scholarly journals PPAR-gamma Signaling in Metabolic Homeostasis

2016 ◽  
Vol 8 (3) ◽  
pp. 147
Author(s):  
Rina Triana ◽  
Nurrani Mustika Dewi ◽  
Siska Darmayanti ◽  
Eka Herawati ◽  
Maria Novalentina ◽  
...  
Keyword(s):  
Metabolic Disorders ◽  
Gastrointestinal Disease ◽  
Expression Profiles ◽  
Ppar Gamma ◽  
Peroxisome Proliferator ◽  
Metabolic Homeostasis ◽  
Ppar Γ ◽  
Natural And Synthetic

BACKGROUND: Peroxisome proliferator-activated receptor (PPAR)-γ, or also known as nuclear receptor subfamily 1 group C member 3 (NR1C3), is a PPAR which serves as master regulator of adipocytes differentiation, and plays an important role in lipid metabolism or adipogenesis. Recent study showed that PPAR-γ is expressed in most tissue and also has critical impact in many metabolic homeostasis disorders.CONTENT: Dysregulation of PPAR-γ is correlated to the development of obesity, type 2 diabetes, atherosclerosis, cardiovascular disease, acute kidney injury, autoimmune disease, gastrointestinal disease and Alzheimer’s disease. Abundant number of new emerging compounds, with in vitro and in vivo effectiveness as natural and synthetic agonists of PPARs, are investigated, developed and used as the treatment of metabolic disorders of glucose and/or lipid and other diseases.SUMMARY: Based on all studies explanation, targeting PPAR-γ is proven to be a good therapeutic method for reducing negative effect of several metabolic homeostasis disorder. Now, many natural and synthetic agonists of PPARs are used as the treatment of metabolic disorders of glucose and/or lipid or another metabolic homeostasis disorder. Such agonists have different properties and specificities for individual PPARs receptors, different absorption and distribution, and distinctive gene expression profiles, which ultimately lead to different clinical outcomes.KEYWORDS: PPAR-γ, dysregulation, agonist, adipogenesis, metabolic disorder, homeostasis

scholarly journals Piperine Alleviates Doxorubicin-Induced Cardiotoxicity via Activating PPAR-γ in Mice

PPAR Research ◽  
2019 ◽  
Vol 2019 ◽  
pp. 1-11 ◽  
Author(s):  
Jie Yan ◽  
Si-Chi Xu ◽  
Chun-Yan Kong ◽  
Xiao-Yang Zhou ◽  
Zhou-Yan Bian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiac Injury ◽  
Inflammatory Factors ◽  
Peroxisome Proliferator ◽  
Protective Effects ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Myocardial Oxidative Stress

Background. Oxidative stress, inflammation and cardiac apoptosis were closely involved in doxorubicin (DOX)-induced cardiac injury. Piperine has been reported to suppress inflammatory response and pyroptosis in macrophages. However, whether piperine could protect the mice against DOX-related cardiac injury remain unclear. This study aimed to investigate whether piperine inhibited DOX-related cardiac injury in mice. Methods. To induce DOX-related acute cardiac injury, mice in DOX group were intraperitoneally injected with a single dose of DOX (15 mg/kg). To investigate the protective effects of piperine, mice were orally treated for 3 weeks with piperine (50 mg/kg, 18:00 every day) beginning two weeks before DOX injection. Results. Piperine treatment significantly alleviated DOX-induced cardiac injury, and improved cardiac function. Piperine also reduced myocardial oxidative stress, inflammation and apoptosis in mice with DOX injection. Piperine also improved cell viability, and reduced oxidative damage and inflammatory factors in cardiomyocytes. We also found that piperine activated peroxisome proliferator-activated receptor-γ (PPAR-γ), and the protective effects of piperine were abolished by the treatment of the PPAR-γ antagonist in vivo and in vitro. Conclusions. Piperine could suppress DOX-related cardiac injury via activation of PPAR-γ in mice.

