Role Of Peroxisome Proliferator-activated Receptors Research Articles

The Role of Peroxisome Proliferator-Activated Receptors (PPARs) in Pan-Cancer.

Peroxisome proliferator-activated receptors (PPARs) are members of nuclear transcription factors. The functions of the PPAR family (PPARA, PPARD, and PPARG) and their coactivators (PPARGC1A and PPARGC1B) in maintenance of lipid and glucose homeostasis have been unveiled. However, the roles of PPARs in cancer development remain elusive. In this work, we made use of 11,057 samples across 33 TCGA tumor types to analyze the relationship between PPAR transcriptional expression and tumorigenesis as well as drug sensitivity. We performed multidimensional analyses on PPARA, PPARG, PPARD, PPARGC1A, and PPARGC1B, including differential expression analysis in pan-cancer, immune subtype analysis, clinical analysis, tumor purity analysis, stemness correlation analysis, and drug responses. PPARs and their coactivators expressed differently in different types of cancers, in different immune subtypes. This analysis reveals various expression patterns of the PPAR family at a level of pan-cancer and provides new clues for the therapeutic strategies of cancer.

Role of peroxisome proliferator-activated receptors in stroke prevention and therapy-The best is yet to come?

Role of peroxisome proliferator-activated receptors (PPARs) in the pathophysiology of stroke and protective effects of PPAR ligands have been widely investigated in the last 20years. Activation of all three PPAR isoforms, but especially PPAR-γ, was documented to limit postischemic injury in the numerous in vivo, as well as in in vitro studies. PPARs have been demonstrated to act on multiple mechanisms and were shown to activate multiple protective pathways related to inflammation, apoptosis, BBB protection, neurogenesis, and oxidative stress. The aim of this review was to summarize two decades of PPAR research in stroke with emphasis on in vivo animal studies. We focus on each PPAR receptor separately and detail their implication in stroke. This review also discusses recent clinical efforts in the field and the epidemiological data with regard to role of PPAR polymorphisms in susceptibility to stroke, and tries to draw conclusions and describe future perspectives.

Role of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Different Disease States: Recent Updates.

Peroxisome proliferator-activated receptor (PPAR), a ligand dependant transcription factor, is a member of the nuclear receptor superfamily. PPAR exists in three isoforms i.e. PPAR alpha (PPARα), PPAR beta (PPARβ), and PPAR gamma (PPARγ). These are multi-functional transcription factors and help in regulating inflammation, type 2 diabetes, lipid concentration in the body, metastasis, and tumor growth or angiogenesis. Activation of PPARγ causes inhibition of growth of cultured human breast, gastric, lung, prostate, and other cancer cells. PPARγ is mainly involved in fatty acid storage, glucose metabolism, and homeostasis and adipogenesis regulation. A large number of natural and synthetic ligands bind to PPARγ and modulate its activity. Ligands such as thiazolidinedione, troglitazone, rosiglitazone, pioglitazone effectively bind to PPARγ; however, most of these were found to display severe side effects such as hepatotoxicity, weight gain, cardiovascular complications and bladder tumor. Now the focus is shifted towards the development of dual-acting or pan PPAR ligands. The current review article describes the functions and role of PPARγ in various disease states. In addition, recently reported PPARγ ligands and pan PPAR ligands were discussed in detail. It is envisaged that the present review article may help in the development of potent PPAR ligands with no or minimal side effects.

Activation of PPARγ reduces N-acetyl-cysteine -induced hypercorticoidism by down-regulating MC2R expression into adrenal glands

