The Peroxisome Proliferator-Activated Receptor-γ Agonist Pioglitazone Represses Inflammation in a Peroxisome Proliferator-Activated Receptor-α–Dependent Manner In Vitro and In Vivo in Mice

The peroxisome proliferator-activated receptor- (PPAR) plays a key role in lipid metabolism and energy combustion. Chronic activation of PPAR in rodents leads to the development of hepatocellular carcinomas. The ability of PPAR to induce expression of its target genes depends on Mediator, an evolutionarily conserved complex of cofactors and, in particular, the subunit 1 (Med1) of this complex. Here, we report the identification and characterization of PPAR-interacting cofactor (PRIC)-295 (PRIC295), a novel coactivator protein, and show that it interacts with the Med1 and Med24 subunits of the Mediator complex. PRIC295 contains 10 LXXLL signature motifs that facilitate nuclear receptor binding and interacts with PPAR and five other members of the nuclear receptor superfamily in a ligand-dependent manner. PRIC295 enhances the transactivation function of PPAR, PPAR, and ER. These data demonstrate that PRIC295 interacts with nuclear receptors such as PPAR and functions as a transcription coactivator underin vitroconditions and may play an important role in mediating the effectsin vivoas a member of the PRIC complex with Med1 and Med24.

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The endocrine disruptor mono-(2-ethylhexyl)phthalate promotes adipocyte differentiation and induces obesity in mice

Bioscience Reports ◽

10.1042/bsr20120042 ◽

2012 ◽

Vol 32 (6) ◽

pp. 619-629 ◽

Cited By ~ 106

Author(s):

Chanjuan Hao ◽

Xuejia Cheng ◽

Hongfei Xia ◽

Xu Ma

Keyword(s):

Target Genes ◽

Adipocyte Differentiation ◽

Cell Model ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Glucose Levels ◽

Ethylhexyl Phthalate

The environmental obesogen hypothesis proposes that exposure to endocrine disruptors during developmental ‘window’ contributes to adipogenesis and the development of obesity. MEHP [mono-(2-ethylhexyl) phthalate], a metabolite of the widespread plasticizer DEHP [di-(2-ethylhexyl) phthalate], has been found in exposed organisms and identified as a selective PPARγ (peroxisome-proliferator-activated receptor γ) modulator. However, implication of MEHP on adipose tissue development has been poorly investigated. In the present study, we show the dose-dependent effects of MEHP on adipocyte differentiation and GPDH (glycerol-3-phosphate dehydrogenase) activity in the murine 3T3-L1 cell model. MEHP induced the expression of PPARγ as well as its target genes required for adipogenesis in vitro. Moreover, MEHP perturbed key regulators of adipogenesis and lipogenic pathway in vivo. In utero exposure to a low dose of MEHP significantly increased b.w. (body weight) and fat pad weight in male offspring at PND (postnatal day) 60. In addition, serum cholesterol, TAG (triacylglycerol) and glucose levels were also significantly elevated. These results suggest that perinatal exposure to MEHP may be expected to increase the incidence of obesity in a sex-dependent manner and can act as a potential chemical stressor for obesity and obesity-related disorders.

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PPARβ/δ Agonist GW501516 Inhibits Tumorigenesis and Promotes Apoptosis of the Undifferentiated Nasopharyngeal Carcinoma C666-1 Cells by Regulating miR-206

Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics ◽

10.3727/096504019x15518706875814 ◽

2019 ◽

Vol 27 (8) ◽

pp. 923-933 ◽

Cited By ~ 1

Author(s):

Linglan Gu ◽

Yi Shi ◽

Weimin Xu ◽

Yangyang Ji

Keyword(s):

Nasopharyngeal Carcinoma ◽

Critical Role ◽

Current Data ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Promoting Effect ◽

