International Journal of Molecular Sciences

Editorial

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7 pages, 3205 KiB

Open AccessEditorial

PPARs as Key Mediators in the Regulation of Metabolism and Inflammation

by Manuel Vázquez-Carrera and Walter Wahli

Int. J. Mol. Sci. 2022, 23(9), 5025; https://doi.org/10.3390/ijms23095025 - 30 Apr 2022

Cited by 11 | Viewed by 2481

Abstract

Nuclear receptors (NRs) form a large family of ligand-dependent transcription factors that control the expression of a multitude of genes involved in diverse, vital biological processes [...] Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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Research

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19 pages, 4179 KiB

Open AccessArticle

Functional and Structural Insights into Human PPARα/δ/γ Subtype Selectivity of Bezafibrate, Fenofibric Acid, and Pemafibrate

by Akihiro Honda, Shotaro Kamata, Makoto Akahane, Yui Machida, Kie Uchii, Yui Shiiyama, Yuki Habu, Saeka Miyawaki, Chihiro Kaneko, Takuji Oyama and Isao Ishii

Int. J. Mol. Sci. 2022, 23(9), 4726; https://doi.org/10.3390/ijms23094726 - 25 Apr 2022

Cited by 14 | Viewed by 4703

Abstract

Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some [...] Read more.

Among the agonists against three peroxisome proliferator-activated receptor (PPAR) subtypes, those against PPARα (fibrates) and PPARγ (glitazones) are currently used to treat dyslipidemia and type 2 diabetes, respectively, whereas PPARδ agonists are expected to be the next-generation metabolic disease drug. In addition, some dual/pan PPAR agonists are currently being investigated via clinical trials as one of the first curative drugs against nonalcoholic fatty liver disease (NAFLD). Because PPARα/δ/γ share considerable amino acid identity and three-dimensional structures, especially in ligand-binding domains (LBDs), clinically approved fibrates, such as bezafibrate, fenofibric acid, and pemafibrate, could also act on PPARδ/γ when used as anti-NAFLD drugs. Therefore, this study examined their PPARα/δ/γ selectivity using three independent assays—a dual luciferase-based GAL4 transactivation assay for COS-7 cells, time-resolved fluorescence resonance energy transfer-based coactivator recruitment assay, and circular dichroism spectroscopy-based thermostability assay. Although the efficacy and efficiency highly varied between agonists, assay types, and PPAR subtypes, the three fibrates, except fenofibric acid that did not affect PPARδ-mediated transactivation and coactivator recruitment, activated all PPAR subtypes in those assays. Furthermore, we aimed to obtain cocrystal structures of PPARδ/γ-LBD and the three fibrates via X-ray diffraction and versatile crystallization methods, which we recently used to obtain 34 structures of PPARα-LBD cocrystallized with 17 ligands, including the fibrates. We herein reveal five novel high-resolution structures of PPARδ/γ–bezafibrate, PPARγ–fenofibric acid, and PPARδ/γ–pemafibrate, thereby providing the molecular basis for their application beyond dyslipidemia treatment. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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13 pages, 1558 KiB

Open AccessArticle

Gene Doping with Peroxisome-Proliferator-Activated Receptor Beta/Delta Agonists Alters Immunity but Exercise Training Mitigates the Detection of Effects in Blood Samples

by Brigitte Sibille, Isabelle Mothe-Satney, Gwenaëlle Le Menn, Doriane Lepouse, Sébastien Le Garf, Elodie Baudoin, Joseph Murdaca, Claudine Moratal, Noura Lamghari, Giulia Chinetti, Jaap G. Neels and Anne-Sophie Rousseau

Int. J. Mol. Sci. 2021, 22(21), 11497; https://doi.org/10.3390/ijms222111497 - 25 Oct 2021

Cited by 1 | Viewed by 2006

Abstract

Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method [...] Read more.

Synthetic ligands of peroxisome-proliferator-activated receptor beta/delta (PPARβ/δ) are being used as performance-enhancing drugs by athletes. Since we previously showed that PPARβ/δ activation affects T cell biology, we wanted to investigate whether a specific blood T cell signature could be employed as a method to detect the use of PPARβ/δ agonists. We analyzed in primary human T cells the in vitro effect of PPARβ/δ activation on fatty acid oxidation (FAO) and on their differentiation into regulatory T cells (Tregs). Furthermore, we conducted studies in mice assigned to groups according to an 8-week exercise training program and/or a 6-week treatment with 3 mg/kg/day of GW0742, a PPARβ/δ agonist, in order to (1) determine the immune impact of the treatment on secondary lymphoid organs and to (2) validate a blood signature. Our results show that PPARβ/δ activation increases FAO potential in human and mouse T cells and mouse secondary lymphoid organs. This was accompanied by increased Treg polarization of human primary T cells. Moreover, Treg prevalence in mouse lymph nodes was increased when PPARβ/δ activation was combined with exercise training. Lastly, PPARβ/δ activation increased FAO potential in mouse blood T cells. Unfortunately, this signature was masked by training in mice. In conclusion, beyond the fact that it is unlikely that this signature could be used as a doping-control strategy, our results suggest that the use of PPARβ/δ agonists could have potential detrimental immune effects that may not be detectable in blood samples. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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19 pages, 3479 KiB