We previously demonstrated that oral supplementation with antioxidants induced hyperactivity of hypothalamus-pituitary-adrenal (HPA) axis, attested by hypercorticoidism, through an up-regulation of adrenocorticotrophic hormone (ACTH) receptors (MC2R) in adrenal. This study analyzed the role of peroxisome proliferator-activated receptor (PPAR)-γ on HPA axis hyperactivity induced by N-acetyl-cysteine (NAC). Male Swiss-Webster mice were orally treated with NAC for 1, 3, 5, 10, 15, or 18 consecutive days. The PPAR-γ agonist rosiglitazone and/or antagonist GW9662 were daily-injected i.p. for 5 consecutive days, starting concomitantly with NAC treatment. Rosiglitazone treatment inhibited NAC-induced adrenal hypertrophy and hypercorticoidism. Rosiglitazone also significantly reversed the NAC-induced increase in the MC2R expression in adrenal, but not steroidogenic acute regulatory protein (StAR). NAC treatment reduces the expression of PPARγ in the adrenals, but rosiglitazone did not restore the expression of this cytoprotective gene. In addition, GW9662 blocked the ability of rosiglitazone to decrease plasma corticosterone levels in NAC-treated mice. In conclusion, our findings showed that antioxidant supplementation induced a state of hypercorticoidism through down-regulation of PPARγ expression in the adrenals, in a mechanism probably related to a down-regulation of ACTH receptor expression.

The metabolite, alpha-ketoglutarate inhibits non-alcoholic fatty liver disease progression by targeting lipid metabolism

BackgroundNon-alcoholic liver disease is of increased concern and contributing to economic burdens not only in developing countries but in developed countries as well. Identifying the biomarker of early diagnosis and early intervention approaches for non-alcoholic liver disease is unmet and required further investigation. Although the alpha-ketoglutarate (α-KG) is recently proposed to be a potential biomarker in differentiating patients with obesity from those with non-alcoholic liver disease, how α-ketoglutatate is involved in the fatty liver progression is not clear. MethodsA high-fat diet (HFD) feeding animal model, liver functional assays, and molecular approaches were adopted to clarify the impact of α-KG in fatty liver progression. ResultsIn the current study, it was found that dietary α-KG would inhibit weight gain in male and female mice fed with a normal chew or HFD. HFD feeding caused fatty liver in male mice, but α-KG treatment could substantially inhibit hepatic steatosis progression. Biochemical studies revealed the possible linkage of α-KG protective functions to lipid metabolism. Further analysis identified the important role of peroxisome proliferator-activated receptors in beneficial α-KG-mediated effects on fatty liver progression. ConclusionsThe current study demonstrates the therapeutic potential of α-KG and how it may be used, via dietary supplementation, as a preventive intervention for non-alcoholic liver disease in obese patients.

Differential effects of selective- and pan-PPAR agonists on experimental steatohepatitis and hepatic macrophages☆

Peroxisome proliferator-activated receptors (PPARs) are essential regulators of whole-body metabolism, but also modulate inflammation in immune cells, notably macrophages. We compared the effects of selective PPAR agonists to those of the pan-PPAR agonist lanifibranor in non-alcoholic fatty liver disease (NAFLD), and studied isoform-specific effects on hepatic macrophage biology. Lanifibranor or selective PPARα (fenofibrate), PPARγ (pioglitazone) and PPARδ (GW501516) agonists were therapeutically administered in choline-deficient, amino acid-defined high-fat diet (CDAA-HFD)- and Western diet (WD)-fed mouse models of NAFLD. Acute liver injury was induced by carbon tetrachloride (CCl4). The role of PPARs on macrophage functionality was studied in isolated hepatic macrophages, bone marrow-derived macrophages stimulated with palmitic acid, and circulating monocytes from patients with NAFLD. Lanifibranor improved all histological features of steatohepatitis in CDAA-HFD-fed mice, including liver fibrosis, thereby combining and exceeding specific effects of the single PPAR agonists. Its potent anti-steatotic efficacy was confirmed in a 3D liver biochip model with primary cells. Infiltrating hepatic monocyte-derived macrophages were reduced following PPAR agonist administration, especially with lanifibranor, even after short-term treatment, paralleling improved steatosis and hepatitis. Lanifibranor similarly decreased steatosis, liver injury and monocyte infiltration in the WD model. In the acute CCl4 model, neither single nor pan-PPAR agonists directly affected monocyte recruitment. Hepatic macrophages isolated from WD-fed mice displayed a metabolically activated phenotype. Lanifibranor attenuated the accompanying inflammatory activation in both murine palmitic acid-stimulated bone marrow-derived macrophages, as well as patient-derived circulating monocytes, in a PPARδ-dependent fashion. Pan-PPAR agonists combine the beneficial effects of selective PPAR agonists and may counteract inflammation and disease progression more potently. PPARδ agonism and lanifibranor directly modulate macrophage activation, but not infiltration, thereby synergizing with beneficial metabolic effects of PPARα/γ agonists. Peroxisome proliferated-activated receptors (PPARs) are essential regulators of metabolism and inflammation. We demonstrated that the pan-PPAR agonist lanifibranor ameliorated all aspects of non-alcoholic fatty liver disease in independent experimental mouse models. Non-alcoholic fatty liver disease and fatty acids induce a specific polarization status in macrophages, which was altered by lanifibranor to increase expression of lipid handling genes, thereby decreasing inflammation. PPAR isoforms have differential therapeutic effects on fat-laden hepatocytes, activated hepatic stellate cells and inflammatory macrophages, supporting the clinical development of pan-PPAR agonists.