Apoptotic Pathway ◽

Peroxisome Proliferator Activated Receptor

In previous investigations, we reported that peroxisome proliferator-activated receptor β/δ (PPARβ/δ) activation by GW501516 inhibits proliferation and promotes apoptosis in the undifferentiated C666-1 nasopharyngeal carcinoma (NPC) cells by modulating caspase-dependent apoptotic pathway. In the present study, the mechanism by which GW501516 induces apoptosis was explored from the perspective of microRNA (miRNA) expression. Among the assayed miRNAs that were involved in regulating the expression of antiapoptotic protein Bcl-2, miR-206 was increased significantly and specifically by GW501516 in C666-1 cells at both the in vitro level and at the in vivo xenograft samples. The induction on miR-206 expression caused by GW501516 was capable of being antagonized by the PPARβ/δ antagonist GSK3787 and AMPK antagonist dorsomorphin in C666-1 cells. GW501516’s suppression on the growth and apoptosis of C666-1 cells was found to be dependent on the presence of miR-206. miR-206 overexpression resulted in suppressed proliferation and colony formation ability, and further triggered increased apoptosis in C666-1 cells in a caspase-dependent manner. The expression of cleaved caspase 3 and caspase 9, and the ratio of Bax to Bcl-2 were elevated remarkably by miR-206. Consistent with the in vitro result, miR-206 was corroborated to suppress the ectopic NPC xenograft tumorigenesis that derived from the C666-1 cells in BALB/c nu/nu mice. Taken together, the current data demonstrated that miR-206 plays a critical role in the direct apoptosis-promoting effect induced by GW501516 in C666-1 cells. Furthermore, the emphasized tumor-suppressive role of miR-206 in the C666-1 cells indicates that it has the potential to provide a new therapeutic approach for the undifferentiated NPC.

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Anti-Diabetic Countermeasures Against Tobacco Smoke-Dependent Cerebrovascular Toxicity: Use and Effect of Rosiglitazone

International Journal of Molecular Sciences ◽

10.3390/ijms20174225 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4225 ◽

Cited By ~ 5

Author(s):

Farzane Sivandzade ◽

Luca Cucullo

Keyword(s):

Cerebrovascular Disorders ◽

Protective Role ◽

Peroxisome Proliferator ◽

Related Factor ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Cerebrovascular Dysfunction ◽

Public Health Hazards

Tobacco smoking (TS) is one of the most addictive habit sand a main public health hazards, impacting the vascular endothelium through oxidative stress (OS) stimuli, exposure to nicotine, and smoking-induced inflammation in a dose-dependent manner. Increasing evidence also suggested that TS increases glucose intolerance and the risk factor of developing type-2 diabetes mellitus (2DM), which, along with TS, is connected to blood–brain barrier (BBB) injuries, and heightens the risk of cerebrovascular disorders. Although the exact mechanism of rosiglitazone (RSG) is unknown, our previous in vitro work showed how RSG, an oral anti-diabetic drug belonging to the family of thiazolidinedione class, can protect BBB integrity through enhancement of nuclear factor erythroid 2-related factor (Nrf2) activity. Herein, we have validated the protective role of rosiglitazone against TS-induced BBB impairment in vivo. Our results revealed that RSG as a peroxisome proliferator-activated receptor gamma (PPARγ), activates counteractive mechanisms primarily associated with the upregulation of Nrf2 and PPARγ pathways which reduce TS-dependent toxicity at the cerebrovascular level. In line with these findings, our results show that RSG reduces inflammation and protects BBB integrity. In conclusion, RSG offers a novel and promising therapeutic application to reduce TS-induced cerebrovascular dysfunction through activation of the PPARγ-dependent and/or PPARγ-independent Nrf2 pathway.

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Peroxisome Proliferator-Activated Receptor Alpha Mediates the Beneficial Effects of Atorvastatin in Experimental Colitis

Frontiers in Immunology ◽

10.3389/fimmu.2021.618365 ◽

2021 ◽

Vol 12 ◽

Author(s):

Paulo José Basso ◽

Helioswilton Sales-Campos ◽

Viviani Nardini ◽

Murillo Duarte-Silva ◽

Vanessa Beatriz Freitas Alves ◽

...

