PPARs in Liver Diseases and Cancer: Epigenetic Regulation by MicroRNAs

Peroxisome-proliferator-activated receptors (PPARs) are ligand-activated nuclear receptors that exert in the liver a transcriptional activity regulating a whole spectrum of physiological functions, including cholesterol and bile acid homeostasis, lipid/glucose metabolism, inflammatory responses, regenerative mechanisms, and cell differentiation/proliferation. Dysregulations of the expression, or activity, of specific PPAR isoforms in the liver are therefore believed to represent critical mechanisms contributing to the development of hepatic metabolic diseases, disorders induced by hepatic viral infections, and hepatocellular adenoma and carcinoma. In this regard, specific PPAR agonists have proven to be useful to treat these metabolic diseases, but for cancer therapies, the use of PPAR agonists is still debated. Interestingly, in addition to previously described mechanisms regulating PPARs expression and activity, microRNAs are emerging as new important regulators of PPAR expression and activity in pathophysiological conditions and therefore may represent future therapeutic targets to treat hepatic metabolic disorders and cancers. Here, we reviewed the current knowledge about the general roles of the different PPAR isoforms in common chronic metabolic and infectious liver diseases, as well as in the development of hepatic cancers. Recent works highlighting the regulation of PPARs by microRNAs in both physiological and pathological situations with a focus on the liver are also discussed.

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PPAR Regulation of Inflammatory Signaling in CNS Diseases

PPAR Research ◽

10.1155/2008/658520 ◽

2008 ◽

Vol 2008 ◽

pp. 1-12 ◽

Cited By ~ 69

Author(s):

John J. Bright ◽

Saravanan Kanakasabai ◽

Wanida Chearwae ◽

Sharmistha Chakraborty

Keyword(s):

Hormone Receptors ◽

Inflammatory Responses ◽

Current Knowledge ◽

Signaling Networks ◽

Peroxisome Proliferator ◽

Inflammatory Signaling ◽

Cns Diseases ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors ◽

Privileged Site

Central nervous system (CNS) is an immune privileged site, nevertheless inflammation associates with many CNS diseases. Peroxisome proliferator-activated receptors (PPARs) are a family of nuclear hormone receptors that regulate immune and inflammatory responses. Specific ligands for PPAR, , and isoforms have proven effective in the animal models of multiple sclerosis (MS), Alzheimer's disease, Parkinson's disease, and trauma/stroke, suggesting their use in the treatment of neuroinflammatory diseases. The activation of NF-B and Jak-Stat signaling pathways and secretion of inflammatory cytokines are critical in the pathogenesis of CNS diseases. Interestingly, PPAR agonists mitigate CNS disease by modulating inflammatory signaling network in immune cells. In this manuscript, we review the current knowledge on how PPARs regulate neuroinflammatory signaling networks in CNS diseases.

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Peroxisome proliferator-activated receptor α and γ agonists differently regulate classical and alternative macrophage activation

Immunometabolism ◽

10.1515/immun-2015-0001 ◽

2015 ◽

Vol 2 (1) ◽

Author(s):

Erja-Leena Paukkeri ◽

Antti Pekurinen ◽

Eeva Moilanen

Keyword(s):

