The Role of PPARs in Disease - Volume III
A special issue of Cells (ISSN 2073-4409).
Deadline for manuscript submissions: 15 November 2024 | Viewed by 10354
Special Issue Editors
Interests: vessel formation in development and disease; transcriptional control; epigenetics; cancer; cardiovascular disease
Special Issues, Collections and Topics in MDPI journals
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, i.e., 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 the 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, PPARβ/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 the first Special Issue on “The Role of PPARs in Disease” of Cells in 2019–2020. Despite the global health crisis, 11 papers were published in this Special Issue, which have received until now more than 60,000 views and more than 450 citations. In 2021–2022, we guest-edited the second Special Issue on the topic “The Role of PPARs in Disease II”. This Special Issue attracted even higher attention. Overall, 20 papers were finally published in this Special Issue, which have already received nearly 52,000 views and 130 citations.
We hope that this new Special Issue of Cells, with the continuous efforts of the scientific community, will be equally or even more successful. This Special Issue 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,
Dr. Kay-Dietrich Wagner
Dr. Nicole Wagner
Guest Editors
Manuscript Submission Information
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Keywords
- PPAR
- immune function
- liver
- adipose tissue
- cardiovascular system
- muscle
- neurological and psychiatric diseases
- cancer
- transcriptional regulation
- ligands
- agonists/antagonists
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Related Special Issues
- The Role of PPARs in Disease in Cells (11 articles)
- The Role of PPARs in Disease II in Cells (20 articles)
Planned Papers
The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.
Title: Exploring the role of PPARs and Endothelial dysfunction in MASLD
Authors: Ana Paula Madariaga Traconis; Varenka Julieta Barbero Becerra; M Uribe
Affiliation: Medica Sur
Abstract: Peroxisome proliferator-activated receptors (PPARs) are a family of transcription factors that belong to the superfamily of nuclear hormone receptors expressed in various tissues, with each isoform having a distinct localization and function. In general, PPARs have an important role in fatty acid catabolism, the reduction of reactive oxygen species, and endothelial function. Specifically, PPAR functions through mechanisms such as transrepression of nuclear factor kappa B (NF-B), thereby modulating inflammatory responses and maintaining hepatic homeostasis. Together, PPAR and PPAR influence endothelial function and vascular health, which are critically affected in the context of MASLD. The complex interplay between PPARs, endothelial dysfunction, and MASLD highlights the potential of PPARs as a pharmacological target for therapeutic interventions. Recent advances in understanding the role of PPAR in modulating inflammation and endothelial function have led to the exploration of PPAR agonists in clinical trials and experimental studies. Agents such as lanifibranor, elafibranor, daidzein, and Iicarin have shown promise in improving metabolic, hepatic, and cardiovascular health in patients with MASLD. This review aimed to provide a comprehensive overview of the role of PPARs in endothelial dysfunction and MASLD, exploring their mechanisms in disease progression and potential pharmacological targeting.
Title: The Tumor Suppressor Par-4 Regulates Adipogenesis by Transcriptional Repression of PPARγ
Authors: James Sledziona; Ravshan Burikhanov; Nathalia Araujo; Jieyun Jiang; Nikhil Hebbar; Vivek M Rangnekar
Affiliation: University of Kentucky
Abstract: Prostate apoptosis response-4 (Par-4, also known as PAWR) is a ubiquitously expressed tumor suppressor protein that induces apoptosis selectively in cancer cells, while leaving normal cells unaffected. Our previous studies indicated that genetic loss of Par-4 promotes hepatic steatosis, adiposity and insulin-resistance in chow-fed mice. Moreover, low plasma levels of Par-4 are associated with obesity in human subjects. The mechanisms underlying obesity in rodents and humans are multi-faceted, and those associated with adipogenesis can be functionally resolved in cell cultures. We therefore used pluripotent mouse embryonic fibroblasts (MEFs) or preadipocyte cell lines responsive to adipocyte differentiation cues to determine the potential role of Par-4 in adipocytes. We report that pluripotent MEFs from Par-4-/- mice undergo rapid differentiation to mature adipocytes with an increase in lipid droplet accumulation relative to MEFs from Par-4+/+ mice. Knockdown of Par-4 in 3T3-L1 pre-adipocyte cultures by RNA-interference induces rapid differentiation to mature adipocytes. Interestingly, basal expression of PPARγ, a master regulator of de novo lipid synthesis and adipogenesis, is induced during adipogenesis in the cell lines, and PPARγ induction and the adipogenesis effect of Par-4 loss is reversed by replenishment of Par-4. Mechanistically, Par-4 downregulates PPARγ expression by directly binding to its upstream promoter, as judged by chromatin immunoprecipitation and luciferase-reporter studies. Thus, Par-4 transcriptionally suppresses the PPARγ promoter to regulate adipogenesis.
Title: Class Effect Unveiled: PPARγ Agonists and MEK Inhibitors in Cancer Cell Differentiation
Authors: Rakefet Ruth Ben-Yishay; Opher Globus; Nora Balint-Lahat; Sheli Arbili Yarhi; Neta Bar-Hai; Vered Bar; Sara Aharon; Anna Kosenko; Adi Zundelevich; Raanan Berger; Dana Ishay Ronen
Affiliation: Institute of Oncology, Sheba Medical Center, Ramat Gan, Israel
Abstract: We have previously demonstrated a trans-differentiation therapeutic approach targeting invasivededif-ferentiated cancer cells. Using a combination of a PPARγ agonist and MEK inhibitors, we forced the dif-ferentiation of disseminating breast cancer cells into post-mitotic adipocytes. Utilizing murine breast cancer cells we demonstrate a broad class effect of PPARγ agonists and MEK inhibitors in inducing cancer cell trans-differentiation into adipocytes. Both Rosiglitazone and Pioglitazone effectively induced adipogenesis in cancer cells, marked by PPARγ and C/EBPα upregulation, cytoskeleton rearrengement and lipid droplet accumulation. All tested MEK inhibitors promoted adipogenesis in the presence of TGFβ, with Cobimetinib showing the most prominent effects. Ex vivo cultures from a metastatic triple-negative breast cancer pa-tient demonstrated a synergistic upregulation of PPARγ with the combination of Pioglitazone and Cobi-metinib. Our results highlight the potential for new therapeutic strategies targeting cancer cell plasticity and dedifferentiation phenotype in aggressive breast cancer subtypes.