PPARs Triad in Human Health and Disease: Agonistic and Antagonistic Interplay of the Receptors

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (15 October 2021) | Viewed by 12359

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Department of Life, Health and Environmental Sciences, Università degli Studi dell'Aquila, L'Aquila, Italy
Interests: energetic metabolism; neurosciences; brain development; neurodegeneration
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Special Issue Information

Dear Colleagues,

In developed societies, chronic disorders such as diabetes, obesity, neurodegenerative and progressive conditions, atherosclerosis, and cancer are responsible for the most deaths. These diseases involve genetic, environmental, and nutritional factors. There is evidence that a group of related nuclear receptors, named peroxisome proliferator-activated receptors (PPARs), may be involved in these disorders. The family of PPARs is characterized by three different members: PPARα, PPARβ/δ, and PPARγ. PPARα activity is principally involved in the metabolism of lipids, carbohydrates, and amino acids; PPARβ/δ controls fatty acid oxidation in cardiac and skeletal muscles; PPARγ is mainly implicated in the regulation of lipid biosynthesis, adipogenesis and energy balance, and lipid biosynthesis. There is convincing evidence indicating that both natural and synthetic ligands, including fatty acids, eicosanoids, fibrates, and thiazolidinediones, can be potential therapeutic strategies to control the expression and function of PPARs for the treatment of various human disorders. In addition, it appears that each PPAR may exert agonist or antagonist actions on the others in the different tissues. Thus, the aim of this Special Issue is to bring together the recent advances in the various aspects of the action of PPARs, from basic science to applied therapeutic approaches, and provide new insights into our understanding of the PPARs triad.

Dr. Annamaria Cimini
Guest Editor

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Keywords

  • nuclear receptors
  • human diseases
  • human tissues
  • in vivo models
  • in vitro models
  • agonists
  • antagonists

Published Papers (4 papers)