Macrophage Activation ◽

Inflammatory Responses ◽

Therapeutic Potential ◽

Alternative Activation ◽

Peroxisome Proliferator ◽

Activation Markers ◽

Peroxisome Proliferator Activated Receptor ◽

Arginase 1 ◽

Pparγ Agonist ◽

Ppar Agonists

AbstractPeroxisome proliferator-activated receptor (PPAR) agonists, fibrates and thiazolidinediones, are commonly used drugs in the treatment of dyslipidemia and diabetes. Their targets, PPARα and PPARγ, have also been shown to have a role in the regulation of inflammatory responses linking metabolism and inflammation. In the present study we investigated the effects of PPAR agonists on macrophage activation. In addition to the proinflammatory classical activation, we also focused on interleukin (IL) 4 and 13 -induced alternative activation which is a significant macrophage phenotype in tissue repairing processes and in fibrosing diseases. PPARα agonists GW7647 and fenofibrate as well as PPARγ agonist GW1929 inhibited lipopolysaccharide-induced classical macrophage activation and production of the characteristic biomarkers of this phenotype, i.e. IL-6 and nitric oxide, in murine J774 macrophages. Remarkably, the PPARα agonists also inhibited IL-4 and IL-13 –induced expression of alternative activation markers arginase-1, fizz1 and mannose receptor 1 whereas the PPARγ agonist GW1929 enhanced their expression in J774 macrophages. The PPARα agonists GW7647 and fenofibrate also attenuated the production of alternative activation markers chemokine (C-C motif) ligand 13 and plateletderived growth factor in human THP-1 macrophages. The present findings show that PPARα and PPARγ agonists differently regulate classical and alternative macrophage phenotypes. Furthermore, PPARα activation was introduced as a novel concept to down-regulate alternative macrophage activation indicating that PPARα agonists have therapeutic potential in conditions associated with aberrant alternative macrophage activation such as fibrosing diseases.

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Peroxisome Proliferator-Activated Receptors and the Heart: Lessons from the Past and Future Directions

PPAR Research ◽

10.1155/2015/271983 ◽

2015 ◽

Vol 2015 ◽

pp. 1-18 ◽

Cited By ~ 36

Author(s):

Wang-Soo Lee ◽

Jaetaek Kim

Keyword(s):

Nuclear Family ◽

Current Knowledge ◽

Therapeutic Option ◽

Lessons Learned ◽

Peroxisome Proliferator ◽

Main Role ◽

Future Directions ◽

Drug Candidates ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear family of ligand activated transcriptional factors and comprise three different isoforms, PPAR-α, PPAR-β/δ, and PPAR-γ. The main role of PPARs is to regulate the expression of genes involved in lipid and glucose metabolism. Several studies have demonstrated that PPAR agonists improve dyslipidemia and glucose control in animals, supporting their potential as a promising therapeutic option to treat diabetes and dyslipidemia. However, substantial differences exist in the therapeutic or adverse effects of specific drug candidates, and clinical studies have yielded inconsistent data on their cardioprotective effects. This review summarizes the current knowledge regarding the molecular function of PPARs and the mechanisms of the PPAR regulation by posttranslational modification in the heart. We also describe the results and lessons learned from important clinical trials on PPAR agonists and discuss the potential future directions for this class of drugs.

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Stromal cell-derived factor-1 (SDF-1) as a target in liver diseases

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00193.2016 ◽

2016 ◽

Vol 311 (2) ◽

pp. G203-G209 ◽

Cited By ~ 25

Author(s):

Anke Liepelt ◽

Frank Tacke

Keyword(s):

