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The Role of PPARs in Disease II
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The Role of PPARs in Disease II

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Cardiovascular System".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 60632

Printed Edition Available!
A printed edition of this Special Issue is available here.

Special Issue Editors

Dr. Kay-Dietrich Wagner

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Guest Editor
Université Côte d’Azur, CNRS, INSERM, iBV, 06107 Nice, France
Interests: vessel formation in development and disease; transcriptional control; epigenetics; cancer; cardiovascular disease
Special Issues, Collections and Topics in MDPI journals
Dr. Nicole Wagner

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Guest Editor
Institute of Biology Valrose, University of Nice Sophia Antipolis, 06107 Nice, France
Interests: PPARs; cancer; development; angiogenesis; transcriptional regulation; tumor angiogenesis; mechanisms of tumor progression; cancer treatment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors. They 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, modulate 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. Specific synthetic agonists for all PPARs are available. PPARα and PPARγ agonists are already in clinical use for the treatment of hyperlipidemia and type 2 diabetes, respectively. More recently, PPAR β/δ activation came into focus as an interesting novel approach for the treatment of metabolic syndrome and associated cardiovascular diseases.

In summary, PPARs are linked to metabolic disorders and are interesting pharmaceutical targets. PPARs play important roles in a variety of disorders, e.g., cardiovascular, hepatic, neurological, psychiatric, and immunological diseases, and cancer. We guest-edited a first Special Issue on “The Role of PPARs in Disease” in Cells in 2019–2020. Despite the global health crisis, 11 papers were published in this Special Issue, which have received until now nearly 17,000 views and 112 citations. The impact factor of Cells increased dramatically in the previous year to 6.6.

We hope that this new Special Issue of Cells will bring together the most recent and exciting advances in understanding the various aspects of the action of PPARs, from basic science to applied therapeutic approaches.

Sincerely yours,

Dr. Kay-Dietrich Wagner
Guest Editor

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • PPAR
  • immune function
  • liver
  • adipose tissue
  • cardiovascular system
  • muscle
  • neurological and psychiatric disease
  • cancer
  • transcriptional regulation
  • ligands
  • agonists/antagonists

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Published Papers (20 papers)

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Editorial

Jump to: Research, Review

8 pages, 256 KiB  
Editorial
Recent Insights into the Role of PPARs in Disease
by Nicole Wagner and Kay-Dietrich Wagner
Cells 2023, 12(12), 1572; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12121572 - 07 Jun 2023
Cited by 2 | Viewed by 1286
Abstract
Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that play important roles in cell proliferation, differentiation, metabolism, and cancer [...] Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)