Keyword(s):

Intestinal Inflammation ◽

Experimental Colitis ◽

Predictive Biomarker ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Beneficial Effects ◽

Anti Inflammatory

The current therapeutic options for Inflammatory Bowel Diseases (IBD) are limited. Even using common anti-inflammatory, immunosuppressive or biological therapies, many patients become unresponsive to the treatments, immunosuppressed or unable to restrain secondary infections. Statins are cholesterol-lowering drugs with non-canonical anti-inflammatory properties, whose underlying mechanisms of action still remain poorly understood. Here, we described that in vitro atorvastatin (ATO) treatment was not toxic to splenocytes, constrained cell proliferation and modulated IL-6 and IL-10 production in a dose-dependent manner. Mice exposed to dextran sulfate sodium (DSS) for colitis induction and treated with ATO shifted their immune response from Th17 towards Th2, improved the clinical and histological aspects of intestinal inflammation and reduced the number of circulating leukocytes. Both experimental and in silico analyses revealed that PPAR-α expression is reduced in experimental colitis, which was reversed by ATO treatment. While IBD patients also downregulate PPAR-α expression, the responsiveness to biological therapy relied on the restoration of PPAR-α levels. Indeed, the in vitro and in vivo effects induced by ATO treatment were abrogated in Ppara-/- mice or leukocytes. In conclusion, the beneficial effects of ATO in colitis are dependent on PPAR-α, which could also be a potential predictive biomarker of therapy responsiveness in IBD.

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Estrogen receptor mediates the effects of pseudoprotodiocsin on adipogenesis in 3T3-L1 cells

AJP Cell Physiology ◽

10.1152/ajpcell.00538.2009 ◽

2010 ◽

Vol 299 (1) ◽

pp. C128-C138 ◽

Cited By ~ 28

Author(s):

Jing Xiao ◽

Nai-li Wang ◽

Bing Sun ◽

Guo-ping Cai

Keyword(s):

Leucine Zipper ◽

Binding Protein ◽

Adipogenic Differentiation ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Underlying Mechanisms

Estrogen receptors (ERs) play a pivotal role in adipogenesis; therefore, compounds targeting ERs may also affect fat formation. Recent studies have shown that the Dioscorea plant (commonly called yam) exhibits an antiobesity effect on rodents. However, the active compounds and underlying mechanisms responsible for this effect are not yet fully understood. We evaluated the effects of pseudoprotodiocsin (PPD), a steroid saponin from Dioscorea nipponica Makino (a type of Dioscorea), on adipogenesis and the mechanisms underlying this effect. Treatment with PPD at the onset of adipogenic differentiation resulted in significantly decreased adipogenesis in both in vitro and in vivo experimental systems. An increased amount of ERα mRNA, protein, and the accumulation of ERα in the nucleus were also observed. However, the expression pattern of ERβ was not altered. Furthermore, the antiadipogenic effect of PPD was found to be ER dependent. It was also accompanied by the decreased expression of several genes involved in adipogenesis, including lipoprotein lipase (LPL), leptin, CCAAT/enhancer-binding-protein-α (C/EBPα), and peroxisome proliferator-activated receptor-γ (PPARγ), as well as the increased expression of some negative factors of adipogenesis, including preadipocyte factor 1 (Pre-1), GATA-binding protein 2 (GATA-2), GC-induced leucine-zipper protein (GILZ), and C/EBP homologous protein (CHOP-10). In addition to its estrogenic action, PPD also abolished the p38 mitogen-activated protein kinase (p38 MAPK) activation. Our results suggest that PPD inhibits adipogenesis in an ER-dependent manner and induces the expression of ERα. These findings may provide a lead toward a novel agent that can be used to treat obesity.