Troglitazone, a Selective Ligand for PPARγ, Induces Cell-cycle Arrest in Human Oral SCC Cells.

We attempted to clarify the role of Peroxisome proliferator-activated receptor γ (PPARγ) and its ligand, troglitazone (TRO) on oral squamous cell carcinoma (SCC). The expression of PPARγ gene was examined in 47 human oral SCC tissues and two human oral SCC cell lines, CA9-22 and HSC-4. The effects of TRO on the growth and cell-cycle progression of human oral SCC cells were examined. PPARγ mRNA was detected in 20 of 47 oral SCC tissues and two human oral SCC cells. TRO significantly suppressed the growth of the cells, but did not induce apoptosis. CA9-22 cells treated with TRO showed an increased fraction in the G1 phase and decreased fractions in the S and G2-M phases. TRO did not induce apoptosis in oral SCC cells, but did inhibit the growth of the cells by arresting the cell cycle at G1 phase.

Peroxisome proliferator-activated receptor γ (PPARγ) suppresses the proliferation and metastasis of patients with urothelial carcinoma after renal transplantation by inhibiting LEF1/β-catenin signaling

ABSTRACT This study is to investigate the role of peroxisome proliferator-activated receptor γ (PPARγ) in the progression of urothelial carcinoma (UC) after renal transplants (RT). A total of 114 UC patients were gathered, including 60 cases of primary UC and 54 cases UC after RT. RT-PCR was used to detect the mRNA expression of the 54 patients with UC after RT, and immunohistochemistry and western blot were used to examine the protein expression. The proliferative ability of two UC cell lines, and 5637, were measured by WST-1 assay. Transwell system was used to analyze the migration and invasion of UC cells. PPARγ agonist Rosiglitazone and the antagonist GW9662 were used to alter the PPARγ expression. siRNA targeting LEF1 and expression vector containing full-length cDNA of LEF1 regulated the expression of LEF1. Pathway analysis indicated that PPARγ expression was significantly down regulated. Compared with normal urothelium and primary UC, the expression of PPARγ in UC was significantly decreased in RT group. PPARγ expression was correlated with tumor size, clinical stage, pathological and recurrence. PPARγ inactivates LEF1/β-catenin signaling in UC cells. PPARγ decreased the protein expression of MMP2, and calpain-2. PPARγ suppresses the proliferation, and invasion of UC cells depending on the expression of LEF1. PPARγ inhibited tumor proliferation and metastasis by inhibiting LEF1/β-catenin signaling, and the expression of PPARγ in UC after RT decreased significantly. Our findings also suggested that PPARγ may be a potential biomarker for the diagnosis of UC after RT.

Characterisation of stem and proliferating cells on the retina and lens of loach Misgurnus anguillicaudatus.