Research

Jump to: Editorial, Review

29 pages, 7063 KiB  
Article
Selective PPAR-Delta/PPAR-Gamma Activation Improves Cognition in a Model of Alzheimer’s Disease
by Ian Steinke, Manoj Govindarajulu, Priyanka Das Pinky, Jenna Bloemer, Sieun Yoo, Tracey Ward, Taylor Schaedig, Taylor Young, Fajar Setyo Wibowo, Vishnu Suppiramaniam and Rajesh H. Amin
Cells 2023, 12(8), 1116; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12081116 - 08 Apr 2023
Cited by 5 | Viewed by 2467
Abstract
Background: The continuously increasing association of Alzheimer’s disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in [...] Read more.
Background: The continuously increasing association of Alzheimer’s disease (AD) with increased mortality rates indicates an unmet medical need and the critical need for establishing novel molecular targets for therapeutic potential. Agonists for peroxisomal proliferator activating receptors (PPAR) are known to regulate energy in the body and have shown positive effects against Alzheimer’s disease. There are three members of this class (delta, gamma, and alpha), with PPAR-gamma being the most studied, as these pharmaceutical agonists offer promise for AD because they reduce amyloid beta and tau pathologies, display anti-inflammatory properties, and improve cognition. However, they display poor brain bioavailability and are associated with several adverse side effects on human health, thus limiting their clinical application. Methods: We have developed a novel series of PPAR-delta and PPAR-gamma agonists in silico with AU9 as our lead compound that displays selective amino acid interactions focused upon avoiding the Tyr-473 epitope in the PPAR-gamma AF2 ligand binding domain. Results: This design helps to avoid the unwanted side effects of current PPAR-gamma agonists and improve behavioral deficits and synaptic plasticity while reducing amyloid-beta levels and inflammation in 3xTgAD animals. Conclusions: Our innovative in silico design of PPAR-delta/gamma agonists may offer new perspectives for this class of agonists for AD. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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15 pages, 1564 KiB  
Article
Exploring the Nerve Regenerative Capacity of Compounds with Differing Affinity for PPARγ In Vitro and In Vivo
by Melissa L. D. Rayner, Simon C. Kellaway, Isabel Kingston, Owein Guillemot-Legris, Holly Gregory, Jess Healy and James B. Phillips
Cells 2023, 12(1), 42; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12010042 - 22 Dec 2022
Cited by 4 | Viewed by 2233
Abstract
Damage to peripheral nerves can cause debilitating consequences for patients such as lifelong pain and disability. At present, no drug treatments are routinely given in the clinic following a peripheral nerve injury (PNI) to improve regeneration and remyelination of damaged nerves. Appropriately targeted [...] Read more.
Damage to peripheral nerves can cause debilitating consequences for patients such as lifelong pain and disability. At present, no drug treatments are routinely given in the clinic following a peripheral nerve injury (PNI) to improve regeneration and remyelination of damaged nerves. Appropriately targeted therapeutic agents have the potential to be used at different stages following nerve damage, e.g., to maintain Schwann cell viability, induce and sustain a repair phenotype to support axonal growth, or promote remyelination. The development of therapies to promote nerve regeneration is currently of high interest to researchers, however, translation to the clinic of drug therapies for PNI is still lacking. Studying the effect of PPARγ agonists for treatment of peripheral nerve injures has demonstrated significant benefits. Ibuprofen, a non-steroidal anti-inflammatory drug (NSAID), has reproducibly demonstrated benefits in vitro and in vivo, suggested to be due to its agonist action on PPARγ. Other NSAIDs have demonstrated differing levels of PPARγ activation based upon their affinity. Therefore, it was of interest to determine whether affinity for PPARγ of selected drugs corresponded to an increase in regeneration. A 3D co-culture in vitro model identified some correlation between these two properties. However, when the drug treatments were screened in vivo, in a crush injury model in a rat sciatic nerve, the same correlation was not apparent. Further differences were observed between capacity to increase axon number and improvement in functional recovery. Despite there not being a clear correlation between affinity and size of effect on regeneration, all selected PPARγ agonists improved regeneration, providing a panel of compounds that could be explored for use in the treatment of PNI. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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19 pages, 2746 KiB  
Article
A Possible Modulator of Vitiligo Metabolic Impairment: Rethinking a PPARγ Agonist
by Federica Papaccio, Barbara Bellei, Monica Ottaviani, Andrea D’Arino, Mauro Truglio, Silvia Caputo, Giovanni Cigliana, Lorenzo Sciuto, Emilia Migliano, Alessia Pacifico, Paolo Iacovelli and Mauro Picardo
Cells 2022, 11(22), 3583; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11223583 - 12 Nov 2022
Cited by 5 | Viewed by 2225
Abstract
Vitiligo is a complex disease wherein derangements in multiple pathways determine the loss of functional melanocytes. Since its pathogenesis is not yet completely understood, vitiligo lacks a definitive safe and efficacious treatment. At present, different therapies are available; however, each modality has its [...] Read more.