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Interaction with MEK Causes Nuclear Export and Downregulation of Peroxisome Proliferator-Activated Receptor γ

Molecular and Cellular Biology ◽

10.1128/mcb.00601-06 ◽

2006 ◽

Vol 27 (3) ◽

pp. 803-817 ◽

Cited By ~ 125

Author(s):

Elke Burgermeister ◽

Dana Chuderland ◽

Tamar Hanoch ◽

Markus Meyer ◽

Mordechai Liscovitch ◽

...

Keyword(s):

Nuclear Export ◽

Intracellular Signaling ◽

Subcellular Fractionation ◽

Mitogen Activated Protein Kinase ◽

Peroxisome Proliferator ◽

Dependent Manner ◽

Peroxisome Proliferator Activated Receptor ◽

Nuclear Shuttling

ABSTRACT The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) cascade plays a central role in intracellular signaling by many extracellular stimuli. One target of the ERK cascade is peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that promotes differentiation and apoptosis. It was previously demonstrated that PPARγ activity is attenuated upon mitogenic stimulation due to phosphorylation of its Ser84 by ERKs. Here we show that stimulation by tetradecanoyl phorbol acetate (TPA) attenuates PPARγ's activity in a MEK-dependent manner, even when Ser84 is mutated to Ala. To elucidate the mechanism of attenuation, we found that PPARγ directly interacts with MEKs, which are the activators of ERKs, but not with ERKs themselves, both in vivo and in vitro. This interaction is facilitated by MEKs' phosphorylation and is mediated by the basic D domain of MEK1 and the AF2 domain of PPARγ. Immunofluorescence microscopy and subcellular fractionation revealed that MEK1 exports PPARγ from the nucleus, and this finding was supported by small interfering RNA knockdown of MEK1 and use of a cell-permeable interaction-blocking peptide, which prevented TPA-induced export of PPARγ from the nucleus. Thus, we show here a novel mode of downregulation of PPARγ by its MEK-dependent redistribution from the nucleus to the cytosol. This unanticipated role for the stimulation-induced nuclear shuttling of MEKs shows that MEKs can regulate additional signaling components besides the ERK cascade.

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Adipocyte PHLPP2 inhibition prevents obesity-induced fatty liver

Nature Communications ◽

10.1038/s41467-021-22106-2 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

KyeongJin Kim ◽

Jin Ku Kang ◽

Young Hoon Jung ◽

Sang Bae Lee ◽

Raffaela Rametta ◽

...

Keyword(s):

Fatty Liver ◽

Whole Body ◽

Acid Oxidation ◽

Chow Diet ◽

Peroxisome Proliferator ◽

Obese Mice ◽

Ph Domain ◽

Peroxisome Proliferator Activated Receptor

AbstractIncreased adiposity confers risk for systemic insulin resistance and type 2 diabetes (T2D), but mechanisms underlying this pathogenic inter-organ crosstalk are incompletely understood. We find PHLPP2 (PH domain and leucine rich repeat protein phosphatase 2), recently identified as the Akt Ser473 phosphatase, to be increased in adipocytes from obese mice. To identify the functional consequence of increased adipocyte PHLPP2 in obese mice, we generated adipocyte-specific PHLPP2 knockout (A-PHLPP2) mice. A-PHLPP2 mice show normal adiposity and glucose metabolism when fed a normal chow diet, but reduced adiposity and improved whole-body glucose tolerance as compared to Cre- controls with high-fat diet (HFD) feeding. Notably, HFD-fed A-PHLPP2 mice show increased HSL phosphorylation, leading to increased lipolysis in vitro and in vivo. Mobilized adipocyte fatty acids are oxidized, leading to increased peroxisome proliferator-activated receptor alpha (PPARα)-dependent adiponectin secretion, which in turn increases hepatic fatty acid oxidation to ameliorate obesity-induced fatty liver. Consistently, adipose PHLPP2 expression is negatively correlated with serum adiponectin levels in obese humans. Overall, these data implicate an adipocyte PHLPP2-HSL-PPARα signaling axis to regulate systemic glucose and lipid homeostasis, and suggest that excess adipocyte PHLPP2 explains decreased adiponectin secretion and downstream metabolic consequence in obesity.