Open AccessArticle

Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice

by Mariano Schiffrin, Carine Winkler, Laure Quignodon, Aurélien Naldi, Martin Trötzmüller, Harald Köfeler, Hugues Henry, Paolo Parini, Béatrice Desvergne and Federica Gilardi

Int. J. Mol. Sci. 2021, 22(18), 9969; https://doi.org/10.3390/ijms22189969 - 15 Sep 2021

Cited by 14 | Viewed by 3759

Abstract

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and [...] Read more.

Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargF^Δ/Δ) and whole-body PPARγ-null (Pparg^Δ/Δ) mice. We identified a clear sex dimorphism occurring only in Pparg^Δ/Δ mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized Pparg^Δ/Δ mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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21 pages, 5352 KiB

Open AccessArticle

Pemafibrate Prevents Retinal Dysfunction in a Mouse Model of Unilateral Common Carotid Artery Occlusion

by Deokho Lee, Yohei Tomita, Heonuk Jeong, Yukihiro Miwa, Kazuo Tsubota, Kazuno Negishi and Toshihide Kurihara

Int. J. Mol. Sci. 2021, 22(17), 9408; https://doi.org/10.3390/ijms22179408 - 30 Aug 2021

Cited by 19 | Viewed by 4420

Abstract

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vision. Previously, pemafibrate, a selective peroxisome proliferator-activated [...] Read more.

Cardiovascular diseases lead to retinal ischemia, one of the leading causes of blindness. Retinal ischemia triggers pathological retinal glial responses and functional deficits. Therefore, maintaining retinal neuronal activities and modulating pathological gliosis may prevent loss of vision. Previously, pemafibrate, a selective peroxisome proliferator-activated receptor alpha modulator, was nominated as a promising drug in retinal ischemia. However, a protective role of pemafibrate remains untouched in cardiovascular diseases-mediated retinal ischemia. Therefore, we aimed to unravel systemic and retinal alterations by treating pemafibrate in a new murine model of retinal ischemia caused by cardiovascular diseases. Adult C57BL/6 mice were orally administered pemafibrate (0.5 mg/kg) for 4 days, followed by unilateral common carotid artery occlusion (UCCAO). After UCCAO, pemafibrate was continuously supplied to mice until the end of experiments. Retinal function (a-and b-waves and the oscillatory potentials) was measured using electroretinography on day 5 and 12 after UCCAO. Moreover, the retina, liver, and serum were subjected to qPCR, immunohistochemistry, or ELISA analysis. We found that pemafibrate enhanced liver function, elevated serum levels of fibroblast growth factor 21 (FGF21), one of the neuroprotective molecules in the eye, and protected against UCCAO-induced retinal dysfunction, observed with modulation of retinal gliosis and preservation of oscillatory potentials. Our current data suggest a promising pemafibrate therapy for the suppression of retinal dysfunction in cardiovascular diseases. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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16 pages, 24630 KiB

Open AccessArticle

Resveratrol and Quercetin as Regulators of Inflammatory and Purinergic Receptors to Attenuate Liver Damage Associated to Metabolic Syndrome

by Agustina Cano-Martínez, Rocío Bautista-Pérez, Vicente Castrejón-Téllez, Elizabeth Carreón-Torres, Israel Pérez-Torres, Eulises Díaz-Díaz, Javier Flores-Estrada, Verónica Guarner-Lans and María Esther Rubio-Ruíz

Int. J. Mol. Sci. 2021, 22(16), 8939; https://doi.org/10.3390/ijms22168939 - 19 Aug 2021

Cited by 16 | Viewed by 3664

Abstract

Nonalcoholic fatty liver disease (NAFLD) is considered a manifestation of metabolic syndrome (MS) and is characterized by the accumulation of triglycerides and a varying degree of hepatic injury, inflammation, and repair. Moreover, peroxisome-proliferator-activated receptors (PPARs) play a critical role in the pathophysiological processes [...] Read more.

