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Regulatory Role of PPARs in the Disease
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Regulatory Role of PPARs in the Disease

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (31 January 2021) | Viewed by 26904

Special Issue Editor

Prof. Dr. Iwona Bogacka

E-Mail Website
Guest Editor
Department of Animal Anatomy and Physiology, University of Warmia and Mazury in Olsztyn, Olsztyn, Poland
Interests: endocrinology; reproductive biology; inflammation; molecular biology

Special Issue Information

Dear Colleagues,

Peroxisome proliferator-activated receptors are members of the nuclear receptor superfamily comprising the following three isoforms: PPARα, PPARβ/δ, and PPARγ. They act as ligand-dependent transcription factors activated by fatty acids and fatty acid derivatives. All PPARs are mostly involved in the regulation of lipid and glucose metabolism as well as maintenance of energy homeostasis. Their role has been highlighted in adipogenesis, cell proliferation, and differentiation as well as vascular biology. PPARs have been functionally related to numerous pathological conditions such as obesity, diabetes, cancer, inflammation, and cardiovascular and neurodegenerative diseases. Therefore, PPARs can be considered as important therapeutic targets to treat a wide range of human diseases. This Special Issue of the International Journal of Molecular Sciences will focus on the function of PPARs in the ensemble of pathophysiological processes at the molecular level, including their potential significance in medicine. Authors are invited to submit their latest research within the scope of this Special Issue.

Prof. Iwona Bogacka
Guest Editor

Manuscript Submission Information

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Keywords

  • nuclear receptors
  • transcription factors
  • PPARα
  • PPARβ/δ
  • PPARγ
  • fatty acids
  • molecular biology
  • disease
  • pathophysiological processes
  • pathology
  • therapeutics

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Published Papers (7 papers)