The eye of the fish has a lifelong persistent neurogenesis unlike eye of mammals, so it's highly interesting to study retinal neurogenesis and its genetic control to give complete knowledge about the cause of this property in fish in comparison to mammals. We performed fluorescent in situ hybridisation for loach Misgurnus anguillicaudatus bmi1, msi1 and sox2 genes, which are used as an indicator of the sites of multipotent stem cells. Proliferating cell nuclear antigen (PCNA), bromodeoxyuridine (BRDU) and KI67 markers were used as indicators of proliferating cells and glial fibrillary acidic protein (GFAP) immunofluorescence was used for detection of the glial property of cells, as well as, immunohistochemistry detected the role of peroxisome proliferator-activated receptor (PPAR)α and γ in retinal neurogenesis. Our results determined that the lens and the retina of loach M. anguillicaudatus contain proliferative and pluripotent stem cells that have both glial and neuroepithelial properties, which add new cells continuously throughout life even without injury-induced proliferation. The PPARα has an essential function in providing energy supply for retinal neurogenesis more than PPARγ.

Cardioprotective Effects of Atorvastatin Are Mediated Through PPARγ in Paraquat-Exposed Rats.

Paraquat poisoning is one of leading intoxication worldwide without an effective antidote and treatment protocol. Among the other organs, cardiotoxicity of paraquat has been frequently reported. The protective effects of atorvastatin (STN) on paraquat-induced cardiotoxicity and the role of peroxisome proliferator-activated receptors γ in the mediation of STN effects were investigated. Forty-two male Wistar rats were aliquoted into control or test groups. The animals in test groups in addition of paraquat received saline normal (PQ), pioglitazone (PGT), atorvastatin (STN), PGT + STN, PGT + GW9662, and/or STN + GW9662 for 14 days. PGT and STN lowered lipid peroxidation rate, nitric oxide concentration, and activity of myeloperoxidase and CK/MB in the heart. PGT and STN protected from thiol molecules reduction and PQ-induced histopathological injuries. STN regulated the PQ-induced upregulation of COX-II expression in the heart. All STN-related protective effects were reversed by GW9662 as PPARγ antagonist. These data suggest a cardioprotective effect for STN against the PQ-induced inflammation and oxidative stress. The pharmacologic approach of these findings indicates that STN through PPARγ pathway lowered the PQ-induced cardiotoxicity.

Lifestyle and Food Habits Impact on Chronic Diseases: Roles of PPARs.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that exert important functions in mediating the pleiotropic effects of diverse exogenous factors such as physical exercise and food components. Particularly, PPARs act as transcription factors that control the expression of genes implicated in lipid and glucose metabolism, and cellular proliferation and differentiation. In this review, we aim to summarize the recent advancements reported on the effects of lifestyle and food habits on PPAR transcriptional activity in chronic disease.

The Journey of Thiazolidinediones as Modulators of PPARs for the Management of Diabetes: A Current Perspective.

Peroxisome Proliferator-Activated Receptors (PPARs) also known as glitazone receptors are a family of receptors that regulate the expression of genes and have an essential role in carbohydrate, lipid and protein metabolism apart from other functions. PPARs come in 3 sub-types: PPAR-α, PPAR-β/δ and PPAR-γ - with PPAR-γ having 2 isoforms - γ1 and γ2. Upon activation, the PPARs regulate the transcription of various genes involved in lipid and glucose metabolism, adipocyte differentiation, increasing insulin sensitivity, prevention of oxidative stress and to a certain extent, modulation of immune responses via macrophages that have been implicated in the pathogenesis of insulin resistance. Hence, PPARs are an attractive molecular target for designing new anti-diabetic drugs. This has led to a boost in the research efforts directed towards designing of PPAR ligands - particularly ones that can selectively and specifically activate one or more of the PPAR subtypes. Though, PPAR- γ full agonists such as Thiazolidinediones (TZDs) are well established agents for dyslipidemia and type 2 diabetes mellitus (T2D), the side effect profile associated with TZDs has potentiated an imminent need to come up with newer agents that act through this pathway. Several newer derivatives having TZD scaffold have been designed using structure based drug designing technique and computational tools and tested for their PPAR binding affinity and efficacy in combating T2D and some have shown promising activities. This review would focus on the role of PPARs in the management of T2D; recently reported TZD derivatives which acted as agonists of PPAR- γ and its subtypes and are potentially useful in the new drug discovery for the disease.

