself of pre-existing neoplastic cells, allowing them to progress to tumors. New findings from our laboratories show that the aged liver is exceedingly sensitive to the antiapoptotic effect of PPAR agonists. In addition, aged livers showed remarkably higher levels of the antiapoptotic protein Bcl-2 than livers of young, adult, and middle-aged animals. Interestingly, the PPARa agonist Wy-14,643 significantly diminished elements of the proapoptotic machinery (e.g., Bax, caspases, and fas) in the aged liver, while remarkably increasing elements of this machinery in younger animals. Taken together, while activation of PPARs appears to inhibit apoptosis in livers of senescent animals, activating these receptors seems to stimulate the apoptotic machinery in young animals. This paradoxical effect may be responsible for the exaggerated sensitivity of the aged liver to the carcinogenic effect of agents that activate PPARs.

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Role of peroxisome proliferator-activated receptors in the control of alcohol dependence and concomitant liver pathology

Proceedings of the National Academy of Sciences of Belarus Medical series ◽

10.29235/1814-6023-2019-16-2-244-256 ◽

2019 ◽

Vol 16 (2) ◽

pp. 244-256

Author(s):

I. N. Semenenya ◽

A. H. Shlyahtun ◽

H. F. Raduta

Keyword(s):

Liver Disease ◽

Alcohol Dependence ◽

Alcoholic Liver Disease ◽

Therapeutic Potential ◽

Scattered Data ◽

Peroxisome Proliferator ◽

Liver Pathology ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors

The article is aimed to summarize the scattered data on the role of peroxisome proliferator-activated receptors (PPAR) and the possibility of using PPAR’s agonists for treatment of alcohol dependence and alcoholic liver disease. Earlier it was shown that some PPAR agonists can reduce ethanol consumption and preference in rodents. Several hypotheses considering the antialcoholic activity of PPAR agonists and the roles of PPAR in the development of alcohol dependence were discussed. In light of these data, the therapeutic potential of PPARs agonists as an agent for the treatment of alcoholism, has been reviewed.

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PGC-1α Protects against Hepatic Ischemia Reperfusion Injury by Activating PPARα and PPARγ and Regulating ROS Production

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6677955 ◽

2021 ◽

Vol 2021 ◽

pp. 1-19

Author(s):

Chaoqun Wang ◽

Zihao Li ◽

Baolei Zhao ◽

Yaohua Wu ◽

Yao Fu ◽

...

Keyword(s):

Ischemia Reperfusion Injury ◽

Ischemia Reperfusion ◽

Peroxisome Proliferator ◽

Hepatic Ischemia ◽

Peroxisome Proliferator Activated Receptors ◽

Hepatic Ischemia Reperfusion ◽

Serum Aminotransferases

Peroxisome proliferator-activated receptors (PPARs) α and γ have been shown to be protective in hepatic ischemia/reperfusion (I/R) injury. However, the precise role of PPARγ coactivator-1α (PGC-1α), which can coactivate both of these receptors, in hepatic I/R injury, remains largely unknown. This study was designed to test our hypothesis that PGC-1α is protective during hepatic I/R injury in vitro and in vivo. Our results show that endogenous PGC-1α is basally expressed in normal livers and is moderately increased by I/R. Ectopic PGC-1α protects against hepatic I/R and hepatocyte anoxia/reoxygenation (A/R) injuries, whereas knockdown of endogenous PGC-1α aggravates such injuries, as evidenced by assessment of the levels of serum aminotransferases and inflammatory cytokines, necrosis, apoptosis, cell viability, and histological examination. The EMSA assay shows that the activation of PPARα and PPARγ is increased or decreased by the overexpression or knockdown of PGC-1α, respectively, during hepatic I/R and hepatocyte A/R injuries. In addition, the administration of specific antagonists of either PPARα (MK886) or PPARγ (GW9662) can effectively decrease the protective effect of PGC-1α against hepatic I/R and hepatocyte A/R injuries. We also demonstrate an important regulatory role of PGC-1α in reactive oxygen species (ROS) metabolism during hepatic I/R, which is correlated with the induction of ROS-detoxifying enzymes and is also dependent on the activations of PPARα and PPARγ. These data demonstrate that PGC-1α protects against hepatic I/R injury, mainly by regulating the activation of PPARα and PPARγ. Thus, PGC-1α may be a promising therapeutic target for the protection of the liver against I/R injury.