Vitiligo is a complex disease wherein derangements in multiple pathways determine the loss of functional melanocytes. Since its pathogenesis is not yet completely understood, vitiligo lacks a definitive safe and efficacious treatment. At present, different therapies are available; however, each modality has its baggage of disadvantages and side effects. Recently we have described several metabolic abnormalities in cells from pigmented skin of vitiligo patients, including alterations of glucose metabolism. Therefore, we conducted a study to evaluate the effect of Pioglitazone (PGZ), a Peroxisome proliferator-activated receptor-γ (PPARγ) agonist, on cells from pigmented vitiligo skin. We treated vitiligo melanocytes and fibroblasts with low doses of PGZ and evaluated the effects on mitochondrial alterations, previously reported by our and other groups. Treatment with PGZ significantly increased mRNA and protein levels of several anaerobic glycolytic enzymes, without increasing glucose consumption. The PGZ administration fully restored the metabolic network, replacing mitochondrial membrane potential and mitochondrial DNA (mtDNA) copy number. These effects, together with a significant increase in ATP content and a decrease in reactive oxygen species (ROS) production, provide strong evidence of an overall improvement of mitochondria bioenergetics in vitiligo cells. Moreover, the expression of HMGB1, Hsp70, defined as a part of DAMPs, and PD-L1 were significantly reduced. In addition, PGZ likely reverts premature senescence phenotype. In summary, the results outline a novel mode of action of Pioglitazone, which may turn out to be relevant to the development of effective new vitiligo therapeutic strategies. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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23 pages, 2733 KiB  
Article
The Potential for Placental Activation of PPARγ to Improve the Angiogenic Profile in Preeclampsia
by Brooke Grimaldi, Hamid-Reza Kohan-Ghadr and Sascha Drewlo
Cells 2022, 11(21), 3514; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11213514 - 06 Nov 2022
Cited by 5 | Viewed by 1861
Abstract
Preeclampsia (PE) is one of the most common causes of maternal-fetal morbidity and mortality world-wide. While the underlying causes of PE remain elusive, aberrant trophoblast differentiation and function are thought to cause an imbalance of secreted angiogenic proteins resulting in systemic endothelial dysfunction [...] Read more.
Preeclampsia (PE) is one of the most common causes of maternal-fetal morbidity and mortality world-wide. While the underlying causes of PE remain elusive, aberrant trophoblast differentiation and function are thought to cause an imbalance of secreted angiogenic proteins resulting in systemic endothelial dysfunction and organ damage in the mother. The placental dysfunction is also characterized by a reduction of the transcription factor, peroxisome proliferator activated receptor γ (PPARγ) which normally promotes trophoblast differentiation and healthy placental function. This study aimed to understand how placental activation of PPARγ effects the secretion of angiogenic proteins and subsequently endothelial function. To study this, healthy and PE placental tissues were cultured with or without the PPARγ agonist, Rosiglitazone, and a Luminex assay was performed to measure secreted proteins from the placenta. To assess the angiogenic effects of placental activation of PPARγ, human umbilical vein endothelial cells (HUVECs) were cultured with the placental conditioned media and the net angiogenic potential of these cells was measured by a tube formation assay. This is the first study to show PPARγ’s beneficial effect on the angiogenic profile in the human preeclamptic placenta through the reduction of anti-angiogenic angiopoietin-2 and soluble endoglin and the upregulation of pro-angiogenic placental growth factor, fibroblast growth factor-2, heparin-binding epidermal growth factor, and follistatin. The changes in the angiogenic profile were supported by the increased angiogenic potential observed in the HUVECs when cultured with conditioned media from rosiglitazone-treated preeclamptic placentas. The restoration of these disrupted pathways by activation of PPARγ in the preeclamptic placenta offers potential to improve placental and endothelial function in PE. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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18 pages, 1994 KiB  
Article
Alternatively Spliced Landscape of PPARγ mRNA in Podocytes Is Distinct from Adipose Tissue
by Claire Bryant, Amy Webb, Alexander S. Banks, Dawn Chandler, Rajgopal Govindarajan and Shipra Agrawal
Cells 2022, 11(21), 3455; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11213455 - 01 Nov 2022
Cited by 2 | Viewed by 1780
Abstract
Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-γ (PPARγ) [...] Read more.