Nonalcoholic fatty liver disease (NAFLD) is considered a manifestation of metabolic syndrome (MS) and is characterized by the accumulation of triglycerides and a varying degree of hepatic injury, inflammation, and repair. Moreover, peroxisome-proliferator-activated receptors (PPARs) play a critical role in the pathophysiological processes in the liver. There is extensive evidence of the beneficial effect of polyphenols such as resveratrol (RSV) and quercetin (QRC) on the treatment of liver pathology; however, the mechanisms underlying their beneficial effects have not been fully elucidated. In this work, we show that the mechanisms underlying the beneficial effects of RSV and QRC against inflammation in liver damage in our MS model are due to the activation of novel pathways which have not been previously described such as the downregulation of the expression of toll-like receptor 4 (TLR4), neutrophil elastase (NE) and purinergic receptor P2Y2. This downregulation leads to a decrease in apoptosis and hepatic fibrosis with no changes in hepatocyte proliferation. In addition, PPAR alpha and gamma expression were altered in MS but their expression was not affected by the treatment with the natural compounds. The improvement of liver damage by the administration of polyphenols was reflected in the normalization of serum transaminase activities. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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17 pages, 7351 KiB

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Analysis of PPARγ Signaling Activity in Psoriasis

by Vladimir Sobolev, Anastasia Nesterova, Anna Soboleva, Alexandre Mezentsev, Evgenia Dvoriankova, Anastas Piruzyan, Elena Denisova, Olga Melnichenko and Irina Korsunskaya

Int. J. Mol. Sci. 2021, 22(16), 8603; https://doi.org/10.3390/ijms22168603 - 10 Aug 2021

Cited by 23 | Viewed by 2996

Abstract

In our previous work, we built the model of PPARγ dependent pathways involved in the development of the psoriatic lesions. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which regulates the expression of many proinflammatory genes. We [...] Read more.

In our previous work, we built the model of PPARγ dependent pathways involved in the development of the psoriatic lesions. Peroxisome proliferator-activated receptor gamma (PPARγ) is a nuclear receptor and transcription factor which regulates the expression of many proinflammatory genes. We tested the hypothesis that low levels of PPARγ expression promote the development of psoriatic lesions triggering the IL17-related signaling cascade. Skin samples of normally looking and lesional skin donated by psoriasis patients and psoriatic CD3⁺ Tcells samples (n = 23) and samples of healthy CD3⁺ T cells donated by volunteers (n = 10) were analyzed by real-time PCR, ELISA and immunohistochemistry analysis. We found that the expression of PPARγ is downregulated in human psoriatic skin and laser treatment restores the expression. The expression of IL17, STAT3, FOXP3, and RORC in psoriatic skin before and after laser treatment were correlated with PPARγ expression according to the reconstructed model of PPARγ pathway in psoriasis.In conclusion, we report that PPARγ weakens the expression of genes that contribute in the development of psoriatic lesion. Our data show that transcriptional regulation of PPARγ expression by FOSL1 and by STAT3/FOSL1 feedback loop may be central in the psoriatic skin and T-cells. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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15 pages, 3122 KiB

Open AccessArticle

Synthesis of a Coumarin-Based PPARγ Fluorescence Probe for Competitive Binding Assay

by Chisato Yoshikawa, Hiroaki Ishida, Nami Ohashi and Toshimasa Itoh

Int. J. Mol. Sci. 2021, 22(8), 4034; https://doi.org/10.3390/ijms22084034 - 14 Apr 2021

Cited by 7 | Viewed by 2901

Abstract

Peroxisome proliferator-activated receptor γ (PPARγ) is a molecular target of metabolic syndrome and inflammatory disease. PPARγ is an important nuclear receptor and numerous PPARγ ligands were developed to date; thus, efficient assay methods are important. Here, we investigated the incorporation of 7-diethylamino coumarin [...] Read more.

Peroxisome proliferator-activated receptor γ (PPARγ) is a molecular target of metabolic syndrome and inflammatory disease. PPARγ is an important nuclear receptor and numerous PPARγ ligands were developed to date; thus, efficient assay methods are important. Here, we investigated the incorporation of 7-diethylamino coumarin into the PPARγ agonist rosiglitazone and used the compound in a binding assay for PPARγ. PPARγ-ligand-incorporated 7-methoxycoumarin, 1, showed weak fluorescence intensity in a previous report. We synthesized PPARγ-ligand-incorporating coumarin, 2, in this report, and it enhanced the fluorescence intensity. The PPARγ ligand 2 maintained the rosiglitazone activity. The obtained partial agonist 6 appeared to act through a novel mechanism. The fluorescence intensity of 2 and 6 increased by binding to the ligand binding domain (LBD) of PPARγ and the affinity of reported PPARγ ligands were evaluated using the probe. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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20 pages, 2265 KiB