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Research

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22 pages, 3059 KiB  
Article
Epidermal PPARγ Is a Key Homeostatic Regulator of Cutaneous Inflammation and Barrier Function in Mouse Skin
by Raymond L. Konger, Ethel Derr-Yellin, Teresa A. Zimmers, Terrence Katona, Xiaoling Xuei, Yunlong Liu, Hong-Ming Zhou, Ed Ronald Simpson, Jr. and Matthew J. Turner
Int. J. Mol. Sci. 2021, 22(16), 8634; https://doi.org/10.3390/ijms22168634 - 11 Aug 2021
Cited by 11 | Viewed by 3600
Abstract
Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we [...] Read more.
Both agonist studies and loss-of-function models indicate that PPARγ plays an important role in cutaneous biology. Since PPARγ has a high level of basal activity, we hypothesized that epidermal PPARγ would regulate normal homeostatic processes within the epidermis. In this current study, we performed mRNA sequencing and differential expression analysis of epidermal scrapings from knockout mice and wildtype littermates. Pparg-/-epi mice exhibited a 1.5-fold or greater change in the expression of 11.8% of 14,482 identified transcripts. Up-regulated transcripts included those for a large number of cytokines/chemokines and their receptors, as well as genes associated with inflammasome activation and keratinization. Several of the most dramatically up-regulated pro-inflammatory genes in Pparg-/-epi mouse skin included Igfl3, 2610528A11Rik, and Il1f6. RT-PCR was performed from RNA obtained from non-lesional full-thickness skin and verified a marked increase in these transcripts, as well as transcripts for Igflr1, which encodes the receptor for Igfl3, and the 2610528A11Rik receptor (Gpr15). Transcripts for Il4 were detected in Pparg-/-epi mouse skin, but transcripts for Il17 and Il22 were not detected. Down-regulated transcripts included sebaceous gland markers and a number of genes associated with lipid barrier formation. The change in these transcripts correlates with an asebia phenotype, increased transepidermal water loss, alopecia, dandruff, and the appearance of spontaneous inflammatory skin lesions. Histologically, non-lesional skin showed hyperkeratosis, while inflammatory lesions were characterized by dermal inflammation and epidermal acanthosis, spongiosis, and parakeratosis. In conclusion, loss of epidermal Pparg alters a substantial set of genes that are associated with cutaneous inflammation, keratinization, and sebaceous gland function. The data indicate that epidermal PPARγ plays an important role in homeostatic epidermal function, particularly epidermal differentiation, barrier function, sebaceous gland development and function, and inflammatory signaling. Full article
(This article belongs to the Special Issue Regulatory Role of PPARs in the Disease)
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21 pages, 2897 KiB  
Article
NRF2 and PPAR-γ Pathways in Oligodendrocyte Progenitors: Focus on ROS Protection, Mitochondrial Biogenesis and Promotion of Cell Differentiation
by Chiara De Nuccio, Antonietta Bernardo, Carmen Troiano, Maria Stefania Brignone, Mario Falchi, Anita Greco, Michela Rosini, Filippo Basagni, Cristina Lanni, Melania Maria Serafini, Luisa Minghetti and Sergio Visentin
Int. J. Mol. Sci. 2020, 21(19), 7216; https://doi.org/10.3390/ijms21197216 - 29 Sep 2020
Cited by 27 | Viewed by 4124
Abstract
An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is [...] Read more.
An adequate protection from oxidative and inflammatory reactions, together with the promotion of oligodendrocyte progenitor (OP) differentiation, is needed to recover from myelin damage in demyelinating diseases. Mitochondria are targets of inflammatory and oxidative insults and are essential in oligodendrocyte differentiation. It is known that nuclear factor-erythroid 2-related factor/antioxidant responsive element (NRF2/ARE) and peroxisome proliferator-activated receptor gamma/PPAR-γ response element (PPAR-γ/PPRE) pathways control inflammation and overcome mitochondrial impairment. In this study, we analyzed the effects of activators of these pathways on mitochondrial features, protection from inflammatory/mitochondrial insults and cell differentiation in OP cultures, to depict the specificities and similarities of their actions. We used dimethyl-fumarate (DMF) and pioglitazone (pio) as agents activating NRF2 and PPAR-γ, respectively, and two synthetic hybrids acting differently on the NRF2/ARE pathway. Only DMF and compound 1 caused early effects on the mitochondria. Both DMF and pio induced mitochondrial biogenesis but different antioxidant repertoires. Moreover, pio induced OP differentiation more efficiently than DMF. Finally, DMF, pio and compound 1 protected from tumor necrosis factor-alpha (TNF-α) insult, with pio showing faster kinetics of action and compound 1 a higher activity than DMF. In conclusion, NRF2 and PPAR-γ by inducing partially overlapping pathways accomplish complementary functions aimed at the preservation of mitochondrial function, the defense against oxidative stress and the promotion of OP differentiation. Full article
(This article belongs to the Special Issue Regulatory Role of PPARs in the Disease)
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13 pages, 3603 KiB  
Article
Peroxisome Proliferator-Activated Receptor Beta/Delta Agonist Suppresses Inflammation and Promotes Neovascularization
by Yutaro Tobita, Takeshi Arima, Yuji Nakano, Masaaki Uchiyama, Akira Shimizu and Hiroshi Takahashi
Int. J. Mol. Sci. 2020, 21(15), 5296; https://doi.org/10.3390/ijms21155296 - 26 Jul 2020
Cited by 18 | Viewed by 2325
Abstract
The effects of peroxisome proliferator-activated receptor (PPAR)β/δ ophthalmic solution were investigated in a rat corneal alkali burn model. After alkali injury, GW501516 (PPARβ/δ agonist) or vehicle ophthalmic solution was topically instilled onto the rat’s cornea twice a day until day 7. Pathological findings [...] Read more.