The role of Toll-like receptor proteins (TLR) 2 and 4 in mediating inflammation in proximal tubules

2013 ◽  
Vol 305 (2) ◽  
pp. F143-F154 ◽  
Author(s):  
Harshini Mudaliar ◽  
Carol Pollock ◽  
Muralikrishna Gangadharan Komala ◽  
Steven Chadban ◽  
Huiling Wu ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Inflammatory Responses ◽  
Proximal Tubules ◽  
Peroxisome Proliferator ◽  
Tlr2 Expression ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Diagnostic Threshold

Inflammatory responses are central to the pathogenesis of diabetic nephropathy. Toll-like receptors (TLRs) are ligand-activated membrane-bound receptors which induce inflammatory responses predominantly through the activation of NF-κB. TLR2 and 4 are present in proximal tubular cells and are activated by endogenous ligands upregulated in diabetic nephropathy, including high-mobility group box-1 (HMGB1) and fibronectin. Human proximal tubules were exposed to 5 mM (control), 11.2 mM (approximating the clinical diagnostic threshold for diabetes mellitus), and 30 mM (high) glucose for 72 h or 7 days. Cells were harvested for protein, mRNA, and nuclear extract to assess for TLR2, 4, and inflammatory markers. Glucose (11.2 mM) maximally increased TLR2 and 4 expression, HMGB1 release, and NF-κB activation with increased expression of cytokines. However, only TLR2 expression and subsequent NF-κB binding were sustained at 7 days. Recombinant HMGB1 induced NF-κB activation, which was prevented by both TLR2 silencing [small interfering (si)RNA] and TLR4 inhibition. Peroxisome proliferator-activated receptor-γ (PPAR-γ) transcription was reduced by exposure to 11.2 mM glucose with an increase observed at 30 mM glucose at 24 h. This may reflect a compensatory increase in PPAR-γ induced by exposure to 30 mM glucose, limiting the inflammatory response. Therefore, short-term moderate increases in glucose in vitro increase HMGB1, which mediates NF-κB activation through both TLR2 and 4. Furthermore, in vivo, streptozotocin-induced diabetic mice exhibited an increase in tubular TLR2 and HMGB1 expression. These results collectively suggest that TLR2 is likely to be the predominant long-term mediator of NF-κB activation in transducing inflammation in diabetic nephropathy.

scholarly journals PPAR Beta/Delta and the Hallmarks of Cancer

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1133 ◽  
Author(s):  
Nicole Wagner ◽  
Kay-Dietrich Wagner
Keyword(s):  
Target Genes ◽  
Therapeutic Targets ◽  
Ppar Gamma ◽  
Nuclear Hormone Receptor ◽  
Cancer Growth ◽  
Peroxisome Proliferator ◽  
Hallmarks Of Cancer ◽  
Ppar Alpha

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. Three different isoforms, PPAR alpha, PPAR beta/delta and PPAR gamma have been identified. They all form heterodimers with retinoic X receptors to activate or repress downstream target genes dependent on the presence/absence of ligands and coactivators or corepressors. PPARs differ in their tissue expression profile, ligands and specific agonists and antagonists. PPARs attract attention as potential therapeutic targets for a variety of diseases. PPAR alpha and gamma agonists are in clinical use for the treatment of dyslipidemias and diabetes. For both receptors, several clinical trials as potential therapeutic targets for cancer are ongoing. In contrast, PPAR beta/delta has been suggested as a therapeutic target for metabolic syndrome. However, potential risks in the settings of cancer are less clear. A variety of studies have investigated PPAR beta/delta expression or activation/inhibition in different cancer cell models in vitro, but the relevance for cancer growth in vivo is less well documented and controversial. In this review, we summarize critically the knowledge of PPAR beta/delta functions for the different hallmarks of cancer biological capabilities, which interplay to determine cancer growth.

Peroxisome proliferator-activated receptors and cardiovascular remodeling

2005 ◽  
Vol 288 (3) ◽  
pp. H1037-H1043 ◽  
Author(s):  
Ernesto L. Schiffrin
Keyword(s):  
Cardiovascular Disease ◽  
Target Genes ◽  
Acid Oxidation ◽  
Peroxisome Proliferator ◽  
Fat Cell ◽  
Ppar Γ ◽  
Peroxisome Proliferator Activated Receptors ◽  
Prevention Of Cardiovascular Disease