Podocytes are highly differentiated epithelial cells, and their structural and functional integrity is compromised in a majority of glomerular and renal diseases, leading to proteinuria, chronic kidney disease, and kidney failure. Traditional agonists (e.g., pioglitazone) and selective modulators (e.g., GQ-16) of peroxisome-proliferator-activated-receptor-γ (PPARγ) reduce proteinuria in animal models of glomerular disease and protect podocytes from injury via PPARγ activation. This indicates a pivotal role for PPARγ in maintaining glomerular function through preservation of podocytes distinct from its well-understood role in driving insulin sensitivity and adipogenesis. While its transcriptional role in activating adipokines and adipogenic genes is well-established in adipose tissue, liver and muscle, understanding of podocyte PPARγ signaling remains limited. We performed a comprehensive analysis of PPARγ mRNA variants due to alternative splicing, in human podocytes and compared with adipose tissue. We found that podocytes express the ubiquitous PPARγ Var 1 (encoding γ1) and not Var2 (encoding γ2), which is mostly restricted to adipose tissue and liver. Additionally, we detected expression at very low level of Var4, and barely detectable levels of other variants, Var3, Var11, VartORF4 and Var9, in podocytes. Furthermore, a distinct podocyte vs. adipocyte PPAR-promoter-response-element containing gene expression, enrichment and pathway signature was observed, suggesting differential regulation by podocyte specific PPARγ1 variant, distinct from the adipocyte-specific γ2 variant. In summary, podocytes and glomeruli express several PPARγ variants, including Var1 (γ1) and excluding adipocyte-specific Var2 (γ2), which may have implications in podocyte specific signaling and pathophysiology. This suggests that that new selective PPARγ modulators can be potentially developed that will be able to distinguish between the two forms, γ1 and γ2, thus forming a basis of novel targeted therapeutic avenues. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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12 pages, 2542 KiB  
Article
Activation of PPARα Ameliorates Cardiac Fibrosis in Dsg2-Deficient Arrhythmogenic Cardiomyopathy
by Zirui Qiu, Yawen Zhao, Tian Tao, Wenying Guo, Ruonan Liu, Jingmin Huang and Geyang Xu
Cells 2022, 11(20), 3184; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11203184 - 11 Oct 2022
Cited by 8 | Viewed by 1877
Abstract
Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterized by progressive fibro-fatty replacement of cardiac myocytes. Up to now, the existing therapeutic modalities for ACM are mostly palliative. About 50% of ACM is caused by mutations in genes encoding desmosomal proteins [...] Read more.
Background: Arrhythmogenic cardiomyopathy (ACM) is a genetic heart muscle disease characterized by progressive fibro-fatty replacement of cardiac myocytes. Up to now, the existing therapeutic modalities for ACM are mostly palliative. About 50% of ACM is caused by mutations in genes encoding desmosomal proteins including Desmoglein-2 (Dsg2). In the current study, the cardiac fibrosis of ACM and its underlying mechanism were investigated by using a cardiac-specific knockout of Dsg2 mouse model. Methods: Cardiac-specific Dsg2 knockout (CS-Dsg2−/−) mice and wild-type (WT) mice were respectively used as the animal model of ACM and controls. The myocardial collagen volume fraction was determined by histological analysis. The expression levels of fibrotic markers such as α-SMA and Collagen I as well as signal transducers such as STAT3, SMAD3, and PPARα were measured by Western blot and quantitative real-time PCR. Results: Increased cardiac fibrosis was observed in CS-Dsg2−/− mice according to Masson staining. PPARα deficiency and hyperactivation of STAT3 and SMAD3 were observed in the myocardium of CS-Dsg2−/− mice. The biomarkers of fibrosis such as α-SMA and Collagen I were upregulated after gene silencing of Dsg2 in HL-1 cells. Furthermore, STAT3 gene silencing by Stat3 siRNA inhibited the expression of fibrotic markers. The activation of PPARα by fenofibrate or AAV9-Pparα improved the cardiac fibrosis and decreased the phosphorylation of STAT3, SMAD3, and AKT in CS-Dsg2−/− mice. Conclusions: Activation of PPARα alleviates the cardiac fibrosis in ACM. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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14 pages, 2858 KiB  
Article
Suppression of Hepatic PPARα in Primary Biliary Cholangitis Is Modulated by miR-155
by Monika Adamowicz, Agnieszka Kempinska-Podhorodecka, Joanna Abramczyk, Jesus M. Banales, Piotr Milkiewicz and Malgorzata Milkiewicz
Cells 2022, 11(18), 2880; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11182880 - 15 Sep 2022
Cited by 6 | Viewed by 1955
Abstract
Background: PPARα is a ligand-activated transcription factor that shows protective effects against metabolic disorders, inflammation and apoptosis. Primary biliary cholangitis and primary sclerosing cholangitis result in the intrahepatic accumulation of bile acids that leads to liver dysfunction and damage. Small, non-coding RNAs such [...] Read more.
