The Role of PPARs in Disease - Volume III

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

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

• The Role of PPARs in Disease in Cells (11 articles)
• The Role of PPARs in Disease II in Cells (20 articles)

Title: PPAR-mediated bile acid glucuronidation: therapeutic targets for the treatment of cholestatic liver diseases
Authors: Gina M Gallucci; Colleen M Hayes; James L. Boyer; David Assis; Olivier Barbier; Nisanne S Ghonem
Affiliation: University of Rhode Island
Abstract: Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Currently, the only approved treatments for PBC are Ursodeoxycholic acid (UDCA) and Obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients only partially respond to UDCA, and more advanced cases usually do not respond. Also, UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. When left untreated, these diseases can progress to fibrosis, and cirrhosis, and eventually result in liver failure and the need for a liver transplant. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience a sub-therapeutic response to UDCA or OCA. PPARalpha is predominantly found in the liver and plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5’-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARa agonists, e.g., fibrates, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC who do not respond to UDCA. Currently, newer PPAR agonists that target additional PPAR isoforms (b/d, g) are under development as an adjunct therapy for PBC, although their anti-cholestatic mechanisms are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.

Title: The role of Endothelial dysfunction in MASLD
Authors: Ana P Madariaga T, Varenka J Barbero Becerra
Affiliation: Medica Sur Clinic & Foundation
Abstract: n/a

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: pparg activation in breast cancer.
Authors: Dana Ishay-Ronen
Affiliation: /
Abstract: na