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Research

19 pages, 4654 KiB  
Article
Activation of PPARα by Fenofibrate Attenuates the Effect of Local Heart High Dose Irradiation on the Mouse Cardiac Proteome
by Omid Azimzadeh, Vikram Subramanian, Wolfgang Sievert, Juliane Merl-Pham, Kateryna Oleksenko, Michael Rosemann, Gabriele Multhoff, Michael J. Atkinson and Soile Tapio
Biomedicines 2021, 9(12), 1845; https://doi.org/10.3390/biomedicines9121845 - 6 Dec 2021
Cited by 5 | Viewed by 2933
Abstract
Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect [...] Read more.
Radiation-induced cardiovascular disease is associated with metabolic remodeling in the heart, mainly due to the inactivation of the transcription factor peroxisome proliferator-activated receptor alpha (PPARα), thereby inhibiting lipid metabolic enzymes. The objective of the present study was to investigate the potential protective effect of fenofibrate, a known agonist of PPARα on radiation-induced cardiac toxicity. To this end, we compared, for the first time, the cardiac proteome of fenofibrate- and placebo-treated mice 20 weeks after local heart irradiation (16 Gy) using label-free proteomics. The observations were further validated using immunoblotting, enzyme activity assays, and ELISA. The analysis showed that fenofibrate restored signalling pathways that were negatively affected by irradiation, including lipid metabolism, mitochondrial respiratory chain, redox response, tissue homeostasis, endothelial NO signalling and the inflammatory status. The results presented here indicate that PPARα activation by fenofibrate attenuates the cardiac proteome alterations induced by irradiation. These findings suggest a potential benefit of fenofibrate administration in the prevention of cardiovascular diseases, following radiation exposure. Full article
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17 pages, 3018 KiB  
Article
When Activator and Inhibitor of PPARα Do the Same: Consequence for Differentiation of Human Intestinal Cells
by Katerina Cizkova, Tereza Foltynkova, Jiri Hanyk, Zbynek Kamencak and Zdenek Tauber
Biomedicines 2021, 9(9), 1255; https://doi.org/10.3390/biomedicines9091255 - 17 Sep 2021
Cited by 3 | Viewed by 2431
Abstract
Peroxisome proliferator-activated receptor α (PPARα) is a ligand-dependent transcription factor that plays a role in various processes including differentiation of several cell types. We investigated the role of PPARα in the differentiation of intestinal cells using HT-29 and Caco2 cell lines as a [...] Read more.
Peroxisome proliferator-activated receptor α (PPARα) is a ligand-dependent transcription factor that plays a role in various processes including differentiation of several cell types. We investigated the role of PPARα in the differentiation of intestinal cells using HT-29 and Caco2 cell lines as a model as well as human normal colon and colorectal carcinoma tissues. We detected a significant increase in PPARα expression in differentiated HT-29 cells as well as in normal surface colon epithelium where differentiated cells are localised. Thus, it seems that PPARα may play a role in differentiation of intestinal cells. Interestingly, we found that both PPARα activators (fenofibrate and WY-14643) as well as its inhibitor (GW6471) regulated proliferation and differentiation of HT-29 cells in vitro in the same way. Both compounds led to a decrease in proliferation accompanied by a significant increase in expression of villin, intestinal alkaline phosphatase (differentiation markers). Moreover, the same trend in villin expression was observed in Caco2 cells. Furthermore, villin expression was independent of subcellular localisation of PPARα. In addition, we found similar levels of PPARα expression in colorectal carcinomas in comparison to adjacent normal epithelium. All these findings support the hypothesis that differentiation of intestinal epithelium is PPARα-independent. Full article
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16 pages, 3061 KiB  
Article
PFOS Inhibited Normal Functional Development of Placenta Cells via PPARγ Signaling
by Jing Li, Xiaojie Quan, Saifei Lei, Zhenyao Huang, Qi Wang and Pengfei Xu
Biomedicines 2021, 9(6), 677; https://doi.org/10.3390/biomedicines9060677 - 15 Jun 2021
Cited by 10 | Viewed by 3189
Abstract
Perfluorooctane sulfonic acid (PFOS), a persistent environmental pollutant, has adverse effects on gestation pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is involved in angiogenesis, metabolic processes, anti-inflammatory, and reproductive development. However, the function of PPARγ in PFOS evoked disadvantageous effects on the [...] Read more.
Perfluorooctane sulfonic acid (PFOS), a persistent environmental pollutant, has adverse effects on gestation pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is involved in angiogenesis, metabolic processes, anti-inflammatory, and reproductive development. However, the function of PPARγ in PFOS evoked disadvantageous effects on the placenta remain uncertain. Here, we explored the role of PPARγ in PFOS-induced placental toxicity. Cell viability, cell migration, angiogenesis, and mRNA expression were monitored by CCK-8 assay, wound healing assay, tube formation assay, and real-time PCR, respectively. Activation and overexpression of PPARγ were conducted by rosiglitazone or pcDNA-PPARγ, and inhibition and knockdown of PPARγ were performed by GW9662 or si-PPARγ. Results revealed that PFOS decreased cell growth, migration, angiogenesis, and increased inflammation in human HTR-8/SVneo and JEG-3 cells. Placenta diameter and fetal weight decreased in mice treated with PFOS (12.5 mg/kg). In addition, rosiglitazone or pcDNA-PPARγ rescued cell proliferation, migration, angiogenesis, and decreased inflammation induced by PFOS in HTR8/SVneo and JEG-3 cells. Furthermore, GW9662 or si-PPARγ exacerbated the inhibition of cell viability, migration, angiogenesis, and aggravated inflammation induced by PFOS in HTR-8/SVneo and JEG-3 cells. Meanwhile, the results of mRNA expression level were consistent with the cell representation. In conclusion, our findings revealed that PFOS induced placenta cell toxicity and functional damage through PPARγ pathway. Full article
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21 pages, 4838 KiB  
Article
Pharmacological Blockade of PPARα Exacerbates Inflammatory Pain-Related Impairment of Spatial Memory in Rats
by Jessica C. Gaspar, Catherine Healy, Mehnaz I. Ferdousi, Michelle Roche and David P. Finn
Biomedicines 2021, 9(6), 610; https://doi.org/10.3390/biomedicines9060610 - 27 May 2021
Cited by 9 | Viewed by 2826
Abstract
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that exist in three isoforms: PPARα, PPARβ/δ and PPARγ. Studies suggest that the PPAR signalling system may modulate pain, anxiety and cognition. The aim of the present study was to investigate whether endogenous signalling via [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors that exist in three isoforms: PPARα, PPARβ/δ and PPARγ. Studies suggest that the PPAR signalling system may modulate pain, anxiety and cognition. The aim of the present study was to investigate whether endogenous signalling via PPARs differentially modulates innate anxiety responses and mnemonic function in the presence and absence of inflammatory pain. We examined the effects of intraperitoneal administration of GW6471 (PPARα antagonist), GSK0660 (PPARβ/δ antagonist), GW9662 (PPARγ antagonist), and N-palmitoylethanolamide (PEA) on rat behaviour in the elevated plus maze (EPM), open field (OF), light-dark box (LDB), and novel object recognition (NOR) tests in the presence or absence of chronic inflammatory pain. Complete Freund’s Adjuvant (CFA)-injected rats exhibited impaired recognition and spatial mnemonic performance in the NOR test and pharmacological blockade of PPARα further impaired spatial memory in CFA-treated rats. N-oleoylethanolamide (OEA) levels were higher in the dorsal hippocampus in CFA-injected animals compared to their counterparts. The results suggest a modulatory effect of CFA-induced chronic inflammatory pain on cognitive processing, but not on innate anxiety-related responses. Increased OEA-PPARα signalling may act as a compensatory mechanism to preserve spatial memory function following CFA injection. Full article
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