RESUMO
Various liver diseases pose great threats to humans. Although the etiologies of these liver diseases are quite diverse, they share similar pathologic phenotypes and molecular mechanisms such as oxidative stress, lipid and glucose metabolism disturbance, hepatic Kupffer cell (KC) proinflammatory polarization and inflammation, insulin resistance, and hepatic stellate cell (HSC) activation and proliferation. Peroxisome proliferator-activated receptor ß/δ (PPARß/δ) is expressed in various types of liver cells with relatively higher expression in KCs and HSCs. Accumulating evidence has revealed the versatile functions of PPARß/δ such as controlling lipid homeostasis, inhibiting inflammation, regulating glucose metabolism, and restoring insulin sensitivity, suggesting that PPARß/δ may serve as a potential molecular drug target for various liver diseases. This article aims to provide a concise review of the structure, expression pattern and biological functions of PPARß/δ in the liver and its roles in various liver diseases, and to discuss potential future research perspectives.
Assuntos
Hepatopatias , PPAR delta , PPAR beta , Humanos , PPAR beta/fisiologia , PPAR beta/metabolismo , PPAR delta/fisiologia , PPAR delta/metabolismo , Hepatopatias/metabolismo , Hepatopatias/tratamento farmacológico , Terapia de Alvo Molecular , Resistência à InsulinaRESUMO
Peroxisome proliferator-activated receptors [PPARs; PPARα, PPARß/δ (also known as PPARδ), and PPARγ] widely recognized for their important role in glucose/lipid homeostasis, have recently received significant attention due to their additional anti-inflammatory and neuroprotective effects. Several newly developed PPAR agonists have shown high selectivity for specific PPAR isoforms in vitro and in vivo, offering the potential to achieve desired therapeutic outcomes while reducing the risk of adverse effects. In this review, we discuss the latest preclinical and clinical studies of the activation of PPARs by synthetic, natural, and isoform-specific (full, partial, and dual) agonists for the treatment of neuroinflammatory diseases, including HIV-associated neurocognitive disorders (HAND), Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and cerebral ischemia.
Assuntos
PPAR delta , PPAR beta , Humanos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/fisiologia , Doenças Neuroinflamatórias , PPAR delta/agonistas , PPAR delta/fisiologia , PPAR beta/fisiologia , PPAR alfa/agonistas , PPAR alfa/fisiologia , PPAR gama/agonistas , PPAR gama/fisiologia , HipoglicemiantesRESUMO
Peroxisome proliferator-activated receptors (PPARs) are nuclear hormone receptors expressed in the skin. Three PPAR isotypes, α (NRC1C1), ß or δ (NRC1C2) and γ (NRC1C3), have been identified. After activation through ligand binding, PPARs heterodimerize with the 9-cis-retinoic acid receptor (RXR), another nuclear hormone receptor, to bind to specific PPAR-responsive elements in regulatory regions of target genes mainly involved in organogenesis, cell proliferation, cell differentiation, inflammation and metabolism of lipids or carbohydrates. Endogenous PPAR ligands are fatty acids and fatty acid metabolites. In past years, much emphasis has been given to PPARα and γ in skin diseases. PPARß/δ is the least studied PPAR family member in the skin despite its key role in several important pathways regulating inflammation, keratinocyte proliferation and differentiation, metabolism and the oxidative stress response. This review focuses on the role of PPARß/δ in keratinocytes and its involvement in psoriasis and atopic dermatitis. Moreover, the relevance of targeting PPARß/δ to alleviate skin inflammation is discussed.
Assuntos
Dermatite Atópica/metabolismo , Queratinócitos/metabolismo , PPAR delta/fisiologia , Psoríase/metabolismo , Pele/metabolismo , Anaerobiose , Animais , Dimerização , Eicosanoides/metabolismo , Ácidos Graxos/metabolismo , Glicólise , Humanos , Camundongos , Camundongos Mutantes , Especificidade de Órgãos , Fosforilação , Isoformas de Proteínas/fisiologia , Processamento de Proteína Pós-Traducional , Proteólise , Receptores X de Retinoides/metabolismo , Pele/patologiaRESUMO
α-Amyrin, a natural pentacyclic triterpene, has an antihyperglycemic effect in mice and dual PPARδ/γ action in 3T3-L1 adipocytes, and potential in the control of type 2 diabetes (T2D). About 80% of glucose uptake occurs in skeletal muscle cells, playing a significant role in insulin resistance (IR) and T2D. Peroxisome-proliferator activated receptors (PPARs), in particular PPARδ and PPARγ, are involved in the regulation of lipids and carbohydrates and, along with adenosine-monophosphate (AMP) - activated protein kinase (AMPK) and protein kinase B (Akt), are implicated in translocation of glucose transporter 4 (GLUT4); however, it is still unknown whether α-amyrin can affect these pathways in skeletal muscle cells. Our objective was to determine the action of α-amyrin in PPARδ, PPARγ, AMPK, and Akt in C2C12 myoblasts. The expression of PPARδ, PPARγ, fatty acid transporter protein (FATP), and GLUT4 was quantified using reverse transcription quantitative PCR and Western blot. α-Amyrin increased these markers along with phospho-AMPK (p-AMPK) but not p-Akt. Molecular docking showed that α-amyrin acts as an AMPK-allosteric activator, and may be related to GLUT4 translocation, as evidenced by confocal microscopy. These data support that α-amyrin could have an insulin-mimetic action in C2C12 myoblasts and should be considered as a bioactive molecule for new multitarget drugs with utility in T2D and other metabolic diseases.