Background: PPARα is a ligand-activated transcription factor that shows protective effects against metabolic disorders, inflammation and apoptosis. Primary biliary cholangitis and primary sclerosing cholangitis result in the intrahepatic accumulation of bile acids that leads to liver dysfunction and damage. Small, non-coding RNAs such as miR-155 and miR-21 are associated with silencing PPARα. Methods: The expression of miR-155, miR-21 and PPARα were evaluated using real-time PCR on liver tissue, as well as on human hepatocytes (HepG2) or cholangiocytes (NHCs) following exposure to lipopolysaccharide (LPS), glycodeoxycholic acid (GCDCA), lithocholic acid (LCA) and/or ursodeoxycholic acid (UDCA). Results: A reduction of PPARα in primary biliary cholangitis (PBC) livers was associated with miR-21 and miR-155 upregulation. Experimental overexpression of either miR-155 or miR-21 inhibited PPARα in hepatocytes, whereas, in cholangiocytes, only miR-21 suppressed PPARα. Both GCDCA and LCA induced the cell type-specific upregulation of miR-155 or miR-21. In HepG2, LPS-induced miR-155 expression was blocked by a cotreatment with UDCA and was associated with PPARα upregulation. In NHC cells, the expression of miR-21 was induced by LPS but did not affect PPARα expression. Conclusions: Hepatic PPARα expression is reduced in PBC livers as a likely result of miR-155 overexpression. UDCA effectively reduced both baseline and LPS-induced miR-155 expression, thus preventing the suppression of PPARα. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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19 pages, 2592 KiB  
Article
Rosiglitazone Ameliorates Cardiac and Skeletal Muscle Dysfunction by Correction of Energetics in Huntington’s Disease
by Marta Tomczyk, Alicja Braczko, Paulina Mierzejewska, Magdalena Podlacha, Oliwia Krol, Patrycja Jablonska, Agata Jedrzejewska, Karolina Pierzynowska, Grzegorz Wegrzyn, Ewa M. Slominska and Ryszard T. Smolenski
Cells 2022, 11(17), 2662; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11172662 - 27 Aug 2022
Cited by 6 | Viewed by 1871
Abstract
Huntington’s disease (HD) is a rare neurodegenerative disease that is accompanied by skeletal muscle atrophy and cardiomyopathy. Tissues affected by HD (central nervous system [CNS], skeletal muscle, and heart) are known to suffer from deteriorated cellular energy metabolism that manifests already at presymptomatic [...] Read more.
Huntington’s disease (HD) is a rare neurodegenerative disease that is accompanied by skeletal muscle atrophy and cardiomyopathy. Tissues affected by HD (central nervous system [CNS], skeletal muscle, and heart) are known to suffer from deteriorated cellular energy metabolism that manifests already at presymptomatic stages. This work aimed to test the effects of peroxisome proliferator-activated receptor (PPAR)-γ agonist—rosiglitazone on grip strength and heart function in an experimental HD model—on R6/1 mice and to address the mechanisms. We noted that rosiglitazone treatment lead to improvement of R6/1 mice grip strength and cardiac mechanical function. It was accompanied by an enhancement of the total adenine nucleotides pool, increased glucose oxidation, changes in mitochondrial number (indicated as increased citric synthase activity), and reduction in mitochondrial complex I activity. These metabolic changes were supported by increased total antioxidant status in HD mice injected with rosiglitazone. Correction of energy deficits with rosiglitazone was further indicated by decreased accumulation of nucleotide catabolites in HD mice serum. Thus, rosiglitazone treatment may not only delay neurodegeneration but also may ameliorate cardio- and myopathy linked to HD by improvement of cellular energetics. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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16 pages, 4607 KiB  
Article
Transcriptomics Reveals Discordant Lipid Metabolism Effects between In Vitro Models Exposed to Elafibranor and Liver Samples of NAFLD Patients after Bariatric Surgery
by Joost Boeckmans, Alexandra Gatzios, Anja Heymans, Matthias Rombaut, Vera Rogiers, Joery De Kock, Tamara Vanhaecke and Robim M. Rodrigues
Cells 2022, 11(5), 893; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11050893 - 04 Mar 2022
Cited by 7 | Viewed by 3484
Abstract
Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in [...] Read more.
Background and aims: Non-alcoholic steatohepatitis (NASH) is a life-threatening stage of non-alcoholic fatty liver disease (NAFLD) for which no drugs have been approved. We have previously shown that human-derived hepatic in vitro models can be used to mimic key cellular mechanisms involved in the progression of NASH. In the present study, we first characterize the transcriptome of multiple in vitro NASH models. Subsequently, we investigate how elafibranor, which is a peroxisome proliferator-activated receptor (PPAR)-α/δ agonist that has recently failed a phase 3 clinical trial as a potential anti-NASH compound, modulates the transcriptome of these models. Finally, we compare the elafibranor-induced gene expression modulation to transcriptome data of patients with improved/resolved NAFLD/NASH upon bariatric surgery, which is the only proven clinical NASH therapy. Methods: Human whole genome microarrays were used for the transcriptomics evaluation of hepatic in vitro models. Comparison to publicly available clinical datasets was conducted using multiple bioinformatic application tools. Results: Primary human hepatocytes (PHH), HepaRG, and human skin stem cell-derived hepatic progenitors (hSKP-HPC) exposed to NASH-inducing triggers exhibit up to 35% overlap with datasets of liver samples from NASH patients. Exposure of the in vitro NASH models to elafibranor partially reversed the transcriptional modulations, predicting an inhibition of toll-like receptor (TLR)-2/4/9-mediated inflammatory responses, NFκB-signaling, hepatic fibrosis, and leukocyte migration. These transcriptomic changes were also observed in the datasets of