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Biomolecules
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PPARs as Key Regulators in Different Diseases
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PPARs as Key Regulators in Different Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Molecular Medicine".

Deadline for manuscript submissions: 30 April 2024 | Viewed by 10356

Special Issue Editors

Dr. Roberta Montanari

E-Mail Website
Guest Editor
Institute of Crystallography, National Research Council, Monterotondo, 00015 Rome, Italy
Interests: structural biology; PPARs; protein crystallography; molecular mechanisms
Dr. Davide Capelli

E-Mail Website
Guest Editor
Institute of Crystallography, National Research Council, Monterotondo, 00015 Rome, Italy
Interests: structural biology; PPARs; protein crystallography; molecular mechanisms

Special Issue Information

Dear Colleagues,

It is well-established that sedentary living and high-fat food consumption are the main causes of obesity in developed countries. The epidemic of obesity is associated with increased rates of diabetes, hypertension, heart diseases, and many types of cancer and neurodegenerative diseases, resulting in a chronically sick population. In this context, there is no doubt that peroxisome proliferator-activated receptors (PPARs) α, β/δ, and γ play key roles as modulators of lipid homeostasis, in addition to having effects on a variety of cell signals involved in cellular differentiation and development, inflammation, homeostasis, tumorigenesis, etc. If, on the one hand, this makes PPARs and their ligands appealing for their therapeutic potential, on the other hand, their “pluripotent functionality” is associated with a negative perception of PPAR targeting because of insidious side effects that result from this feature. This Special Issue sheds light on new perspectives on PPARs targeting, in terms of both metabolic diseases and other pathologies, with special attention to the structural aspects governing PPARs functions. Alternatively, we would like to invite review articles that address the above-mentioned issues either from a structural or a biological perspective. Any original research papers contributing significantly to advancing our understanding of molecular mechanisms underlying PPARs functions by presenting innovative interpretations are highly welcome.

We look forward to reading your contributions.

Dr. Roberta Montanari
Dr. Davide Capelli
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

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. Biomolecules is an international peer-reviewed open access monthly 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

  • PPARs
  • metabolic diseases
  • cell signaling
  • post-translational modification
  • selective modulators

Published Papers (6 papers)

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Research

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13 pages, 551 KiB  
Article
Metabolic Biomarkers in Adults with Type 2 Diabetes: The Role of PPAR-γ2 and PPAR-β/δ Polymorphisms
by Sandra A. Reza-López, Susana González-Gurrola, Oscar O. Morales-Morales, Janette G. Moreno-González, Ana M. Rivas-Gómez, Everardo González-Rodríguez, Verónica Moreno-Brito, Angel Licón-Trillo and Irene Leal-Berumen
Biomolecules 2023, 13(12), 1791; https://doi.org/10.3390/biom13121791 - 14 Dec 2023
Cited by 1 | Viewed by 1024
Abstract
Glucose and lipid metabolism regulation by the peroxisome proliferator-activated receptors (PPARs) has been extensively reported. However, the role of their polymorphisms remains unclear. Objective: To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-β/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with [...] Read more.
Glucose and lipid metabolism regulation by the peroxisome proliferator-activated receptors (PPARs) has been extensively reported. However, the role of their polymorphisms remains unclear. Objective: To determine the relation between PPAR-γ2 rs1801282 (Pro12Ala) and PPAR-β/δ rs2016520 (+294T/C) polymorphisms and metabolic biomarkers in adults with type 2 diabetes (T2D). Materials and Methods: We included 314 patients with T2D. Information on anthropometric, fasting plasma glucose (FPG), HbA1c and lipid profile measurements was taken from clinical records. Genomic DNA was obtained from peripheral blood. End-point PCR was used for PPAR-γ2 rs1801282, while for PPAR-β/δ rs2016520 the PCR product was digested with Bsl-I enzyme. Data were compared with parametric or non-parametric tests. Multivariate models were used to adjust for covariates and interaction effects. Results: minor allele frequency was 12.42% for PPAR-γ2 rs1801282-G and 13.85% for PPAR-β/δ rs2016520-C. Both polymorphisms were related to waist circumference; they showed independent effects on HbA1c, while they interacted for FPG; carriers of both PPAR minor alleles had the highest values. Interactions between FPG and polymorphisms were identified in their relation to triglyceride level. Conclusions: PPAR-γ2 rs1801282 and PPAR-β/δ rs2016520 polymorphisms are associated with anthropometric, glucose, and lipid metabolism biomarkers in T2D patients. Further research is required on the molecular mechanisms involved. Full article
(This article belongs to the Special Issue PPARs as Key Regulators in Different Diseases)
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Graphical abstract