Docosahexaenoic acid inhibits hepatic stellate cell activation to attenuate liver fibrosis in a PPARγ-dependent manner

Docosahexaenoic acid (DHA) has been found to have a hepatoprotective effect. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in DHA regulation of liver fibrosis. DHA was found to inhibit hepatic stellate cell (HSC)-LX2 cell viability and downregulate marker proteins of HSC activation. Furthermore, DHA induced cell cycle arrest at G1 phase in HSCs. Antagonism of PPARγ by GW9662 abrogated the effects of DHA on HSCs. Computer-aided molecular docking predicted that DHA bound to PPARγ via hydrogen bonding with residues Ser289, His323, Tyr473, and His499. We overexpressed Ser289 mutant PPARγ in HSC-LX2 cells and investigated fibrotic marker modulation, and found that DHA effects on HSCs were diminished. Thus, bonding with the Ser289 residue might be indispensable for DHA to activate PPARγ to exert its inhibiting effect on activated HSCs. Last, data from a CCl4-treated mouse model confirmed that PPARγ activation was required for DHA to attenuate liver fibrosis.

The effects of a high cholesterol diet on AT1 signaling during pregnancy

Current therapies for pregnancy-related hypertension and its complications remain inadequate, although an increasing role for maternal susceptibility is becoming evident. Systemic vascular dysfunction in response to imbalances in angiogenic, inflammatory, and constricting factors is implicated in the pathogenesis of gestational hypertension, and growing evidence now links these factors with maternal metabolism. In particular, the crucial role of peroxisome proliferator-activated receptors (PPARs) in maternal vascular adaptation provides further insights into how obesity and gestational diabetes may be linked to pregnancy-induced hypertension and preeclampsia. This is especially important given the rapidly growing prevalence of obesity during pregnancy, and highlights a new approach to treat pregnancy-related hypertension and its complications.

Role of peroxisome proliferator-activated receptors in the control of alcohol dependence and concomitant liver pathology

The article is aimed to summarize the scattered data on the role of peroxisome proliferator-activated receptors (PPAR) and the possibility of using PPAR’s agonists for treatment of alcohol dependence and alcoholic liver disease. Earlier it was shown that some PPAR agonists can reduce ethanol consumption and preference in rodents. Several hypotheses considering the antialcoholic activity of PPAR agonists and the roles of PPAR in the development of alcohol dependence were discussed. In light of these data, the therapeutic potential of PPARs agonists as an agent for the treatment of alcoholism, has been reviewed.

Research progress on the role of peroxisome proliferator-activated receptors α in myocardial energy metabolism

大多数心脏疾病是由于心肌能量代谢不良适应而加剧、进展的，而过氧化物酶体增殖物激活受体（PPAR）α可在基因表达水平调控心肌能量代谢，影响心肌脂肪酸和葡萄糖代谢。该文总结了PPARα对心肌能量代谢的调节机制，讨论了其表达的调控机制及其信号通路在病理状态下对心肌能量代谢方式的影响。.

Alterations in protein expression patterns of spinal peroxisome proliferator-activated receptors after spinal cord injury

ABSTRACTObjectives: Peroxisome proliferator-activated receptors (PPARs) control wound healing processes in damaged tissues. PPAR agonists have neuroprotective effects in spinal cord injury (SCI); however, isotype-specific roles of PPARs are not well understood. Therefore, we evaluated protein expression changes for three isotypes of PPARs at different time points and locations relative to the epicenter after SCI in rats.Methods: A 10-g rod was dropped on the spinal cord which located at the T10 vertebra of rats from a height of 6.25, 12.5, or 50 mm using New York University impactor. We collected the spinal cord at 6, 12, 24, and 72 h and 1, 3, and 5 weeks after SCI. The protein expression of PPARs was analyzed using western blot.Results: The protein expression of PPAR-α declined gradually up to 5 weeks at the epicenter. PPAR-β/δ expression increased from 3 days to 5 weeks at the caudal region, but decreased at the epicenter in the severe injury group. PPAR-γ expression increased significantly at all regions in all three injury groups up to 5 weeks after SCI and increased to a greater extent in the severe injury group. In addition, PPAR-β/δ controlled protein expression of PPAR-α positively, and -γ negatively.Conclusions: The present results suggest that different PPAR isotypes have varied protein expression patterns at the epicenter and in adjacent regions after SCI. Our results suggest that PPARs may have overlapping but distinct roles. These findings will be useful for further studies investigating PPARs in neurological disorders including SCI.

