International Journal of Molecular Sciences

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Open AccessEditorial

PPARs as Key Transcription Regulators at the Crossroads of Metabolism and Inflammation

by Manuel Vázquez-Carrera and Walter Wahli

Int. J. Mol. Sci. 2024, 25(8), 4467; https://doi.org/10.3390/ijms25084467 - 18 Apr 2024

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Abstract

The metabolic and immune systems are complex networks of organs, cells, and proteins that are involved in the extraction of energy from food; this is to run complex cellular processes and defend the body against infections while protecting its own tissues, respectively [...] [...] Read more.

The metabolic and immune systems are complex networks of organs, cells, and proteins that are involved in the extraction of energy from food; this is to run complex cellular processes and defend the body against infections while protecting its own tissues, respectively [...] Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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Research

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18 pages, 11288 KiB

Open AccessArticle

PPARβ/δ Ligands Regulate Oxidative Status and Inflammatory Response in Inflamed Corpus Luteum—An In Vitro Study

by Karol Mierzejewski, Aleksandra Kurzyńska, Zuzanna Gerwel, Monika Golubska, Robert Stryiński and Iwona Bogacka

Int. J. Mol. Sci. 2023, 24(5), 4993; https://doi.org/10.3390/ijms24054993 - 5 Mar 2023

Cited by 4 | Viewed by 2007

Abstract

Inflammation in the female reproductive system causes serious health problems including infertility. The aim of this study was to determine the in vitro effects of peroxisome proliferator-activated receptor-beta/delta (PPARβ/δ) ligands on the transcriptomic profile of the lipopolysaccharide (LPS)-stimulated pig corpus luteum (CL) in [...] Read more.

Inflammation in the female reproductive system causes serious health problems including infertility. The aim of this study was to determine the in vitro effects of peroxisome proliferator-activated receptor-beta/delta (PPARβ/δ) ligands on the transcriptomic profile of the lipopolysaccharide (LPS)-stimulated pig corpus luteum (CL) in the mid-luteal phase of the estrous cycle using RNA-seq technology. The CL slices were incubated in the presence of LPS or in combination with LPS and the PPARβ/δ agonist—GW0724 (1 μmol/L or 10 μmol/L) or the antagonist—GSK3787 (25 μmol/L). We identified 117 differentially expressed genes after treatment with LPS; 102 and 97 differentially expressed genes after treatment, respectively, with the PPARβ/δ agonist at a concentration of 1 μmol/L or 10 μmol/L, as well as 88 after the treatment with the PPARβ/δ antagonist. In addition, biochemical analyses of oxidative status were performed (total antioxidant capacity and activity of peroxidase, catalase, superoxide dismutase, and glutathione S-transferase). This study revealed that PPARβ/δ agonists regulate genes involved in the inflammatory response in a dose-dependent manner. The results indicate that the lower dose of GW0724 showed an anti-inflammatory character, while the higher dose seems to be pro-inflammatory. We propose that GW0724 should be considered for further research to alleviate chronic inflammation (at the lower dose) or to support the natural immune response against pathogens (at the higher dose) in the inflamed corpus luteum. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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10 pages, 1768 KiB

Open AccessArticle

PPARα Induces the Expression of CAR That Works as a Negative Regulator of PPARα Functions in Mouse Livers

by Ryota Shizu, Yuta Otsuka, Chizuru Ishii, Kanako Ezaki and Kouichi Yoshinari

Int. J. Mol. Sci. 2023, 24(4), 3953; https://doi.org/10.3390/ijms24043953 - 16 Feb 2023

Cited by 5 | Viewed by 2306

Abstract

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that controls the transcription of genes responsible for fatty acid metabolism. We have recently reported a possible drug–drug interaction mechanism via the interaction of PPARα with the xenobiotic nuclear receptor constitutive [...] Read more.

The nuclear receptor peroxisome proliferator-activated receptor α (PPARα) is a transcription factor that controls the transcription of genes responsible for fatty acid metabolism. We have recently reported a possible drug–drug interaction mechanism via the interaction of PPARα with the xenobiotic nuclear receptor constitutive androstane receptor (CAR). Drug-activated CAR competes with the transcriptional coactivator against PPARα and prevents PPARα-mediated lipid metabolism. In this study, to elucidate the crosstalk between CAR and PPARα, we focused on the influence of PPARα activation on CAR’s gene expression and activation. Male C57BL/6N mice (8–12 weeks old, n = 4) were treated with PPARα and CAR activators (fenofibrate and phenobarbital, respectively), and hepatic mRNA levels were determined using quantitative reverse transcription PCR. Reporter assays using the mouse Car promoter were performed in HepG2 cells to determine the PPARα-dependent induction of CAR. CAR KO mice were treated with fenofibrate, and the hepatic mRNA levels of PPARα target genes were determined. Treatment of mice with a PPARα activator increased Car mRNA levels as well as genes related to fatty acid metabolism. In reporter assays, PPARα induced the promoter activity of the Car gene. Mutation of the putative PPARα-binding motif prevented PPARα-dependent induction of reporter activity. In electrophoresis mobility shift assay, PPARα bound to the DR1 motif of the Car promoter. Since CAR has been reported to attenuate PPARα-dependent transcription, CAR was considered a negative feedback protein for PPARα activation. Treatment with fenofibrate induced the mRNA levels of PPARα target genes in Car-null mice more than those in wild-type mice, suggesting that CAR functions as a negative feedback factor for PPARα. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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16 pages, 2352 KiB