Open AccessArticle

Co-Incubation with PPARβ/δ Agonists and Antagonists Modeled Using Computational Chemistry: Effect on LPS Induced Inflammatory Markers in Pulmonary Artery

by Noelia Perez Diaz, Lisa A. Lione, Victoria Hutter and Louise S. Mackenzie

Int. J. Mol. Sci. 2021, 22(6), 3158; https://doi.org/10.3390/ijms22063158 - 19 Mar 2021

Cited by 3 | Viewed by 2805

Abstract

Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARβ/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARβ/δ regulates [...] Read more.

Peroxisome proliferator activated receptor beta/delta (PPARβ/δ) is a nuclear receptor ubiquitously expressed in cells, whose signaling controls inflammation. There are large discrepancies in understanding the complex role of PPARβ/δ in disease, having both anti- and pro-effects on inflammation. After ligand activation, PPARβ/δ regulates genes by two different mechanisms; induction and transrepression, the effects of which are difficult to differentiate directly. We studied the PPARβ/δ-regulation of lipopolysaccharide (LPS) induced inflammation (indicated by release of nitrite and IL-6) of rat pulmonary artery, using different combinations of agonists (GW0742 or L−165402) and antagonists (GSK3787 or GSK0660). LPS induced release of NO and IL-6 is not significantly reduced by incubation with PPARβ/δ ligands (either agonist or antagonist), however, co-incubation with an agonist and antagonist significantly reduces LPS-induced nitrite production and Nos2 mRNA expression. In contrast, incubation with LPS and PPARβ/δ agonists leads to a significant increase in Pdk−4 and Angptl−4 mRNA expression, which is significantly decreased in the presence of PPARβ/δ antagonists. Docking using computational chemistry methods indicates that PPARβ/δ agonists form polar bonds with His287, His413 and Tyr437, while antagonists are more promiscuous about which amino acids they bind to, although they are very prone to bind Thr252 and Asn307. Dual binding in the PPARβ/δ binding pocket indicates the ligands retain similar binding energies, which suggests that co-incubation with both agonist and antagonist does not prevent the specific binding of each other to the large PPARβ/δ binding pocket. To our knowledge, this is the first time that the possibility of binding two ligands simultaneously into the PPARβ/δ binding pocket has been explored. Agonist binding followed by antagonist simultaneously switches the PPARβ/δ mode of action from induction to transrepression, which is linked with an increase in Nos2 mRNA expression and nitrite production. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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Review

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35 pages, 1581 KiB

Open AccessReview

PPAR-Targeted Therapies in the Treatment of Non-Alcoholic Fatty Liver Disease in Diabetic Patients

by Naomi F. Lange, Vanessa Graf, Cyrielle Caussy and Jean-François Dufour

Int. J. Mol. Sci. 2022, 23(8), 4305; https://doi.org/10.3390/ijms23084305 - 13 Apr 2022

Cited by 39 | Viewed by 6790

Abstract

Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) [...] Read more.

Peroxisome proliferator-activated receptors (PPAR), ligand-activated transcription factors of the nuclear hormone receptor superfamily, have been identified as key metabolic regulators in the liver, skeletal muscle, and adipose tissue, among others. As a leading cause of liver disease worldwide, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) cause a significant burden worldwide and therapeutic strategies are needed. This review provides an overview of the evidence on PPAR-targeted treatment of NAFLD and NASH in individuals with type 2 diabetes mellitus. We considered current evidence from clinical trials and observational studies as well as the impact of treatment on comorbid metabolic conditions such as obesity, dyslipidemia, and cardiovascular disease. Future areas of research, such as possible sexually dimorphic effects of PPAR-targeted therapies, are briefly reviewed. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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24 pages, 5805 KiB

Open AccessReview

Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Energy Homeostasis of Dairy Animals: Exploiting Their Modulation through Nutrigenomic Interventions

by Faiz-ul Hassan, Asif Nadeem, Zhipeng Li, Maryam Javed, Qingyou Liu, Jahanzaib Azhar, Muhammad Saif-ur Rehman, Kuiqing Cui and Saif ur Rehman

Int. J. Mol. Sci. 2021, 22(22), 12463; https://doi.org/10.3390/ijms222212463 - 18 Nov 2021