Liver Injury ◽

Chemokine Receptors ◽

Liver Diseases ◽

Stromal Cell ◽

Current Knowledge ◽

Suppressor Cells ◽

Cancer Therapies ◽

Liver Sinusoidal Endothelial Cells ◽

Chronic Injury ◽

Stromal Cell Derived Factor

The chemokine stromal cell-derived factor-1 (SDF-1) or CXCL12 is constitutively expressed in healthy liver. However, its expression increases following acute or chronic liver injury. Liver sinusoidal endothelial cells (LSEC), hepatic stellate cells (HSC), and malignant hepatocytes are important sources of SDF-1/CXCL12 in liver diseases. CXCL12 is able to activate two chemokine receptors with different downstream signaling pathways, CXCR4 and CXCR7. CXCR7 expression is relevant on LSEC, while HSC, mesenchymal stem cells, and tumor cells mainly respond via CXCR4. Here, we summarize recent developments in the field of liver diseases involving this chemokine and its receptors. SDF-1-dependent signaling contributes to modulating acute liver injury and subsequent tissue regeneration. By activating HSC and recruiting mesenchymal cells from bone marrow, CXCL12 can promote liver fibrosis progression, while CXCL12-CXCR7 interactions endorse proregenerative responses in chronic injury. Moreover, the SDF-1 pathway is linked to development of hepatocellular carcinoma (HCC) by promoting tumor growth, angiogenesis, and HCC metastasis. High hepatic CXCR4 expression has been suggested as a biomarker indicating poor prognosis of HCC patients. Tumor-infiltrating myeloid-derived suppressor cells (MDSC) also express CXCR4 and migrate toward CXCL12. Thus CXCL12 inhibition might not only directly block HCC growth but also modulate the tumor microenvironment (angiogenesis, MDSC), thereby sensitizing HCC patients to conventional or emerging novel cancer therapies (e.g., sorafenib, regorafenib, nivolumab, pembrolizumab). We herein summarize the current knowledge on the complex interplay between CXCL12 and CXCR4/CXCR7 in liver diseases and discuss approaches on the therapeutic targeting of these axes in hepatitis, fibrosis, and liver cancer.

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Anticancer Role of PPARγAgonists in Hematological Malignancies Found in the Vasculature, Marrow, and Eyes

PPAR Research ◽

10.1155/2010/814609 ◽

2010 ◽

Vol 2010 ◽

pp. 1-36 ◽

Cited By ~ 9

Author(s):

P. J. Simpson-Haidaris ◽

S. J. Pollock ◽

S. Ramon ◽

N. Guo ◽

C. F. Woeller ◽

...

Keyword(s):

Hematological Malignancies ◽

Radiation Treatment ◽

Inflammatory Responses ◽

Combined Therapy ◽

Chemotherapeutic Agents ◽

Peroxisome Proliferator ◽

Cancer Therapies ◽

Peroxisome Proliferator Activated Receptor ◽

Treatment And Prevention

The use of targeted cancer therapies in combination with conventional chemotherapeutic agents and/or radiation treatment has increased overall survival of cancer patients. However, longer survival is accompanied by increased incidence of comorbidities due, in part, to drug side effects and toxicities. It is well accepted that inflammation and tumorigenesis are linked. Because peroxisome proliferator-activated receptor (PPAR)-γagonists are potent mediators of anti-inflammatory responses, it was a logical extension to examine the role of PPARγagonists in the treatment and prevention of cancer. This paper has two objectives: first to highlight the potential uses for PPARγagonists in anticancer therapy with special emphasis on their role when used as adjuvant or combined therapy in the treatment of hematological malignancies found in the vasculature, marrow, and eyes, and second, to review the potential role PPARγand/or its ligands may have in modulating cancer-associated angiogenesis and tumor-stromal microenvironment crosstalk in bone marrow.

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Role of PPARs in Radiation-Induced Brain Injury

PPAR Research ◽

10.1155/2010/234975 ◽

2010 ◽

Vol 2010 ◽

pp. 1-12 ◽

Cited By ~ 23

Author(s):

Sriram Ramanan ◽

Weiling Zhao ◽

David R. Riddle ◽

Mike E. Robbins

Keyword(s):

Brain Injury ◽

Inflammatory Responses ◽

Current Knowledge ◽

Whole Brain Irradiation ◽

Brain Irradiation ◽

Ppar Agonists ◽

The Usa ◽

Radiation Induced

Whole-brain irradiation (WBI) represents the primary mode of treatment for brain metastases; about 200 000 patients receive WBI each year in the USA. Up to 50% of adult and 100% of pediatric brain cancer patients who survive >6 months post-WBI will suffer from a progressive, cognitive impairment. At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect. Recent studies suggest that the pathogenesis of radiation-induced brain injury involves WBI-mediated increases in oxidative stress and/or inflammatory responses in the brain. Therefore, anti-inflammatory strategies can be employed to modulate radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily. Although traditionally known to play a role in metabolism, increasing evidence suggests a role for PPARs in regulating the response to inflammation and oxidative injury. PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease. However, the role of PPARs in radiation-induced brain injury is unclear. In this manuscript, we review the current knowledge and the emerging insights about the role of PPARs in modulating radiation-induced brain injury.