liver samples of patients with resolved NASH. Peroxisome Proliferator Activated Receptor Alpha (PPARA), PPARG Coactivator 1 Alpha (PPARGC1A), and Sirtuin 1 (SIRT1) were identified as the major common upstream regulators upon exposure to elafibranor. Analysis of the downstream mechanistic networks further revealed that angiopoietin Like 4 (ANGPTL4), pyruvate dehydrogenase kinase 4 (PDK4), and perilipin 2 (PLIN2), which are involved in the promotion of hepatic lipid accumulation, were also commonly upregulated by elafibranor in all in vitro NASH models. Contrarily, these genes were not upregulated in liver samples of patients with resolved NASH. Conclusion: Transcriptomics comparison between in vitro NASH models exposed to elafibranor and clinical datasets of NAFLD patients after bariatric surgery reveals commonly modulated anti-inflammatory responses, but discordant modulations of key factors in lipid metabolism. This discordant adverse effect of elafibranor deserves further investigation when assessing PPAR-α/δ agonism as a potential anti-NASH therapy. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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17 pages, 1987 KiB  
Article
Selective PPARα Modulator Pemafibrate and Sodium-Glucose Cotransporter 2 Inhibitor Tofogliflozin Combination Treatment Improved Histopathology in Experimental Mice Model of Non-Alcoholic Steatohepatitis
by Kentaro Murakami, Yusuke Sasaki, Masato Asahiyama, Wataru Yano, Toshiaki Takizawa, Wakana Kamiya, Yoshihiro Matsumura, Motonobu Anai, Tsuyoshi Osawa, Jean-Charles Fruchart, Jamila Fruchart-Najib, Hiroyuki Aburatani, Juro Sakai, Tatsuhiko Kodama and Toshiya Tanaka
Cells 2022, 11(4), 720; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040720 - 18 Feb 2022
Cited by 12 | Viewed by 7011
Abstract
Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 [...] Read more.
Ballooning degeneration of hepatocytes is a major distinguishing histological feature of non-alcoholic steatosis (NASH) progression that can lead to cirrhosis and hepatocellular carcinoma (HCC). In this study, we evaluated the effect of the selective PPARα modulator (SPPARMα) pemafibrate (Pema) and sodium-glucose cotransporter 2 (SGLT2) inhibitor tofogliflozin (Tofo) combination treatment on pathological progression in the liver of a mouse model of NASH (STAM) at two time points (onset of NASH progression and HCC survival). At both time points, the Pema and Tofo combination treatment significantly alleviated hyperglycemia and hypertriglyceridemia. The combination treatment significantly reduced ballooning degeneration of hepatocytes. RNA-seq analysis suggested that Pema and Tofo combination treatment resulted in an increase in glyceroneogenesis, triglyceride (TG) uptake, lipolysis and liberated fatty acids re-esterification into TG, lipid droplet (LD) formation, and Cidea/Cidec ratio along with an increased number and reduced size and area of LDs. In addition, combination treatment reduced expression levels of endoplasmic reticulum stress-related genes (Ire1a, Grp78, Xbp1, and Phlda3). Pema and Tofo treatment significantly improved survival rates and reduced the number of tumors in the liver compared to the NASH control group. These results suggest that SPPARMα and SGLT2 inhibitor combination therapy has therapeutic potential to prevent NASH-HCC progression. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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16 pages, 9134 KiB  
Article
PPARγ Regulates Triclosan Induced Placental Dysfunction
by Jing Li, Xiaojie Quan, Yue Zhang, Ting Yu, Saifei Lei, Zhenyao Huang, Qi Wang, Weiyi Song, Xinxin Yang and Pengfei Xu
Cells 2022, 11(1), 86; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11010086 - 28 Dec 2021
Cited by 15 | Viewed by 2409
Abstract
Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we [...] Read more.
Exposure to the antibacterial agent triclosan (TCS) is associated with abnormal placenta growth and fetal development during pregnancy. Peroxisome proliferator-activated receptor γ (PPARγ) is crucial in placenta development. However, the mechanism of PPARγ in placenta injury induced by TCS remains unknown. Herein, we demonstrated that PPARγ worked as a protector against TCS-induced toxicity. TCS inhibited cell viability, migration, and angiogenesis dose-dependently in HTR-8/SVneo and JEG-3 cells. Furthermore, TCS downregulated expression of PPARγ and its downstream viability, migration, angiogenesis-related genes HMOX1, ANGPTL4, VEGFA, MMP-2, MMP-9, and upregulated inflammatory genes p65, IL-6, IL-1β, and TNF-α in vitro and in vivo. Further investigation showed that overexpression or activation (rosiglitazone) alleviated cell viability, migration, angiogenesis inhibition, and inflammatory response caused by TCS, while knockdown or inhibition (GW9662) of PPARγ had the opposite effect. Moreover, TCS caused placenta dysfunction characterized by the significant decrease in weight and size of the placenta and fetus, while PPARγ agonist rosiglitazone alleviated this damage in mice. Taken together, our results illustrated that TCS-induced placenta dysfunction, which was mediated by the PPARγ pathway. Our findings reveal that activation of PPARγ might be a promising strategy against the adverse effects of TCS exposure on the placenta and fetus. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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Review