Cited by 22 | Viewed by 3015

Abstract

Peroxisome proliferator-activated receptors (PPARs) are the nuclear receptors that could mediate the nutrient-dependent transcriptional activation and regulate metabolic networks through energy homeostasis. However, these receptors cannot work properly under metabolic stress. PPARs and their subtypes can be modulated by nutrigenomic interventions, particularly under [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) are the nuclear receptors that could mediate the nutrient-dependent transcriptional activation and regulate metabolic networks through energy homeostasis. However, these receptors cannot work properly under metabolic stress. PPARs and their subtypes can be modulated by nutrigenomic interventions, particularly under stress conditions to restore cellular homeostasis. Many nutrients such as polyunsaturated fatty acids, vitamins, dietary amino acids and phytochemicals have shown their ability for potential activation or inhibition of PPARs. Thus, through different mechanisms, all these nutrients can modulate PPARs and are ultimately helpful to prevent various metabolic disorders, particularly in transition dairy cows. This review aims to provide insights into the crucial role of PPARs in energy metabolism and their potential modulation through nutrigenomic interventions to improve energy homeostasis in dairy animals. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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25 pages, 1111 KiB

Open AccessReview

The PPARα and PPARγ Epigenetic Landscape in Cancer and Immune and Metabolic Disorders

by Jesús Porcuna, Jorge Mínguez-Martínez and Mercedes Ricote

Int. J. Mol. Sci. 2021, 22(19), 10573; https://doi.org/10.3390/ijms221910573 - 30 Sep 2021

Cited by 32 | Viewed by 8934

Abstract

Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related processes. Correct control of their target genes requires tight regulation of the expression of different PPAR isoforms in each tissue, and the dysregulation of PPAR-dependent [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) are ligand-modulated nuclear receptors that play pivotal roles in nutrient sensing, metabolism, and lipid-related processes. Correct control of their target genes requires tight regulation of the expression of different PPAR isoforms in each tissue, and the dysregulation of PPAR-dependent transcriptional programs is linked to disorders, such as metabolic and immune diseases or cancer. Several PPAR regulators and PPAR-regulated factors are epigenetic effectors, including non-coding RNAs, epigenetic enzymes, histone modifiers, and DNA methyltransferases. In this review, we examine advances in PPARα and PPARγ-related epigenetic regulation in metabolic disorders, including obesity and diabetes, immune disorders, such as sclerosis and lupus, and a variety of cancers, providing new insights into the possible therapeutic exploitation of PPAR epigenetic modulation. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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26 pages, 23255 KiB

Open AccessReview

The Role of PPAR Alpha in the Modulation of Innate Immunity

by Maja Grabacka, Małgorzata Pierzchalska, Przemysław M. Płonka and Piotr Pierzchalski

Int. J. Mol. Sci. 2021, 22(19), 10545; https://doi.org/10.3390/ijms221910545 - 29 Sep 2021

Cited by 58 | Viewed by 9141

Abstract

Peroxisome proliferator-activated receptor α is a potent regulator of systemic and cellular metabolism and energy homeostasis, but it also suppresses various inflammatory reactions. In this review, we focus on its role in the regulation of innate immunity; in particular, we discuss the PPARα [...] Read more.

Peroxisome proliferator-activated receptor α is a potent regulator of systemic and cellular metabolism and energy homeostasis, but it also suppresses various inflammatory reactions. In this review, we focus on its role in the regulation of innate immunity; in particular, we discuss the PPARα interplay with inflammatory transcription factor signaling, pattern-recognition receptor signaling, and the endocannabinoid system. We also present examples of the PPARα-specific immunomodulatory functions during parasitic, bacterial, and viral infections, as well as approach several issues associated with innate immunity processes, such as the production of reactive nitrogen and oxygen species, phagocytosis, and the effector functions of macrophages, innate lymphoid cells, and mast cells. The described phenomena encourage the application of endogenous and pharmacological PPARα agonists to alleviate the disorders of immunological background and the development of new solutions that engage PPARα activation or suppression. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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16 pages, 875 KiB

Open AccessReview

PPARγ and TGFβ—Major Regulators of Metabolism, Inflammation, and Fibrosis in the Lungs and Kidneys

by Gábor Kökény, Laurent Calvier and Georg Hansmann

Int. J. Mol. Sci. 2021, 22(19), 10431; https://doi.org/10.3390/ijms221910431 - 28 Sep 2021

Cited by 59 | Viewed by 7226

Abstract

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated [...] Read more.