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that heterodimerize with the retinoid X receptor and then modulate the function of many target genes. Three PPARs are known: α, β/δ, and γ. The better known are PPAR-α and PPAR-γ, which may be activated by different synthetic agonists, although the endogenous ligands are unknown. PPAR-α is involved in fatty acid oxidation and expressed in the liver, kidney, and skeletal muscle, whereas PPAR-γ is involved in fat cell differentiation, lipid storage, and insulin sensitivity. However, both have been shown to be present in variable amounts in cardiovascular tissues, including endothelium, smooth muscle cells, macrophages, and the heart. The activators of PPAR-α (fibrates) and PPAR-γ (thiazolidinediones or glitazones) antagonized the actions of angiotensin II in vivo and in vitro and exerted cardiovascular antioxidant and anti-inflammatory effects. PPAR activators lowered blood pressure, induced favorable effects on the heart, and corrected vascular structure and endothelial dysfunction in several rodent models of hypertension. Activators of PPARs may become therapeutic agents useful in the prevention of cardiovascular disease beyond their effects on carbohydrate and lipid metabolism. Some side effects, such as weight gain, as well as documented aggravation of advanced heart failure through fluid retention by glitazones, may, however, limit their therapeutic application in prevention of cardiovascular disease.

scholarly journals Sepsis-induced inhibition of neutrophil chemotaxis is mediated by activation of peroxisome proliferator-activated receptor-γ

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 4250-4258 ◽  
Author(s):  
Raju C. Reddy ◽  
Venkata R. Narala ◽  
Venkateshwar G. Keshamouni ◽  
Jami E. Milam ◽  
Michael W. Newstead ◽  
...  
Keyword(s):  
Actin Polymerization ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Human Pmns ◽  
Inflammatory Regulation

AbstractNeutrophils (polymorphonuclear leukocytes [PMNs]) are critical to the immune response, including clearance of infectious pathogens. Sepsis is associated with impaired PMN function, including chemotaxis. PMNs express peroxisome proliferator-activated receptor-γ (PPAR-γ), a ligand-activated nuclear transcription factor involved in immune and inflammatory regulation. The role of PPAR-γ in PMN responses, however, is not well characterized. We report that freshly isolated human PMNs constitutively express PPAR-γ, which is up-regulated by the sepsis-induced cytokines TNF-α and IL-4. PMN chemotactic responses to formylmethionyl-leucyl-phenylalanine (fMLP) and IL-8 were dose-dependently inhibited by treatment with the PPAR-γ ligands troglitazone and 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and by transfection of PMN-like HL-60 cells with a constitutively active PPAR-γ construct. Inhibition of chemotaxis by PPAR-γ ligands correlated with decreases in extracellular signal-regulated kinase-1 and -2 activation, actin polymerization, and adherence to a fibrinogen substrate. Furthermore, PMN expression of PPAR-γ was increased in sepsis patients and mice with either of 2 models of sepsis. Finally, treatment with the PPAR-γ antagonist GW9662 significantly reversed the inhibition of PMN chemotaxis and increased peritoneal PMN recruitment in murine sepsis. This study indicates that PPAR-γ activation is involved in PMN chemotactic responses in vitro and may play a role in the migration of these cells in vivo.

scholarly journals Peroxisome Proliferator-Activated Receptor γ and Its Role in Adipocyte Homeostasis and Thiazolidinedione-Mediated Insulin Sensitization

2018 ◽  
Vol 38 (10) ◽  
Author(s):  
Qiong A. Wang ◽  
Fang Zhang ◽  
Lei Jiang ◽  
Risheng Ye ◽  
Yu An ◽  
...  
Keyword(s):  
Whole Body ◽  
Peroxisome Proliferator ◽  
Metabolic Homeostasis ◽  
Short Term ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fat Depots ◽  
Metabolic Functions ◽  
Sensitizing Effect