18 pages, 4799 KiB  
Article
Biological Screening and Crystallographic Studies of Hydroxy γ-Lactone Derivatives to Investigate PPARγ Phosphorylation Inhibition
by Davide Capelli, Giulia Cazzaniga, Matteo Mori, Antonio Laghezza, Fulvio Loiodice, Martina Quaglia, Elisa Negro, Fiorella Meneghetti, Stefania Villa and Roberta Montanari
Biomolecules 2023, 13(4), 694; https://doi.org/10.3390/biom13040694 - 19 Apr 2023
Cited by 1 | Viewed by 1254
Abstract
PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors [...] Read more.
PPARγ represents a key target for the treatment of type 2 diabetes and metabolic syndrome. To avoid serious adverse effects related to the PPARγ agonism profile of traditional antidiabetic drugs, a new opportunity is represented by the development of molecules acting as inhibitors of PPARγ phosphorylation by the cyclin-dependent kinase 5 (CDK5). Their mechanism of action is mediated by the stabilization of the PPARγ β-sheet containing Ser273 (Ser245 in PPARγ isoform 1 nomenclature). In this paper, we report the identification of new γ-hydroxy-lactone-based PPARγ binders from the screening of an in-house library. These compounds exhibit a non-agonist profile towards PPARγ, and one of them prevents Ser245 PPARγ phosphorylation by acting mainly on PPARγ stabilization and exerting a weak CDK5 inhibitory effect. Full article
(This article belongs to the Special Issue PPARs as Key Regulators in Different Diseases)
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17 pages, 3507 KiB  
Article
Obesity-Linked PPARγ Ser273 Phosphorylation Promotes Beneficial Effects on the Liver, despite Reduced Insulin Sensitivity in Mice
by Maiara Ferreira Terra, Marta García-Arévalo, Thayná Mendonça Avelino, Karina Y. Degaki, Murilo de Carvalho, Felipe Rafael Torres, Angela Saito and Ana Carolina Migliorini Figueira
Biomolecules 2023, 13(4), 632; https://doi.org/10.3390/biom13040632 - 31 Mar 2023
Viewed by 1620
Abstract
Since the removal of thiazolidinediones (TZDs) from the market, researchers have been exploring alternative anti-diabetic drugs that target PPARγ without causing adverse effects while promoting insulin sensitization by blocking serine 273 phosphorylation (Ser273 or S273). Nonetheless, the underlying mechanisms of the relationship between [...] Read more.
Since the removal of thiazolidinediones (TZDs) from the market, researchers have been exploring alternative anti-diabetic drugs that target PPARγ without causing adverse effects while promoting insulin sensitization by blocking serine 273 phosphorylation (Ser273 or S273). Nonetheless, the underlying mechanisms of the relationship between insulin resistance and S273 phosphorylation are still largely unknown, except for the involvement of growth differentiation factor (GDF3) regulation in the process. To further investigate potential pathways, we generated a whole organism knockin mouse line with a single S273A mutation (KI) that blocks the occurrence of its phosphorylation. Our observations of KI mice on different diets and feeding schedules revealed that they were hyperglycemic, hypoinsulinemic, presented more body fat at weaning, and presented an altered plasma and hepatic lipid profile, distinctive liver morphology and gene expression. These results suggest that total blockage of S273 phosphorylation may have unforeseen effects that, in addition to promoting insulin sensitivity, could lead to metabolic disturbances, particularly in the liver. Therefore, our findings demonstrate both the beneficial and detrimental effects of PPAR S273 phosphorylation and suggest selective modulation of this post translational modification is a viable strategy to treat type 2 diabetes. Full article
(This article belongs to the Special Issue PPARs as Key Regulators in Different Diseases)
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Review