Open AccessArticle

Profound Modification of Fatty Acid Profile and Endocannabinoid-Related Mediators in PPARα Agonist Fenofibrate-Treated Mice

by Elisabetta Murru, Anna Lisa Muntoni, Claudia Manca, Sonia Aroni, Marco Pistis, Sebastiano Banni and Gianfranca Carta

Int. J. Mol. Sci. 2023, 24(1), 709; https://doi.org/10.3390/ijms24010709 - 31 Dec 2022

Cited by 4 | Viewed by 2095

Abstract

Fenofibrate (FBR), an oral medication used to treat dyslipidemia, is a ligand of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor that regulates the expression of metabolic genes able to control lipid metabolism and food intake. PPARα natural ligands include fatty acids [...] Read more.

Fenofibrate (FBR), an oral medication used to treat dyslipidemia, is a ligand of the peroxisome proliferator-activated receptor α (PPARα), a nuclear receptor that regulates the expression of metabolic genes able to control lipid metabolism and food intake. PPARα natural ligands include fatty acids (FA) and FA derivatives such as palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), known to have anti-inflammatory and anorexigenic activities, respectively. We investigated changes in the FA profile and FA derivatives by HPLC and LC-MS in male C57BL/6J mice fed a standard diet with or without 0.2% fenofibrate (0.2% FBR) for 21 days. Induction of PPARα by 0.2% FBR reduced weight gain, food intake, feed efficiency, and liver lipids and induced a profound change in FA metabolism mediated by parallel enhanced mitochondrial and peroxisomal β-oxidation. The former effects led to a steep reduction of essential FA, particularly 18:3n3, with a consequent decrease of the n3-highly unsaturated fatty acids (HUFA) score; the latter effect led to an increase of 16:1n7 and 18:1n9, suggesting enhanced hepatic de novo lipogenesis with increased levels of hepatic PEA and OEA, which may activate a positive feedback and further sustain reductions of body weight, hepatic lipids and feed efficiency. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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16 pages, 2249 KiB

Open AccessArticle

TRIB3 Modulates PPARγ-Mediated Growth Inhibition by Interfering with the MLL Complex in Breast Cancer Cells

by Miguel Hernández-Quiles, Rosalie Baak, Alba Orea-Soufi, Anouska Borgman, Suzanne den Haan, Paula Sobrevals Alcaraz, Aldo Jongejan, Robert van Es, Guillermo Velasco, Harmjan Vos and Eric Kalkhoven

Int. J. Mol. Sci. 2022, 23(18), 10535; https://doi.org/10.3390/ijms231810535 - 11 Sep 2022

Cited by 8 | Viewed by 2617

Abstract

Aberrant expression or activity of proteins are amongst the best understood mechanisms that can drive cancer initiation and progression, as well as therapy resistance. TRIB3, a member of the Tribbles family of pseudokinases, is often dysregulated in cancer and has been associated with [...] Read more.

Aberrant expression or activity of proteins are amongst the best understood mechanisms that can drive cancer initiation and progression, as well as therapy resistance. TRIB3, a member of the Tribbles family of pseudokinases, is often dysregulated in cancer and has been associated with breast cancer initiation and metastasis formation. However, the underlying mechanisms by which TRIB3 contributes to these events are unclear. In this study, we demonstrate that TRIB3 regulates the expression of PPARγ, a transcription factor that has gained attention as a potential drug target in breast cancer for its antiproliferative actions. Proteomics and phosphoproteomics analyses together with classical biochemical assays indicate that TRIB3 interferes with the MLL complex and reduces MLL-mediated H3K4 trimethylation of the PPARG locus, thereby reducing PPARγ mRNA expression. Consequently, the overexpression of TRIB3 blunts the antiproliferative effect of PPARγ ligands in breast cancer cells, while reduced TRIB3 expression gives the opposite effect. In conclusion, our data implicate TRIB3 in epigenetic gene regulation and suggest that expression levels of this pseudokinase may serve as a predictor of successful experimental treatments with PPARγ ligands in breast cancer. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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Review

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17 pages, 1920 KiB

Open AccessReview

Osteoarthritis: Role of Peroxisome Proliferator-Activated Receptors

by Weibei Sheng, Qichang Wang, Haotian Qin, Siyang Cao, Yihao Wei, Jian Weng, Fei Yu and Hui Zeng

Int. J. Mol. Sci. 2023, 24(17), 13137; https://doi.org/10.3390/ijms241713137 - 24 Aug 2023

Cited by 12 | Viewed by 2635

Abstract

Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering [...] Read more.