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Eosinophils and Bacteria, the Beginning of a Story

International Journal of Molecular Sciences ◽

10.3390/ijms22158004 ◽

2021 ◽

Vol 22 (15) ◽

pp. 8004

Author(s):

Edna Ondari ◽

Esther Calvino-Sanles ◽

Nicholas J. First ◽

Monica C. Gestal

Keyword(s):

Immune Responses ◽

Respiratory Tract ◽

Bacterial Infections ◽

Viral Infections ◽

Inflammatory Responses ◽

Current Knowledge ◽

Parasitic Infections ◽

Th2 Responses ◽

A Cell ◽

Anti Inflammatory

Eosinophils are granulocytes primarily associated with TH2 responses to parasites or immune hyper-reactive states, such as asthma, allergies, or eosinophilic esophagitis. However, it does not make sense from an evolutionary standpoint to maintain a cell type that is only specific for parasitic infections and that otherwise is somehow harmful to the host. In recent years, there has been a shift in the perception of these cells. Eosinophils have recently been recognized as regulators of immune homeostasis and suppressors of over-reactive pro-inflammatory responses by secreting specific molecules that dampen the immune response. Their role during parasitic infections has been well investigated, and their versatility during immune responses to helminths includes antigen presentation as well as modulation of T cell responses. Although it is known that eosinophils can present antigens during viral infections, there are still many mechanistic aspects of the involvement of eosinophils during viral infections that remain to be elucidated. However, are eosinophils able to respond to bacterial infections? Recent literature indicates that Helicobacter pylori triggers TH2 responses mediated by eosinophils; this promotes anti-inflammatory responses that might be involved in the long-term persistent infection caused by this pathogen. Apparently and on the contrary, in the respiratory tract, eosinophils promote TH17 pro-inflammatory responses during Bordetella bronchiseptica infection, and they are, in fact, critical for early clearance of bacteria from the respiratory tract. However, eosinophils are also intertwined with microbiota, and up to now, it is not clear if microbiota regulates eosinophils or vice versa, or how this connection influences immune responses. In this review, we highlight the current knowledge of eosinophils as regulators of pro and anti-inflammatory responses in the context of both infection and naïve conditions. We propose questions and future directions that might open novel research avenues in the future.

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Control of gene expression and mitochondrial biogenesis in the muscular adaptation to endurance exercise

Essays in Biochemistry ◽

10.1042/bse0420013 ◽

2006 ◽

Vol 42 ◽

pp. 13-29 ◽

Cited By ~ 76

Author(s):

Anna-Maria Joseph ◽

Henriette Pilegaard ◽

Anastassia Litvintsev ◽

Lotte Leick ◽

David A. Hood

Keyword(s):

Gene Expression ◽

Mitochondrial Biogenesis ◽

Protein Import ◽

Metabolic Diseases ◽

Current Knowledge ◽

Mitochondrial Fission ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

Control Of Gene Expression ◽

Genes Encoding

Every time a bout of exercise is performed, a change in gene expression occurs within the contracting muscle. Over the course of many repeated bouts of exercise (i.e. training), the cumulative effects of these alterations lead to a change in muscle phenotype. One of the most prominent of these adaptations is an increase in mitochondrial content, which confers a greater resistance to muscle fatigue. This essay reviews current knowledge on the regulation of exercise-induced mitochondrial biogenesis at the molecular level. The major steps involved include, (i) transcriptional regulation of nuclear-encoded genes encoding mitochondrial proteins by the coactivator peroxisome-proliferator-activated receptor g coactivator-1, (ii) control of mitochondrial DNA gene expression by the transcription factor Tfam, (iii) mitochondrial fission and fusion mechanisms, and (iv) import of nuclear-derived gene products into the mitochondrion via the protein import machinery. It is now known that exercise can modify the rates of several of these steps, leading to mitochondrial biogenesis. An understanding of how exercise can produce this effect could help us decide whether exercise is beneficial for patients suffering from mitochondrial disorders, as well as a variety of metabolic diseases.