The effects of peroxisome proliferator-activated receptor (PPAR)β/δ ophthalmic solution were investigated in a rat corneal alkali burn model. After alkali injury, GW501516 (PPARβ/δ agonist) or vehicle ophthalmic solution was topically instilled onto the rat’s cornea twice a day until day 7. Pathological findings were evaluated, and real-time reverse transcription polymerase chain reaction was performed. GW501516 strongly suppressed infiltration of neutrophils and pan-macrophages, and reduced the mRNA expression of interleukin-6, interleukin-1β, tumor necrosis factor alpha, and nuclear factor-kappa B. On the other hand, GW501516 promoted infiltration of M2 macrophages, infiltration of vascular endothelial cells associated with neovascularization in the wounded area, and expression of vascular endothelial growth factor A mRNA. However, 7-day administration of GW501516 did not promote neovascularization in uninjured normal corneas. Thus, the PPARβ/δ ligand suppressed inflammation and promoted neovascularization in the corneal wound healing process. These results will help to elucidate the role of PPARβ/δ in the field of ophthalmology. Full article
(This article belongs to the Special Issue Regulatory Role of PPARs in the Disease)
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16 pages, 5777 KiB  
Article
Combination of Peroxisome Proliferator-Activated Receptor (PPAR) Alpha and Gamma Agonists Prevents Corneal Inflammation and Neovascularization in a Rat Alkali Burn Model
by Yuji Nakano, Takeshi Arima, Yutaro Tobita, Masaaki Uchiyama, Akira Shimizu and Hiroshi Takahashi
Int. J. Mol. Sci. 2020, 21(14), 5093; https://doi.org/10.3390/ijms21145093 - 19 Jul 2020
Cited by 18 | Viewed by 3529
Abstract
Peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) agonists have anti-inflammatory and anti-neovascularization effects, but few reports have tested the combination of PPARα and PPARγ agonists. In this study, we investigated the therapeutic effects of ophthalmic solutions of agonists of PPARα, PPARγ, and [...] Read more.
Peroxisome proliferator-activated receptor alpha (PPARα) and gamma (PPARγ) agonists have anti-inflammatory and anti-neovascularization effects, but few reports have tested the combination of PPARα and PPARγ agonists. In this study, we investigated the therapeutic effects of ophthalmic solutions of agonists of PPARα, PPARγ, and the combination in a rat corneal alkali burn model. After alkali injury, an ophthalmic solution of 0.05% fenofibrate (PPARα group), 0.1% pioglitazone (PPARγ group), 0.05% fenofibrate + 0.1% pioglitazone (PPARα+γ group), or vehicle (vehicle group) was topically instilled onto the rat’s cornea twice a day. After instillation, upregulation was seen of PPAR mRNA corresponding to each agonist group. Administration of agonists for PPARα, PPARγ, and PPARα+γ suppressed inflammatory cells, neovascularization, and fibrotic changes. In addition, the PPARγ agonist upregulated M2 macrophages, which contributed to wound healing, whereas the PPARα agonist suppressed immature blood vessels in the early phase. Administration of PPARα+γ agonists showed therapeutic effects in corneal wound healing, combining the characteristics of both PPARα and PPARγ agonists. The results indicate that the combination of PPARα and γ agonists may be a new therapeutic strategy. Full article
(This article belongs to the Special Issue Regulatory Role of PPARs in the Disease)
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13 pages, 4653 KiB  
Article
Trans-Cinnamaldehyde Alleviates Amyloid-Beta Pathogenesis via the SIRT1-PGC1α-PPARγ Pathway in 5XFAD Transgenic Mice
by Jimin Do, Namkwon Kim, Seung Ho Jeon, Min Sung Gee, Yeon-Joo Ju, Jong-Ho Kim, Myung Sook Oh and Jong Kil Lee
Int. J. Mol. Sci. 2020, 21(12), 4492; https://doi.org/10.3390/ijms21124492 - 24 Jun 2020
Cited by 17 | Viewed by 3547
Abstract
Abnormal amyloid-β (Aβ) accumulation is the most significant feature of Alzheimer’s disease (AD). Among the several secretases involved in the generation of Aβ, β-secretase (BACE1) is the first rate-limiting enzyme in Aβ production that can be utilized to prevent the development of Aβ-related [...] Read more.
Abnormal amyloid-β (Aβ) accumulation is the most significant feature of Alzheimer’s disease (AD). Among the several secretases involved in the generation of Aβ, β-secretase (BACE1) is the first rate-limiting enzyme in Aβ production that can be utilized to prevent the development of Aβ-related pathologies. Cinnamon extract, used in traditional medicine, was shown to inhibit the aggregation of tau protein and Aβ aggregation. However, the effect of trans-cinnamaldehyde (TCA), the main component of cinnamon, on Aβ deposition is unknown. Five-month-old 5XFAD mice were treated with TCA for eight weeks. Seven-month-old 5XFAD mice were evaluated for cognitive and spatial memory function. Brain samples collected at the conclusion of the treatment were assessed by immunofluorescence and biochemical analyses. Additional in vivo experiments were conducted to elucidate the mechanisms underlying the effect of TCA in the role of Aβ deposition. TCA treatment led to improvements in cognitive impairment and reduced Aβ deposition in the brains of 5XFAD mice. Interestingly, the levels of BACE1 were decreased, whereas the mRNA and protein levels of three well-known regulators of BACE1, silent information regulator 1 (SIRT1), peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC1α), and PPARγ, were increased in TCA-treated 5XFAD mice. TCA led to an improvement in AD pathology by reducing BACE1 levels through the activation of the SIRT1-PGC1α-PPARγ pathway, suggesting that TCA might be a useful therapeutic approach in AD. Full article
(This article belongs to the Special Issue Regulatory Role of PPARs in the Disease)
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Review