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The lipid-lowering drug fenofibrate combined with si-HOTAIR can effectively inhibit the proliferation of gliomas

BMC Cancer ◽

10.1186/s12885-021-08417-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Wei Zhu ◽

Hongyang Zhao ◽

Fenfen Xu ◽

Bin Huang ◽

Xiaojing Dai ◽

...

Keyword(s):

Noncoding Rna ◽

Glioma Cells ◽

Lipid Lowering ◽

Fibric Acid Derivative ◽

Peroxisome Proliferator ◽

Glioma Invasion ◽

Peroxisome Proliferator Activated Receptor ◽

Lncrna Hotair

Abstract Background Fenofibrate is a fibric acid derivative known to have a lipid-lowering effect. Although fenofibrate-induced peroxisome proliferator-activated receptor alpha (PPARα) transcription activation has been shown to play an important role in the malignant progression of gliomas, the underlying mechanisms are poorly understood. Methods In this study, we analyzed TCGA database and found that there was a significant negative correlation between the long noncoding RNA (lncRNA) HOTAIR and PPARα. Then, we explored the molecular mechanism by which lncRNA HOTAIR regulates PPARα in cell lines in vitro and in a nude mouse glioma model in vivo and explored the effect of the combined application of HOTAIR knockdown and fenofibrate treatment on glioma invasion. Results For the first time, it was shown that after knockdown of the expression of HOTAIR in gliomas, the expression of PPARα was significantly upregulated, and the invasion and proliferation ability of gliomas were obviously inhibited. Then, glioma cells were treated with both the PPARα agonist fenofibrate and si-HOTAIR, and the results showed that the proliferation and invasion of glioma cells were significantly inhibited. Conclusions Our results suggest that HOTAIR can negatively regulate the expression of PPARα and that the combination of fenofibrate and si-HOTAIR treatment can significantly inhibit the progression of gliomas. This introduces new ideas for the treatment of gliomas.

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The Novel Role of PGC1α in Bone Metabolism

International Journal of Molecular Sciences ◽

10.3390/ijms22094670 ◽

2021 ◽

Vol 22 (9) ◽

pp. 4670

Author(s):

Cinzia Buccoliero ◽

Manuela Dicarlo ◽

Patrizia Pignataro ◽

Francesco Gaccione ◽

Silvia Colucci ◽

...

Keyword(s):

Bone Metabolism ◽

Osteoblastic Differentiation ◽

In Vivo Studies ◽

Peroxisome Proliferator ◽

Sirtuin 3 ◽

Peroxisome Proliferator Activated Receptor ◽

Increased Risk

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) is a protein that promotes transcription of numerous genes, particularly those responsible for the regulation of mitochondrial biogenesis. Evidence for a key role of PGC1α in bone metabolism is very recent. In vivo studies showed that PGC1α deletion negatively affects cortical thickness, trabecular organization and resistance to flexion, resulting in increased risk of fracture. Furthermore, in a mouse model of bone disease, PGC1α activation stimulates osteoblastic gene expression and inhibits atrogene transcription. PGC1α overexpression positively affects the activity of Sirtuin 3, a mitochondrial nicotinammide adenina dinucleotide (NAD)-dependent deacetylase, on osteoblastic differentiation. In vitro, PGC1α overexpression prevents the reduction of mitochondrial density, membrane potential and alkaline phosphatase activity caused by Sirtuin 3 knockdown in osteoblasts. Moreover, PGC1α influences the commitment of skeletal stem cells towards an osteogenic lineage, while negatively affects marrow adipose tissue accumulation. In this review, we will focus on recent findings about PGC1α action on bone metabolism, in vivo and in vitro, and in pathologies that cause bone loss, such as osteoporosis and type 2 diabetes.

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