ABSTRACT Adipose tissue is a dynamic organ that makes critical contributions to whole-body metabolic homeostasis. Although recent studies have revealed that different fat depots have distinct molecular signatures, metabolic functions and adipogenic mechanisms, peroxisome proliferator-activated receptor γ (PPARγ) is still widely viewed as the master regulator of adipogenesis and critical for maintaining mature adipocyte function. Using an inducible, adipocyte-specific knockout system, we explored the role of PPARγ in mature adipocytes in vivo . Short-term PPARγ deficiency in adipocytes reduces whole-body insulin sensitivity, but adipocytes are viable both in vitro and in vivo . However, after exposure to a high-fat diet, even short-term PPARγ deficiency leads to rapid adipocyte death. When mature adipocytes are depleted of both PPARγ and CCAAT-enhancer-binding protein α (C/EBPα), they are rapidly depleted of lipids and undergo adipocyte death, both in vitro and in vivo . Surprisingly, although thiazolidinediones (TZDs; PPARγ agonists) are thought to act mainly on PPARγ, PPARγ in adipocytes is not required for the whole-body insulin-sensitizing effect of TZDs. This offers new mechanistic aspects of PPARγ/TZD action and its effect on whole-body metabolic homeostasis.

scholarly journals 15-keto-prostaglandin E2 activates host peroxisome proliferator-activated receptor gamma (PPAR-γ) to promote Cryptococcus neoformans growth during infection

2017 ◽  
Author(s):  
Robert J. Evans ◽  
Katherine Pline ◽  
Catherine A. Loynes ◽  
Sarah Needs ◽  
Maceler Aldrovandi ◽  
...  
Keyword(s):  
Cryptococcus Neoformans ◽  
Immune Surveillance ◽  
Fungal Growth ◽  
Prostaglandin E ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ ◽  
Opportunistic Fungal Pathogen

AbstractCryptococcus neoformans is one of the leading causes of invasive fungal infection in humans worldwide. C. neoformans uses macrophages as a proliferative niche to increase infective burden and avoid immune surveillance. However, the specific mechanisms by which C. neoformans manipulates host immunity to promote its growth during infection remain ill-defined. Here we demonstrate that eicosanoid lipid mediators manipulated and/or produced by C. neoformans play a key role in regulating pathogenesis. C. neoformans is known to secrete several eicosanoids that are highly similar to those found in vertebrate hosts. Using eicosanoid deficient cryptococcal mutants Δplb1 and Δlac1, we demonstrate that prostaglandin E2 is required by C. neoformans for proliferation within macrophages and in vivo during infection. Genetic and pharmacological disruption of host PGE2 synthesis is not required for promotion of cryptococcal growth by eicosanoid production. We find that PGE2 must be dehydrogenated into 15-keto-PGE2 to promote fungal growth, a finding that implicated the host nuclear receptor PPAR-γ. C. neoformans infection of macrophages activates host PPAR-γ and its inhibition is sufficient to abrogate the effect of 15-keto-PGE2 in promoting fungal growth during infection. Thus, we describe the first mechanism of reliance on pathogen-derived eicosanoids in fungal pathogenesis and the specific role of 15-keto-PGE2 and host PPAR-γ in cryptococcosis.Author SummaryCryptococcus neoformans is an opportunistic fungal pathogen that is responsible for significant numbers of deaths in the immunocompromised population worldwide. Here we address whether eicosanoids produced by C. neoformans manipulate host innate immune cells during infection. Cryptococcus neoformans produces several eicosanoids that are notable for their similarity to vertebrate eicosanoids, it is therefore possible that fungal-derived eicosanoids may provoke physiological effects in the host. Using a combination of in vitro and in vivo infection models we identify a specific eicosanoid species - prostaglandin E2 – that is required by C. neoformans for growth during infection. We subsequently show that prostaglandin E2 must be converted to 15-keto-prostaglandin E2 within the host before it has these effects. Furthermore, we find that prostaglandin E2/15-keto-prostaglandin E2 mediated virulence is via activation of host PPAR-γ – an intracellular eicosanoid receptor known to interact with 15-keto-PGE2.

scholarly journals Neuroprotection with the Cannabidiol Quinone Derivative VCE-004.8 (EHP-101) against 6-Hydroxydopamine in Cell and Murine Models of Parkinson’s Disease

Molecules ◽  
2021 ◽  
Vol 26 (11) ◽  
pp. 3245
Author(s):  
Sonia Burgaz ◽  
Concepción García ◽  
María Gómez-Cañas ◽  
Alain Rolland ◽  
Eduardo Muñoz ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Peroxisome Proliferator ◽  
Cytoprotective Effect ◽  
Neuroprotective Effects ◽  
Ppar Γ ◽  
Cb2 Receptors ◽  
6 Hydroxydopamine