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, initially recognized in adipose tissue for its role in fatty acid storage and glucose metabolism. It promotes lipid uptake and adipogenesis by increasing insulin sensitivity and adiponectin release. Later, PPARγ was implicated in cardiac development and in critical conditions such as pulmonary arterial hypertension (PAH) and kidney failure. Recently, a cluster of different papers linked PPARγ signaling with another superfamily, the transforming growth factor beta (TGFβ), and its receptors, all of which play a major role in PAH and kidney failure. TGFβ is a multifunctional cytokine that drives inflammation, fibrosis, and cell differentiation while PPARγ activation reverses these adverse events in many models. Such opposite biological effects emphasize the delicate balance and complex crosstalk between PPARγ and TGFβ. Based on solid experimental and clinical evidence, the present review summarizes connections and their implications for PAH and kidney failure, highlighting the similarities and differences between lung and kidney mechanisms as well as discussing the therapeutic potential of PPARγ agonist pioglitazone. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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14 pages, 741 KiB

Open AccessReview

The Regulatory Roles of PPARs in Skeletal Muscle Fuel Metabolism and Inflammation: Impact of PPAR Agonism on Muscle in Chronic Disease, Contraction and Sepsis

by Hannah Crossland, Dumitru Constantin-Teodosiu and Paul L. Greenhaff

Int. J. Mol. Sci. 2021, 22(18), 9775; https://doi.org/10.3390/ijms22189775 - 10 Sep 2021

Cited by 19 | Viewed by 4935

Abstract

The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic [...] Read more.

The peroxisome proliferator-activated receptor (PPAR) family of transcription factors has been demonstrated to play critical roles in regulating fuel selection, energy expenditure and inflammation in skeletal muscle and other tissues. Activation of PPARs, through endogenous fatty acids and fatty acid metabolites or synthetic compounds, has been demonstrated to have lipid-lowering and anti-diabetic actions. This review will aim to provide a comprehensive overview of the functions of PPARs in energy homeostasis, with a focus on the impacts of PPAR agonism on muscle metabolism and function. The dysregulation of energy homeostasis in skeletal muscle is a frequent underlying characteristic of inflammation-related conditions such as sepsis. However, the potential benefits of PPAR agonism on skeletal muscle protein and fuel metabolism under these conditions remains under-investigated and is an area of research opportunity. Thus, the effects of PPARγ agonism on muscle inflammation and protein and carbohydrate metabolism will be highlighted, particularly with its potential relevance in sepsis-related metabolic dysfunction. The impact of PPARδ agonism on muscle mitochondrial function, substrate metabolism and contractile function will also be described. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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15 pages, 1590 KiB

Open AccessReview

The PPARg System in Major Depression: Pathophysiologic and Therapeutic Implications

by Philip W. Gold

Int. J. Mol. Sci. 2021, 22(17), 9248; https://doi.org/10.3390/ijms22179248 - 26 Aug 2021

Cited by 25 | Viewed by 5334

Abstract

To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellular stress, and functions in the CNS in glial cells, neurons, and cerebrovascular endothelial cell in multiple anti-inflammatory and neuroprotective ways. We now know that depression is associated with neurodegeneration [...] Read more.

To an exceptional degree, and through multiple mechanisms, the PPARg system rapidly senses cellular stress, and functions in the CNS in glial cells, neurons, and cerebrovascular endothelial cell in multiple anti-inflammatory and neuroprotective ways. We now know that depression is associated with neurodegeneration in the subgenual prefrontal cortex and hippocampus, decreased neuroplasticity, and defective neurogenesis. Brain-derived neurotrophic factor (BDNF) is markedly depleted in these areas, and is thought to contribute to the neurodegeneration of the subgenual prefrontal cortex and the hippocampus. The PPARg system strongly increases BDNF levels and activity in these brain areas. The PPARg system promotes both neuroplasticity and neurogenesis, both via effects on BDNF, and through other mechanisms. Ample evidence exists that these brain areas transduce many of the cardinal features of depression, directly or through their projections to sites such as the amygdala and nucleus accumbens. Behaviorally, these include feelings of worthlessness, anxiety, dread of the future, and significant reductions in the capacity to anticipate and experience pleasure. Physiologically, these include activation of the CRH and noradrenergic system in brain and the sympathetic nervous system and hypothalamic–pituitary–adrenal axis in the periphery. Patients with depression are also insulin-resistant. The PPARg system influences each of these behavioral and physiological in ways that would ameliorate the manifestations of depressive illness. In addition to the cognitive and behavioral manifestations of depression, depressive illness is associated with the premature onsets of coronary artery disease, stroke, diabetes, and osteoporosis. As a consequence, patients with depressive illness lose approximately seven years of life. Inflammation and insulin resistance are two of the predominant processes that set into motion these somatic manifestations. PPARg agonists significantly ameliorate both pathological processes. In summary, PPARg augmentation can impact positively on multiple significant pathological processes in depression. These include loss of brain tissue, defective neuroplasticity and neurogenesis, widespread inflammation in the central nervous system and periphery, and insulin resistance. Thus, PPARg agonists could potentially have significant antidepressant effects. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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16 pages, 2169 KiB