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19 pages, 1545 KiB  
Review
Inflammatory Bowel Disease: New Insights into the Interplay between Environmental Factors and PPARγ
by Giulia Caioni, Angelo Viscido, Michele d’Angelo, Gloria Panella, Vanessa Castelli, Carmine Merola, Giuseppe Frieri, Giovanni Latella, Annamaria Cimini and Elisabetta Benedetti
Int. J. Mol. Sci. 2021, 22(3), 985; https://doi.org/10.3390/ijms22030985 - 20 Jan 2021
Cited by 31 | Viewed by 4499
Abstract
The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn’s disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology remains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation [...] Read more.
The pathophysiological processes of inflammatory bowel diseases (IBDs), i.e., Crohn’s disease (CD) and ulcerative colitis (UC), are still not completely understood. The exact etiology remains unknown, but it is well established that the pathogenesis of the inflammatory lesions is due to a dysregulation of the gut immune system resulting in over-production of pro-inflammatory cytokines. Increasing evidence underlines the involvement of both environmental and genetic factors. Regarding the environment, the microbiota seems to play a crucial role. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert pleiotropic effects on glucose homeostasis, lipid metabolism, inflammatory/immune processes, cell proliferation, and fibrosis. Furthermore, PPARs modulate interactions with several environmental factors, including microbiota. A significantly impaired PPARγ expression was observed in UC patients’ colonic epithelial cells, suggesting that the disruption of PPARγ signaling may represent a critical step of the IBD pathogenesis. This paper will focus on the role of PPARγ in the interaction between environmental factors and IBD, and it will analyze the most suitable in vitro and in vivo models available to better study these relationships. Full article
(This article belongs to the Special Issue Regulatory Role of PPARs in the Disease)
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23 pages, 392 KiB  
Review
PPARs and Angiogenesis—Implications in Pathology
by Nicole Wagner and Kay-Dietrich Wagner
Int. J. Mol. Sci. 2020, 21(16), 5723; https://doi.org/10.3390/ijms21165723 - 10 Aug 2020
Cited by 48 | Viewed by 4677
Abstract
Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific [...] Read more.
Peroxisome proliferator-activated receptors (PPARs) belong to the family of ligand-activated nuclear receptors. The PPAR family consists of three subtypes encoded by three separate genes: PPARα (NR1C1), PPARβ/δ (NR1C2), and PPARγ (NR1C3). PPARs are critical regulators of metabolism and exhibit tissue and cell type-specific expression patterns and functions. Specific PPAR ligands have been proposed as potential therapies for a variety of diseases such as metabolic syndrome, cancer, neurogenerative disorders, diabetes, cardiovascular diseases, endometriosis, and retinopathies. In this review, we focus on the knowledge of PPAR function in angiogenesis, a complex process that plays important roles in numerous pathological conditions for which therapeutic use of PPAR modulation has been suggested. Full article
(This article belongs to the Special Issue Regulatory Role of PPARs in the Disease)
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