The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB2) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB2 receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB2 receptors in these effects.

scholarly journals Repurposing Small Molecules to Target PPAR-γ as New Therapies for Peripheral Nerve Injuries

Biomolecules ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 1301
Author(s):  
Melissa L. D. Rayner ◽  
Jess Healy ◽  
James B. Phillips
Keyword(s):  
Peripheral Nerve ◽  
Nerve Regeneration ◽  
In Vivo Studies ◽  
Peroxisome Proliferator ◽  
Neural Cells ◽  
Loss Of Function ◽  
Peroxisome Proliferator Activated Receptor ◽  
Ppar Γ

The slow rate of neuronal regeneration that follows peripheral nerve repair results in poor recovery, particularly where reinnervation of muscles is delayed, leading to atrophy and permanent loss of function. There is a clear clinical need to develop drug treatments that can accelerate nerve regeneration safely, restoring connections before the target tissues deteriorate irreversibly. The identification that the Rho/Rho-associated kinase (ROCK) pathway acts to limit neuronal growth rate is a promising advancement towards the development of drugs. Targeting Rho or ROCK directly can act to suppress the activity of this pathway; however, the pathway can also be modulated through the activation of upstream receptors; one of particular interest being peroxisome proliferator-activated receptor gamma (PPAR-γ). The connection between the PPAR-γ receptor and the Rho/ROCK pathway is the suppression of the conversion of inactive guanosine diphosphate (GDP)-Rho to active guanosine triphosphate GTP-Rho, resulting in the suppression of Rho/ROCK activity. PPAR-γ is known for its role in cellular metabolism that leads to cell growth and differentiation. However, more recently there has been a growing interest in targeting PPAR-γ in peripheral nerve injury (PNI). The localisation and expression of PPAR-γ in neural cells following a PNI has been reported and further in vitro and in vivo studies have shown that delivering PPAR-γ agonists following injury promotes nerve regeneration, leading to improvements in functional recovery. This review explores the potential of repurposing PPAR-γ agonists to treat PNI and their prospective translation to the clinic.

The Antifibrogenic Potential of PPARγ Ligands in Pulmonary Fibrosis

2008 ◽  
Vol 56 (2) ◽  
pp. 534-538 ◽  
Author(s):  
Patricia J. Sime
Keyword(s):  
Pulmonary Fibrosis ◽  
Mechanism Of Action ◽  
Lung Fibroblasts ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Relative Paucity ◽  
Ppar Γ ◽  
Organ Systems

Pulmonary fibrosis is characterized by the accumulation of fibroblasts, myofibroblasts, collagen, and other extracellular matrix proteins in the interstitium of the lung, with subsequent scarring and destruction of the alveolar capillary interface. In some cases, pulmonary fibrosis is preceded by lung inflammation and can be treated with anti-inflammatory therapies. However, idiopathic pulmonary fibrosis is characterized by a relative paucity of underlying inflammation and currently has no effective treatment. There is increasing evidence that the transcription factor peroxisome proliferator-activated receptor (PPAR) γ plays an important role in controlling cell differentiation and that PPARγ ligands can modify inflammatory and fibrotic responses. Peroxisome proliferator-activated receptor γ ligands, including the thiazolidinedione class of antidiabetic drugs and novel triterpenoid compounds derived from oleanic acid, inhibit TGF-β-stimulated profibrotic differentiation of lung fibroblasts in vitro and reduce lung scarring in animal models of fibrosis. The mechanism of action of the PPARγ ligands is under investigation but seems to involve both PPARγ-dependent and PPARγ-independent pathways. These in vitro and in vivo data highlight the potentially exciting role of PPARγ ligands as novel therapies for fibrosis of the lung and other organ systems prone to scarring. Many of the synthetic PPARγ ligands are orally active, and several are currently available and Food Drug Administration approved for use in therapy of type 2 diabetes. Further research is urgently required to more clearly elucidate the mechanism of action of these drugs and to develop more potent antifibrotic agents for patients with scarring diseases for whom there are currently few effective therapies.

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