Jump to: Editorial, Research

18 pages, 576 KiB  
Review
Peroxisome Proliferator-Activated Receptor-Targeted Therapies: Challenges upon Infectious Diseases
by In Soo Kim, Prashanta Silwal and Eun-Kyeong Jo
Cells 2023, 12(4), 650; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12040650 - 17 Feb 2023
Cited by 5 | Viewed by 3344
Abstract
Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) α, β, and γ are nuclear receptors that orchestrate the transcriptional regulation of genes involved in a variety of biological responses, such as energy metabolism and homeostasis, regulation of inflammation, cellular development, and differentiation. The many roles played by the PPAR signaling pathways indicate that PPARs may be useful targets for various human diseases, including metabolic and inflammatory conditions and tumors. Accumulating evidence suggests that each PPAR plays prominent but different roles in viral, bacterial, and parasitic infectious disease development. In this review, we discuss recent PPAR research works that are focused on how PPARs control various infections and immune responses. In addition, we describe the current and potential therapeutic uses of PPAR agonists/antagonists in the context of infectious diseases. A more comprehensive understanding of the roles played by PPARs in terms of host-pathogen interactions will yield potential adjunctive personalized therapies employing PPAR-modulating agents. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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33 pages, 2476 KiB  
Review
The Role of PPARs in Breast Cancer
by Binggong Zhao, Zhiqiang Xin, Ping Ren and Huijian Wu
Cells 2023, 12(1), 130; https://0-doi-org.brum.beds.ac.uk/10.3390/cells12010130 - 28 Dec 2022
Cited by 15 | Viewed by 3062
Abstract
Breast cancer is a malignant tumor with high morbidity and lethality. Its pathogenesis is related to the abnormal expression of many genes. The peroxisome proliferator-activated receptors (PPARs) are a class of ligand-dependent transcription factors in the nuclear receptor superfamily. They can regulate the [...] Read more.
Breast cancer is a malignant tumor with high morbidity and lethality. Its pathogenesis is related to the abnormal expression of many genes. The peroxisome proliferator-activated receptors (PPARs) are a class of ligand-dependent transcription factors in the nuclear receptor superfamily. They can regulate the transcription of a large number of target genes, which are involved in life activities such as cell proliferation, differentiation, metabolism, and apoptosis, and regulate physiological processes such as glucose metabolism, lipid metabolism, inflammation, and wound healing. Further, the changes in its expression are associated with various diseases, including breast cancer. The experimental reports related to “PPAR” and “breast cancer” were retrieved from PubMed since the discovery of PPARs and summarized in this paper. This review (1) analyzed the roles and potential molecular mechanisms of non-coordinated and ligand-activated subtypes of PPARs in breast cancer progression; (2) discussed the correlations between PPARs and estrogen receptors (ERs) as the nuclear receptor superfamily; and (3) investigated the interaction between PPARs and key regulators in several signaling pathways. As a result, this paper identifies PPARs as targets for breast cancer prevention and treatment in order to provide more evidence for the synthesis of new drugs targeting PPARs or the search for new drug combination treatments. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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30 pages, 2586 KiB  
Review
Exploring the Regulatory Role of ncRNA in NAFLD: A Particular Focus on PPARs
by Anirban Goutam Mukherjee, Uddesh Ramesh Wanjari, Abilash Valsala Gopalakrishnan, Ramkumar Katturajan, Sandra Kannampuzha, Reshma Murali, Arunraj Namachivayam, Raja Ganesan, Kaviyarasi Renu, Abhijit Dey, Balachandar Vellingiri and Sabina Evan Prince
Cells 2022, 11(24), 3959; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11243959 - 07 Dec 2022
Cited by 3 | Viewed by 3351
Abstract
Liver diseases are responsible for global mortality and morbidity and are a significant cause of death worldwide. Consequently, the advancement of new liver disease targets is of great interest. Non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), has been proven [...] Read more.
Liver diseases are responsible for global mortality and morbidity and are a significant cause of death worldwide. Consequently, the advancement of new liver disease targets is of great interest. Non-coding RNA (ncRNA), such as microRNA (miRNA) and long ncRNA (lncRNA), has been proven to play a significant role in the pathogenesis of virtually all acute and chronic liver disorders. Recent studies demonstrated the medical applications of miRNA in various phases of hepatic pathology. PPARs play a major role in regulating many signaling pathways involved in various metabolic disorders. Non-alcoholic fatty liver disease (NAFLD) is the most prevalent form of chronic liver disease in the world, encompassing a spectrum spanning from mild steatosis to severe non-alcoholic steatohepatitis (NASH). PPARs were found to be one of the major regulators in the progression of NAFLD. There is no recognized treatment for NAFLD, even though numerous clinical trials are now underway. NAFLD is a major risk factor for developing hepatocellular carcinoma (HCC), and its frequency increases as obesity and diabetes become more prevalent. Reprogramming anti-diabetic and anti-obesity drugs is an effective therapy option for NAFLD and NASH. Several studies have also focused on the role of ncRNAs in the pathophysiology of NAFLD. The regulatory effects of these ncRNAs make them a primary target for treatments and as early biomarkers. In this study, the main focus will be to understand the regulation of PPARs through ncRNAs and their role in NAFLD. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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15 pages, 1113 KiB  
Review
Stemness of Normal and Cancer Cells: The Influence of Methionine Needs and SIRT1/PGC-1α/PPAR-α Players
by Youssef Siblini, Farès Namour, Abderrahim Oussalah, Jean-Louis Guéant and Céline Chéry
Cells 2022, 11(22), 3607; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11223607 - 15 Nov 2022
Cited by 3 | Viewed by 2509
Abstract
Stem cells are a population of undifferentiated cells with self-renewal and differentiation capacities. Normal and cancer stem cells share similar characteristics in relation to their stemness properties. One-carbon metabolism (OCM), a network of interconnected reactions, plays an important role in this dependence through [...] Read more.
Stem cells are a population of undifferentiated cells with self-renewal and differentiation capacities. Normal and cancer stem cells share similar characteristics in relation to their stemness properties. One-carbon metabolism (OCM), a network of interconnected reactions, plays an important role in this dependence through its role in the endogenous synthesis of methionine and S-adenosylmethionine (SAM), the universal donor of methyl groups in eukaryotic cells. OCM genes are differentially expressed in stem cells, compared to their differentiated counterparts. Furthermore, cultivating stem cells in methionine-restricted conditions hinders their stemness capacities through decreased SAM levels with a subsequent decrease in histone methylation, notably H3K4me3, with a decrease in stem cell markers. Stem cells’ reliance on methionine is linked to several mechanisms, including high methionine flux or low endogenous methionine biosynthesis. In this review, we provide an overview of the recent discoveries concerning this metabolic dependence and we discuss the mechanisms behind them. We highlight the influence of SIRT1 on SAM synthesis and suggest a role of PGC-1α/PPAR-α in impaired stemness produced by methionine deprivation. In addition, we discuss the potential interest of methionine restriction in regenerative medicine and cancer treatment. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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25 pages, 1425 KiB  