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15 pages, 3287 KiB  
Review
PPARγ Modulators in Lung Cancer: Molecular Mechanisms, Clinical Prospects, and Challenges
by Jiyun Zhang, Miru Tang and Jinsai Shang
Biomolecules 2024, 14(2), 190; https://doi.org/10.3390/biom14020190 - 04 Feb 2024
Viewed by 1268
Abstract
Lung cancer is one of the most lethal malignancies worldwide. Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcriptional factor that governs the expression of genes involved in glucolipid metabolism, energy homeostasis, cell differentiation, and inflammation. Multiple studies have demonstrated that PPARγ [...] Read more.
Lung cancer is one of the most lethal malignancies worldwide. Peroxisome proliferator-activated receptor gamma (PPARγ, NR1C3) is a ligand-activated transcriptional factor that governs the expression of genes involved in glucolipid metabolism, energy homeostasis, cell differentiation, and inflammation. Multiple studies have demonstrated that PPARγ activation exerts anti-tumor effects in lung cancer through regulation of lipid metabolism, induction of apoptosis, and cell cycle arrest, as well as inhibition of invasion and migration. Interestingly, PPARγ activation may have pro-tumor effects on cells of the tumor microenvironment, especially myeloid cells. Recent clinical data has substantiated the potential of PPARγ agonists as therapeutic agents for lung cancer. Additionally, PPARγ agonists also show synergistic effects with traditional chemotherapy and radiotherapy. However, the clinical application of PPARγ agonists remains limited due to the presence of adverse side effects. Thus, further research and clinical trials are necessary to comprehensively explore the actions of PPARγ in both tumor and stromal cells and to evaluate the in vivo toxicity. This review aims to consolidate the molecular mechanism of PPARγ modulators and to discuss their clinical prospects and challenges in tackling lung cancer. Full article
(This article belongs to the Special Issue PPARs as Key Regulators in Different Diseases)
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21 pages, 1595 KiB  
Review
Current Clinical Trial Status and Future Prospects of PPAR-Targeted Drugs for Treating Nonalcoholic Fatty Liver Disease
by Shotaro Kamata, Akihiro Honda and Isao Ishii
Biomolecules 2023, 13(8), 1264; https://doi.org/10.3390/biom13081264 - 18 Aug 2023
Cited by 7 | Viewed by 2451
Abstract
The number of patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is increasing globally and is raising serious concerns regarding the increasing medical and economic burden incurred for their treatment. The progression of NASH to more severe conditions such as cirrhosis and [...] Read more.
The number of patients with nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) is increasing globally and is raising serious concerns regarding the increasing medical and economic burden incurred for their treatment. The progression of NASH to more severe conditions such as cirrhosis and hepatocellular carcinoma requires liver transplantation to avoid death. Therefore, therapeutic intervention is required in the NASH stage, although no therapeutic drugs are currently available for this. Several anti-NASH candidate drugs have been developed that enable treatment via the modulation of distinct signaling cascades and include a series of drugs targeting peroxisome proliferator-activated receptor (PPAR) subtypes (PPARα/δ/γ) that are considered to be attractive because they can regulate both systemic lipid metabolism and inflammation. Multiple PPAR dual/pan agonists have been developed but only a few of them have been evaluated in clinical trials for NAFLD/NASH. Herein, we review the current clinical trial status and future prospects of PPAR-targeted drugs for treating NAFLD/NASH. In addition, we summarize our recent findings on the binding modes and the potencies/efficacies of several candidate PPAR dual/pan agonists to estimate their therapeutic potentials against NASH. Considering that the development of numerous PPAR dual/pan agonists has been abandoned because of their serious side effects, we also propose a repositioning of the already approved, safety-proven PPAR-targeted drugs against NAFLD/NASH. Full article
(This article belongs to the Special Issue PPARs as Key Regulators in Different Diseases)
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12 pages, 974 KiB  
Review
The Potential Roles of Post-Translational Modifications of PPARγ in Treating Diabetes
by Xiaohui Ji, Wenqian Zhang, Liqin Yin, Zunhan Shi, Jinwen Luan, Linshan Chen and Longhua Liu
Biomolecules 2022, 12(12), 1832; https://doi.org/10.3390/biom12121832 - 08 Dec 2022
Cited by 12 | Viewed by 1833
Abstract
The number of patients with type 2 diabetes mellitus (T2DM), which is mainly characterized by insulin resistance and insulin secretion deficiency, has been soaring in recent years. Accompanied by many other metabolic syndromes, such as cardiovascular diseases, T2DM represents a big challenge to [...] Read more.
The number of patients with type 2 diabetes mellitus (T2DM), which is mainly characterized by insulin resistance and insulin secretion deficiency, has been soaring in recent years. Accompanied by many other metabolic syndromes, such as cardiovascular diseases, T2DM represents a big challenge to public health and economic development. Peroxisome proliferator-activated receptor γ (PPARγ), a ligand-activated nuclear receptor that is critical in regulating glucose and lipid metabolism, has been developed as a powerful drug target for T2DM, such as thiazolidinediones (TZDs). Despite thiazolidinediones (TZDs), a class of PPARγ agonists, having been proven to be potent insulin sensitizers, their use is restricted in the treatment of diabetes for their adverse effects. Post-translational modifications (PTMs) have shed light on the selective activation of PPARγ, which shows great potential to circumvent TZDs’ side effects while maintaining insulin sensitization. In this review, we will focus on the potential effects of PTMs of PPARγ on treating T2DM in terms of phosphorylation, acetylation, ubiquitination, SUMOylation, O-GlcNAcylation, and S-nitrosylation. A better understanding of PTMs of PPARγ will help to design a new generation of safer compounds targeting PPARγ to treat type 2 diabetes. Full article
(This article belongs to the Special Issue PPARs as Key Regulators in Different Diseases)
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