Osteoarthritis (OA) represents the foremost degenerative joint disease observed in a clinical context. The escalating issue of population aging significantly exacerbates the prevalence of OA, thereby imposing an immense annual economic burden on societies worldwide. The current therapeutic landscape falls short in offering reliable pharmaceutical interventions and efficient treatment methodologies to tackle this growing problem. However, the scientific community continues to dedicate significant efforts towards advancing OA treatment research. Contemporary studies have discovered that the progression of OA may be slowed through the strategic influence on peroxisome proliferator-activated receptors (PPARs). PPARs are ligand-activated receptors within the nuclear hormone receptor family. The three distinctive subtypes—PPARα, PPARβ/δ, and PPARγ—find expression across a broad range of cellular terminals, thus managing a multitude of intracellular metabolic operations. The activation of PPARγ and PPARα has been shown to efficaciously modulate the NF-κB signaling pathway, AP-1, and other oxidative stress-responsive signaling conduits, leading to the inhibition of inflammatory responses. Furthermore, the activation of PPARγ and PPARα may confer protection to chondrocytes by exerting control over its autophagic behavior. In summation, both PPARγ and PPARα have emerged as promising potential targets for the development of effective OA treatments. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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25 pages, 1361 KiB

Open AccessReview

Development of PPARγ Agonists for the Treatment of Neuroinflammatory and Neurodegenerative Diseases: Leriglitazone as a Promising Candidate

by Pilar Pizcueta, Cristina Vergara, Marco Emanuele, Anna Vilalta, Laura Rodríguez-Pascau and Marc Martinell

Int. J. Mol. Sci. 2023, 24(4), 3201; https://doi.org/10.3390/ijms24043201 - 6 Feb 2023

Cited by 16 | Viewed by 3619

Abstract

Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute [...] Read more.

Increasing evidence suggests that the peroxisome proliferator-activated receptor γ (PPARγ), a member of the nuclear receptor superfamily, plays an important role in physiological processes in the central nervous system (CNS) and is involved in cellular metabolism and repair. Cellular damage caused by acute brain injury and long-term neurodegenerative disorders is associated with alterations of these metabolic processes leading to mitochondrial dysfunction, oxidative stress, and neuroinflammation. PPARγ agonists have demonstrated the potential to be effective treatments for CNS diseases in preclinical models, but to date, most drugs have failed to show efficacy in clinical trials of neurodegenerative diseases including amyotrophic lateral sclerosis, Parkinson’s disease, and Alzheimer’s disease. The most likely explanation for this lack of efficacy is the insufficient brain exposure of these PPARγ agonists. Leriglitazone is a novel, blood–brain barrier (BBB)-penetrant PPARγ agonist that is being developed to treat CNS diseases. Here, we review the main roles of PPARγ in physiology and pathophysiology in the CNS, describe the mechanism of action of PPARγ agonists, and discuss the evidence supporting the use of leriglitazone to treat CNS diseases. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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24 pages, 1018 KiB

Open AccessReview

The PPARα Regulation of the Gut Physiology in Regard to Interaction with Microbiota, Intestinal Immunity, Metabolism, and Permeability

by Maja Grabacka, Przemysław M. Płonka and Małgorzata Pierzchalska

Int. J. Mol. Sci. 2022, 23(22), 14156; https://doi.org/10.3390/ijms232214156 - 16 Nov 2022

Cited by 10 | Viewed by 2996

Abstract

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed throughout the mammalian gut: in epithelial cells, in the villi of enterocytes and in Paneth cells of intestinal crypts, as well as in some immune cells (e.g., lamina propria macrophages, dendritic cells) of the mucosa. This [...] Read more.

Peroxisome proliferator-activated receptor alpha (PPARα) is expressed throughout the mammalian gut: in epithelial cells, in the villi of enterocytes and in Paneth cells of intestinal crypts, as well as in some immune cells (e.g., lamina propria macrophages, dendritic cells) of the mucosa. This review examines the reciprocal interaction between PPARα activation and intestinal microbiota. We refer to the published data confirming that microbiota products can influence PPARα signaling and, on the other hand, PPARα activation is able to affect microbiota profile, viability, and diversity. PPARα impact on the broad spectrum of events connected to metabolism, signaling (e.g., NO production), immunological tolerance to dietary antigens, immunity and permeability of the gut are also discussed. We believe that the phenomena described here play a prominent role in gut homeostasis. Therefore, in conclusion we propose future directions for research, including the application of synthetic activators and natural endogenous ligands of PPARα (i.e., endocannabinoids) as therapeutics for intestinal pathologies and systemic diseases assumed to be related to gut dysbiosis. Full article

(This article belongs to the Special Issue PPARs as Key Mediators of Metabolic and Inflammatory Regulation—2nd Edition)

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