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The Current Knowledge of the Role of PPAR in Hepatic Ischemia-Reperfusion Injury

PPAR Research ◽

10.1155/2012/802384 ◽

2012 ◽

Vol 2012 ◽

pp. 1-14 ◽

Cited By ~ 7

Author(s):

M. Elias-Miró ◽

M. B. Jiménez-Castro ◽

M. Mendes-Braz ◽

A. Casillas-Ramírez ◽

C. Peralta

Keyword(s):

Ischemia Reperfusion Injury ◽

Current Knowledge ◽

Ischemia Reperfusion ◽

Peroxisome Proliferator ◽

Potential Therapeutic Target ◽

Hepatic Ischemia ◽

Ppar Signaling ◽

Peroxisome Proliferator Activated Receptors ◽

Hepatic Ischemia Reperfusion

Strategies to improve the viability of steatotic livers could reduce the risk of dysfunction after surgery and increase the number of organs suitable for transplantation. Peroxisome proliferator-activated receptors (PPARs) are major regulators of lipid metabolism and inflammation. In this paper, we review the PPAR signaling pathways and present some of their lesser-known functions in liver regeneration. Potential therapies based on PPAR regulation will be discussed. The data suggest that further investigations are required to elucidate whether PPAR could be a potential therapeutic target in liver surgery and to determine the most effective therapies that selectively regulate PPAR with minor side effects.

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Parsing the Role of PPARs in Macrophage Processes

Frontiers in Immunology ◽

10.3389/fimmu.2021.783780 ◽

2021 ◽

Vol 12 ◽

Author(s):

Daniel Toobian ◽

Pradipta Ghosh ◽

Gajanan D. Katkar

Keyword(s):

Cell Function ◽

Immune Cell ◽

Inflammatory Diseases ◽

Chronic Inflammatory Disease ◽

Peroxisome Proliferator ◽

Microbial Infection ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors ◽

Nuclear Receptor Family

Cells are richly equipped with nuclear receptors, which act as ligand-regulated transcription factors. Peroxisome proliferator activated receptors (PPARs), members of the nuclear receptor family, have been extensively studied for their roles in development, differentiation, and homeostatic processes. In the recent past, there has been substantial interest in understanding and defining the functions of PPARs and their agonists in regulating innate and adaptive immune responses as well as their pharmacologic potential in combating acute and chronic inflammatory disease. In this review, we focus on emerging evidence of the potential roles of the PPAR subtypes in macrophage biology. We also discuss the roles of dual and pan PPAR agonists as modulators of immune cell function, microbial infection, and inflammatory diseases.

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The Functions of PPARs in Aging and Longevity

PPAR Research ◽

10.1155/2007/39654 ◽

2007 ◽

Vol 2007 ◽

pp. 1-10 ◽

Cited By ~ 16

Author(s):

Adnan Erol

Keyword(s):

Oxidative Stress ◽

Aging Process ◽

Peroxisome Proliferator ◽

Clinical Use ◽

Age Related ◽

Therapeutic Uses ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors ◽

And Oxidative Stress

Peroxisome proliferator-activated receptors (PPARs) are key regulators in various age-associated pathophysiological processes related to energy metabolism and oxidative stress. A progressive rise of oxidative stress and related inflammatory reaction appears the hallmarks of the aging process and many age-related diseases. PPARs are important redox-sensitive transcription factors and their dyregulated activations seem to be major culprits for these pathological processes. Drugs targeting PPARs activity are already in widespread clinical use; however, based on these concepts, this review highlights the understanding of the role of PPARs in aging and indicates the necessary particular attention for the potential therapeutic uses of current PPAR agonists in age-associated diseases.

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

Cells ◽

10.3390/cells10030629 ◽

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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