Pharmacological PPARβ/δ activation upregulates VLDLR in hepatocytes

The very low-density lipoprotein receptor (VLDLR) plays an important function in the control of serum triglycerides and in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the role of peroxisome proliferator-activated receptor (PPAR)β/δ activation in hepatic VLDLR regulation. Treatment of mice fed a high-fat diet with the PPARβ/δ agonist GW501516 increased the hepatic expression of Vldlr. Similarly, exposure of human Huh-7 hepatocytes to GW501516 increased the expression of VLDLR and triglyceride accumulation, the latter being prevented by VLDLR knockdown. Finally, treatment with another PPARβ/δ agonist increased VLDLR levels in the liver of wild-type mice, but not PPARβ/δ-deficient mice, confirming the regulation of hepatic VLDLR by this nuclear receptor. Our results suggest that upregulation of hepatic VLDLR by PPARβ/δ agonists might contribute to the hypolipidemic effect of these drugs by increasing lipoprotein delivery to the liver. Overall, these findings provide new effects by which PPARβ/δ regulate VLDLR levels and may influence serum triglyceride levels and NAFLD development.

Pharmacological PPARβ/δ activation upregulates VLDLR in hepatocytes

The very low-density lipoprotein receptor (VLDLR) plays an important function in the control of serum triglycerides and in the development of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the role of peroxisome proliferator-activated receptor (PPAR)β/δ activation in hepatic VLDLR regulation. Treatment of mice fed a high-fat diet with the PPARβ/δ agonist GW501516 increased the hepatic expression of Vldlr. Similarly, exposure of human Huh-7 hepatocytes to GW501516 increased the expression of VLDLR and triglyceride accumulation, the latter being prevented by VLDLR knockdown. Finally, treatment with another PPARβ/δ agonist increased VLDLR levels in the liver of wild-type mice, but not PPARβ/δ-deficient mice, confirming the regulation of hepatic VLDLR by this nuclear receptor. Our results suggest that upregulation of hepatic VLDLR by PPARβ/δ agonists might contribute to the hypolipidemic effect of these drugs by increasing lipoprotein delivery to the liver. Overall, these findings provide new effects by which PPARβ/δ regulate VLDLR levels and may influence serum triglyceride levels and NAFLD development.

Cardiomyopathy in obesity, insulin resistance and diabetes.

The prevalence of obesity, insulin resistance and diabetes is increasing rapidly. Most patients with these disorders have hypertriglyceridaemia and increased plasma levels of fatty acids, which are taken up and stored in lipid droplets in the heart. Intramyocardial lipids that exceed the capacity for storage and oxidation can be lipotoxic and induce non-ischaemic and non-hypertensive cardiomyopathy, termed diabetic or lipotoxic cardiomyopathy. The clinical features of diabetic cardiomyopathy are cardiac hypertrophy and diastolic dysfunction, which lead to heart failure, especially heart failure with preserved ejection fraction. Although the pathogenesis of the cardiomyopathy is multifactorial, diabetic dyslipidaemia and intramyocardial lipid accumulation are the key pathological features, triggering cellular signalling and modifications of proteins and lipids via generation of toxic metabolic intermediates. Most clinical studies have shown no beneficial effect of anti-diabetic agents and statins on outcomes in heart failure patients without atherosclerotic diseases, indicating the importance of identifying underlying mechanisms and early interventions for diabetic cardiomyopathy. Here, we summarize the molecular mechanisms of diabetic cardiomyopathy, with a special emphasis on cardiac lipotoxicity, and discuss the role of peroxisome proliferator-activated receptor α and dysregulated fatty acid metabolism as potential therapeutic targets.