Open AccessReview

PPARs-Orchestrated Metabolic Homeostasis in the Adipose Tissue

by Chen Sun, Shuyu Mao, Siyu Chen, Wenxiang Zhang and Chang Liu

Int. J. Mol. Sci. 2021, 22(16), 8974; https://doi.org/10.3390/ijms22168974 - 20 Aug 2021

Cited by 68 | Viewed by 6852

Abstract

It has been more than three decades since peroxisome proliferator-activated receptors (PPARs) were first discovered. Many investigations have revealed the central regulators of PPARs in lipid and glucose homeostasis in response to different nutrient conditions. PPARs have attracted much attention due to their [...] Read more.

It has been more than three decades since peroxisome proliferator-activated receptors (PPARs) were first discovered. Many investigations have revealed the central regulators of PPARs in lipid and glucose homeostasis in response to different nutrient conditions. PPARs have attracted much attention due to their ability to improve metabolic syndromes, and they have also been proposed as classical drug targets for the treatment of hyperlipidemia and type 2 diabetes (T2D) mellitus. In parallel, adipose tissue is known to play a unique role in the pathogenesis of insulin resistance and metabolic syndromes due to its ability to “safely” store lipids and secrete cytokines that regulate whole-body metabolism. Adipose tissue relies on a complex and subtle network of transcription factors to maintain its normal physiological function, by coordinating various molecular events, among which PPARs play distinctive and indispensable roles in adipocyte differentiation, lipid metabolism, adipokine secretion, and insulin sensitivity. In this review, we discuss the characteristics of PPARs with special emphasis on the roles of the different isotypes in adipocyte biology. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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31 pages, 3893 KiB

Open AccessReview

Mechanisms Mediating the Regulation of Peroxisomal Fatty Acid Beta-Oxidation by PPARα

by Mounia Tahri-Joutey, Pierre Andreoletti, Sailesh Surapureddi, Boubker Nasser, Mustapha Cherkaoui-Malki and Norbert Latruffe

Int. J. Mol. Sci. 2021, 22(16), 8969; https://doi.org/10.3390/ijms22168969 - 20 Aug 2021

Cited by 97 | Viewed by 11448

Abstract

In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, [...] Read more.

In mammalian cells, two cellular organelles, mitochondria and peroxisomes, share the ability to degrade fatty acid chains. Although each organelle harbors its own fatty acid β-oxidation pathway, a distinct mitochondrial system feeds the oxidative phosphorylation pathway for ATP synthesis. At the same time, the peroxisomal β-oxidation pathway participates in cellular thermogenesis. A scientific milestone in 1965 helped discover the hepatomegaly effect in rat liver by clofibrate, subsequently identified as a peroxisome proliferator in rodents and an activator of the peroxisomal fatty acid β-oxidation pathway. These peroxisome proliferators were later identified as activating ligands of Peroxisome Proliferator-Activated Receptor α (PPARα), cloned in 1990. The ligand-activated heterodimer PPARα/RXRα recognizes a DNA sequence, called PPRE (Peroxisome Proliferator Response Element), corresponding to two half-consensus hexanucleotide motifs, AGGTCA, separated by one nucleotide. Accordingly, the assembled complex containing PPRE/PPARα/RXRα/ligands/Coregulators controls the expression of the genes involved in liver peroxisomal fatty acid β-oxidation. This review mobilizes a considerable number of findings that discuss miscellaneous axes, covering the detailed expression pattern of PPARα in species and tissues, the lessons from several PPARα KO mouse models and the modulation of PPARα function by dietary micronutrients. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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17 pages, 1544 KiB

Open AccessReview

PPAR Gamma and Viral Infections of the Brain

by Pierre Layrolle, Pierre Payoux and Stéphane Chavanas

Int. J. Mol. Sci. 2021, 22(16), 8876; https://doi.org/10.3390/ijms22168876 - 18 Aug 2021

Cited by 15 | Viewed by 4206

Abstract

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the [...] Read more.