Review
The Potential Role of PPARs in the Fetal Origins of Adult Disease
by Jun Guo, Jue Wu, Qinyuan He, Mengshu Zhang, Hong Li and Yanping Liu
Cells 2022, 11(21), 3474; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11213474 - 02 Nov 2022
Cited by 9 | Viewed by 2758
Abstract
The fetal origins of adult disease (FOAD) hypothesis holds that events during early development have a profound impact on one’s risk for the development of future adult disease. Studies from humans and animals have demonstrated that many diseases can begin in childhood and [...] Read more.
The fetal origins of adult disease (FOAD) hypothesis holds that events during early development have a profound impact on one’s risk for the development of future adult disease. Studies from humans and animals have demonstrated that many diseases can begin in childhood and are caused by a variety of early life traumas, including maternal malnutrition, maternal disease conditions, lifestyle changes, exposure to toxins/chemicals, improper medication during pregnancy, and so on. Recently, the roles of Peroxisome proliferator-activated receptors (PPARs) in FOAD have been increasingly appreciated due to their wide variety of biological actions. PPARs are members of the nuclear hormone receptor subfamily, consisting of three distinct subtypes: PPARα, β/δ, and γ, highly expressed in the reproductive tissues. By controlling the maturation of the oocyte, ovulation, implantation of the embryo, development of the placenta, and male fertility, the PPARs play a crucial role in the transition from embryo to fetus in developing mammals. Exposure to adverse events in early life exerts a profound influence on the methylation pattern of PPARs in offspring organs, which can affect development and health throughout the life course, and even across generations. In this review, we summarize the latest research on PPARs in the area of FOAD, highlight the important role of PPARs in FOAD, and provide a potential strategy for early prevention of FOAD. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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34 pages, 2822 KiB  
Review
PPAR-γ Partial Agonists in Disease-Fate Decision with Special Reference to Cancer
by Sangeeta Ballav, Bini Biswas, Vishal Kumar Sahu, Amit Ranjan and Soumya Basu
Cells 2022, 11(20), 3215; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11203215 - 13 Oct 2022
Cited by 11 | Viewed by 4218
Abstract
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and [...] Read more.
Peroxisome proliferator-activated receptor-γ (PPAR-γ) has emerged as one of the most extensively studied transcription factors since its discovery in 1990, highlighting its importance in the etiology and treatment of numerous diseases involving various types of cancer, type 2 diabetes mellitus, autoimmune, dermatological and cardiovascular disorders. Ligands are regarded as the key determinant for the tissue-specific activation of PPAR-γ. However, the mechanism governing this process is merely a contradictory debate which is yet to be systematically researched. Either these receptors get weakly activated by endogenous or natural ligands or leads to a direct over-activation process by synthetic ligands, serving as complete full agonists. Therefore, fine-tuning on the action of PPAR-γ and more subtle modulation can be a rewarding approach which might open new avenues for the treatment of several diseases. In the recent era, researchers have sought to develop safer partial PPAR-γ agonists in order to dodge the toxicity induced by full agonists, akin to a balanced activation. With a particular reference to cancer, this review concentrates on the therapeutic role of partial agonists, especially in cancer treatment. Additionally, a timely examination of their efficacy on various other disease-fate decisions has been also discussed. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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57 pages, 25868 KiB  
Review
Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer
by Nicole Wagner and Kay-Dietrich Wagner
Cells 2022, 11(15), 2432; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11152432 - 05 Aug 2022
Cited by 21 | Viewed by 4577
Abstract
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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15 pages, 14262 KiB  
Review
Potential Therapeutic Effects of PPAR Ligands in Glioblastoma
by Rossella Basilotta, Marika Lanza, Giovanna Casili, Giulia Chisari, Stefania Munao, Lorenzo Colarossi, Laura Cucinotta, Michela Campolo, Emanuela Esposito and Irene Paterniti
Cells 2022, 11(4), 621; https://0-doi-org.brum.beds.ac.uk/10.3390/cells11040621 - 10 Feb 2022
Cited by 12 | Viewed by 3334
Abstract
Glioblastoma (GB), also known as grade IV astrocytoma, represents the most aggressive form of brain tumor, characterized by extraordinary heterogeneity and high invasiveness and mortality. Thus, a great deal of interest is currently being directed to investigate a new therapeutic strategy and in [...] Read more.
Glioblastoma (GB), also known as grade IV astrocytoma, represents the most aggressive form of brain tumor, characterized by extraordinary heterogeneity and high invasiveness and mortality. Thus, a great deal of interest is currently being directed to investigate a new therapeutic strategy and in recent years, the research has focused its attention on the evaluation of the anticancer effects of some drugs already in use for other diseases. This is the case of peroxisome proliferator-activated receptors (PPARs) ligands, which over the years have been revealed to possess anticancer properties. PPARs belong to the nuclear receptor superfamily and are divided into three main subtypes: PPAR-α, PPAR-β/δ, and PPAR-γ. These receptors, once activated by specific natural or synthetic ligands, translocate to the nucleus and dimerize with the retinoid X receptors (RXR), starting the signal transduction of numerous genes involved in many physiological processes. PPARs receptors are activated by specific ligands and participate principally in the preservation of homeostasis and in lipid and glucose metabolism. In fact, synthetic PPAR-α agonists, such as fibrates, are drugs currently in use for the clinical treatment of hypertriglyceridemia, while PPAR-γ agonists, including thiazolidinediones (TZDs), are known as insulin-sensitizing drugs. In this review, we will analyze the role of PPARs receptors in the progression of tumorigenesis and the action of PPARs agonists in promoting, or not, the induction of cell death in GB cells, highlighting the conflicting opinions present in the literature. Full article
(This article belongs to the Special Issue The Role of PPARs in Disease II)
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