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Treatment of Obesity-Related Complications with Novel Classes of Naturally Occurring PPAR Agonists

Journal of Obesity ◽

10.1155/2011/897894 ◽

2011 ◽

Vol 2011 ◽

pp. 1-7 ◽

Cited By ~ 20

Author(s):

Josep Bassaganya-Riera ◽

Amir J. Guri ◽

Raquel Hontecillas

Keyword(s):

Metabolic Diseases ◽

Inflammatory Diseases ◽

Peroxisome Proliferator ◽

Punicic Acid ◽

Ppar Γ ◽

Naturally Occurring ◽

Wide Range ◽

Ppar Agonists ◽

Peroxisome Proliferator Activated Receptors ◽

Treatment Of Obesity

The prevalence of obesity and its associated comorbidities has grown to epidemic proportions in the US and worldwide. Thus, developing safe and effective therapeutic approaches against these widespread and debilitating diseases is important and timely. Activation of peroxisome proliferator-activated receptors (PPARs) α, γ, and δ through several classes of pharmaceuticals can prevent or treat a variety of metabolic and inflammatory diseases, including type II diabetes (T2D). Thus, PPARs represent important molecular targets for developing novel and better treatments for a wide range of debilitating and widespread obesity-related diseases and disorders. However, available PPAR γ agonistic drugs such as Avandia have significant adverse side effects, including weight gain, fluid retention, hepatotoxicity, and congestive heart failure. An alternative to synthetic agonists of PPAR γ is the discovery and development of naturally occurring and safer nutraceuticals that may be dual or pan PPAR agonists. The purpose of this paper is to summarize the health effects of three plant-derived PPAR agonists: abscisic acid (ABA), punicic acid (PUA), and catalpic acid (CAA) in the prevention and treatment of chronic inflammatory and metabolic diseases and disorders.

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Influence of a high-fat diet on gut microbiota, intestinal permeability and metabolic endotoxaemia

British Journal Of Nutrition ◽

10.1017/s0007114512001213 ◽

2012 ◽

Vol 108 (5) ◽

pp. 801-809 ◽

Cited By ~ 283

Author(s):

Ana Paula Boroni Moreira ◽

Tatiana Fiche Salles Texeira ◽

Alessandra Barbosa Ferreira ◽

Maria do Carmo Gouveia Peluzio ◽

Rita de Cássia Gonçalves Alfenas

Keyword(s):

Gut Microbiota ◽

Intestinal Permeability ◽

Metabolic Diseases ◽

Inflammatory Responses ◽

Current Knowledge ◽

Biological Effects ◽

Circulatory System ◽

High Fat ◽

Negative Effects ◽

The Impact

Lipopolysaccharide (LPS) may play an important role in chronic diseases through the activation of inflammatory responses. The type of diet consumed is of major concern for the prevention and treatment of these diseases. Evidence from animal and human studies has shown that LPS can diffuse from the gut to the circulatory system in response to the intake of high amounts of fat. The method by which LPS move into the circulatory system is either through direct diffusion due to intestinal paracellular permeability or through absorption by enterocytes during chylomicron secretion. Considering the impact of metabolic diseases on public health and the association between these diseases and the levels of LPS in the circulatory system, this review will mainly discuss the current knowledge about high-fat diets and subclinical inflammation. It will also describe the new evidence that correlates gut microbiota, intestinal permeability and alkaline phosphatase activity with increased blood LPS levels and the biological effects of this increase, such as insulin resistance. Although the majority of the studies published so far have assessed the effects of dietary fat, additional studies are necessary to deepen the understanding of how the amount, the quality and the structure of the fat may affect endotoxaemia. The potential of food combinations to reduce the negative effects of fat intake should also be considered in future studies. In these studies, the effects of flavonoids, prebiotics and probiotics on endotoxaemia should be investigated. Thus, it is essential to identify dietetic strategies capable of minimising endotoxaemia and its postprandial inflammatory effects.

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