Peroxisome Proliferator-Activated Receptor gamma (PPARγ) is a master regulator of metabolism, adipogenesis, inflammation and cell cycle, and it has been extensively studied in the brain in relation to inflammation or neurodegeneration. Little is known however about its role in viral infections of the brain parenchyma, although they represent the most frequent cause of encephalitis and are a major threat for the developing brain. Specific to viral infections is the ability to subvert signaling pathways of the host cell to ensure virus replication and spreading, as deleterious as the consequences may be for the host. In this respect, the pleiotropic role of PPARγ makes it a critical target of infection. This review aims to provide an update on the role of PPARγ in viral infections of the brain. Recent studies have highlighted the involvement of PPARγ in brain or neural cells infected by immunodeficiency virus 1, Zika virus, or human cytomegalovirus. They have provided a better understanding on PPARγ functions in the infected brain, and revealed that it can be a double-edged sword with respect to inflammation, viral replication, or neuronogenesis. They unraveled new roles of PPARγ in health and disease and could possibly help designing new therapeutic strategies. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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13 pages, 1534 KiB

Open AccessReview

The PPARβ/δ-AMPK Connection in the Treatment of Insulin Resistance

by David Aguilar-Recarte, Xavier Palomer, Walter Wahli and Manuel Vázquez-Carrera

Int. J. Mol. Sci. 2021, 22(16), 8555; https://doi.org/10.3390/ijms22168555 - 9 Aug 2021

Cited by 18 | Viewed by 4817

Abstract

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome [...] Read more.

The current treatment options for type 2 diabetes mellitus do not adequately control the disease in many patients. Consequently, there is a need for new drugs to prevent and treat type 2 diabetes mellitus. Among the new potential pharmacological strategies, activators of peroxisome proliferator-activated receptor (PPAR)β/δ show promise. Remarkably, most of the antidiabetic effects of PPARβ/δ agonists involve AMP-activated protein kinase (AMPK) activation. This review summarizes the recent mechanistic insights into the antidiabetic effects of the PPARβ/δ-AMPK pathway, including the upregulation of glucose uptake, muscle remodeling, enhanced fatty acid oxidation, and autophagy, as well as the inhibition of endoplasmic reticulum stress and inflammation. A better understanding of the mechanisms underlying the effects resulting from the PPARβ/δ-AMPK pathway may provide the basis for the development of new therapies in the prevention and treatment of insulin resistance and type 2 diabetes mellitus. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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22 pages, 1519 KiB

Open AccessReview

PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases

by Hugo Christian Monroy-Ramirez, Marina Galicia-Moreno, Ana Sandoval-Rodriguez, Alejandra Meza-Rios, Arturo Santos and Juan Armendariz-Borunda

Int. J. Mol. Sci. 2021, 22(15), 8298; https://doi.org/10.3390/ijms22158298 - 2 Aug 2021

Cited by 42 | Viewed by 5662

Abstract

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; [...] Read more.

Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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11 pages, 976 KiB

Open AccessReview

Essential Roles of PPARs in Lipid Metabolism during Mycobacterial Infection

by Kazunari Tanigawa, Yuqian Luo, Akira Kawashima, Mitsuo Kiriya, Yasuhiro Nakamura, Ken Karasawa and Koichi Suzuki

Int. J. Mol. Sci. 2021, 22(14), 7597; https://doi.org/10.3390/ijms22147597 - 15 Jul 2021

Cited by 10 | Viewed by 6168

Abstract

The mycobacterial cell wall is composed of large amounts of lipids with varying moieties. Some mycobacteria species hijack host cells and promote lipid droplet accumulation to build the cellular environment essential for their intracellular survival. Thus, lipids are thought to be important for [...] Read more.

The mycobacterial cell wall is composed of large amounts of lipids with varying moieties. Some mycobacteria species hijack host cells and promote lipid droplet accumulation to build the cellular environment essential for their intracellular survival. Thus, lipids are thought to be important for mycobacteria survival as well as for the invasion, parasitization, and proliferation within host cells. However, their physiological roles have not been fully elucidated. Recent studies have revealed that mycobacteria modulate the peroxisome proliferator-activated receptor (PPAR) signaling and utilize host-derived triacylglycerol (TAG) and cholesterol as both nutrient sources and evasion from the host immune system. In this review, we discuss recent findings that describe the activation of PPARs by mycobacterial infections and their role in determining the fate of bacilli by inducing lipid metabolism, anti-inflammatory function, and autophagy. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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19 pages, 921 KiB

Open AccessReview

PPARdelta in Affected Atopic Dermatitis and Psoriasis: A Possible Role in Metabolic Reprograming

by Stefan Blunder, Petra Pavel, Deborah Minzaghi and Sandrine Dubrac

Int. J. Mol. Sci. 2021, 22(14), 7354; https://doi.org/10.3390/ijms22147354 - 8 Jul 2021

Cited by 19 | Viewed by 4476

Abstract

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), β or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, [...] Read more.

Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), β or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARβ/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARβ/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARβ/δ to alleviate skin inflammation is discussed. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation)

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