Assuntos
Proteínas Quinases Ativadas por AMP/fisiologia , Transportador de Glucose Tipo 4/metabolismo , Mioblastos/efeitos dos fármacos , PPAR delta/fisiologia , PPAR gama/fisiologia , Triterpenos Pentacíclicos/farmacologia , Proteínas Quinases Ativadas por AMP/química , Animais , Células Cultivadas , Proteínas de Transporte de Ácido Graxo/fisiologia , Camundongos , Simulação de Acoplamento Molecular , Mioblastos/metabolismo , Triterpenos Pentacíclicos/química , Transporte Proteico/efeitos dos fármacosRESUMO
BACKGROUND: Dexmedetomidine (Dex) exerts an effective therapeutic role in numerous diseases associated with ischemia/reperfusion (I/R) injury via its anti-apoptosis properties. Therefore, this study explores the cardioprotective effects of Dex in cardiac microvascular endothelial cells (CMECs) in response to oxygen-glucose deprivation and re-oxygenation (OGD/R) injury and its potential mechanism. MATERIAL AND METHODS: CMECs were pretreatment with different concentration of Dex, then exposed to OGD/R. Cell viability was measured with CCK-8 assay. Apoptosis was evaluated by flow cytometry, and apoptosis-related protein was determined by Western blot. Autophagy was assessed by transmission electron microscopy and autophagy-related proteins. Besides, the role peroxisome proliferator-activated receptors (PPARδ) in Dex-mediated anti-apoptosis property was validated with agonist and antagonist. RESULTS: OGD/R significantly decreased cell viability, increased reactive oxygen species, caused disorder of autophagy, and increased apoptosis in CMECs. Dex enhanced the viability of the OGD/R-treated CMECs and effectively decreased reactive oxygen species production. Autophagy in CMECs was activated by Dex, as evidenced by the increase in the ratio of LC3B-II/I, expression level of Beclin1 and number of autophagosomes in the OGD/R-induced CMECs. The mechanistic investigation indicated that PPARδ antagonist GW501516 aggravated cell damage following OGD/R, while PPARδ agonist GW6471 partly abolished the Dex-mediated protective effects. CONCLUSIONS: Dex activated the PPARδ-AMPK-PGC-1α pathway-mediated autophagy in CMECs, therefore to inhibit excessive apoptosis induced by OGD/R. Dex may potentially be a therapeutic intervention for myocardial I/R injury.
Assuntos
Vasos Coronários , Dexmedetomidina , Endotélio Vascular/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica , PPAR delta , Substâncias Protetoras , Proteínas Quinases Ativadas por AMP/fisiologia , Agonistas de Receptores Adrenérgicos alfa 2/farmacologia , Autofagia/efeitos dos fármacos , Autofagia/fisiologia , Células Cultivadas , Circulação Coronária/efeitos dos fármacos , Vasos Coronários/efeitos dos fármacos , Vasos Coronários/fisiopatologia , Dexmedetomidina/farmacologia , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Humanos , Microcirculação/efeitos dos fármacos , Microvasos/efeitos dos fármacos , Microvasos/patologia , Microvasos/fisiopatologia , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , PPAR delta/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio , Transdução de SinaisRESUMO
Peroxisome proliferator-activated receptor (PPAR) ß/δ belongs to the family of hormone and lipid-activated nuclear receptors, which are involved in metabolism of long-chain fatty acids, cholesterol, and sphingolipids. Similar to PPAR-α and PPAR-γ, PPAR-ß/δ also acts as a transcription factor activated by dietary lipids and endogenous ligands, such as long-chain saturated and polyunsaturated fatty acids, and selected lipid metabolic products, such as eicosanoids, leukotrienes, lipoxins, and hydroxyeicosatetraenoic acids. Together with other PPARs, PPAR-ß/δ displays transcriptional activity through interaction with retinoid X receptor (RXR). In general, PPARs have been shown to regulate cell differentiation, proliferation, and development and significantly modulate glucose, lipid metabolism, mitochondrial function, and biogenesis. PPAR-ß/δ appears to play a special role in inflammatory processes and due to its proangiogenic and anti-/pro-carcinogenic properties, this receptor has been considered as a therapeutic target for treating metabolic syndrome, dyslipidemia, carcinogenesis, and diabetes. Until now, most studies were carried out in the peripheral organs, and despite of its presence in brain cells and in different brain regions, its role in neurodegeneration and neuroinflammation remains poorly understood. This review is intended to describe recent insights on the impact of PPAR-ß/δ and its novel agonists on neuroinflammation and neurodegenerative disorders, including Alzheimer's and Parkinson's, Huntington's diseases, multiple sclerosis, stroke, and traumatic injury. An important goal is to obtain new insights to better understand the dietary and pharmacological regulations of PPAR-ß/δ and to find promising therapeutic strategies that could mitigate these neurological disorders.
Assuntos
Doenças Neurodegenerativas/fisiopatologia , PPAR delta/fisiologia , PPAR beta/fisiologia , Antineoplásicos/uso terapêutico , Isquemia Encefálica/tratamento farmacológico , Isquemia Encefálica/metabolismo , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/metabolismo , Sistemas de Liberação de Medicamentos , Células Endoteliais/metabolismo , Glioma/tratamento farmacológico , Glioma/metabolismo , Inflamação , Metabolismo dos Lipídeos , Neuroblastoma/tratamento farmacológico , Neuroblastoma/metabolismo , Doenças Neurodegenerativas/tratamento farmacológico , Neuroglia/metabolismo , Neurônios/metabolismo , Fármacos Neuroprotetores/uso terapêutico , Estresse Oxidativo , PPAR delta/agonistas , PPAR beta/agonistas , Receptores X de Retinoides/fisiologia , Transdução de Sinais , Transcrição GênicaRESUMO
A growing body of experimental evidence strongly suggests that cannabidiolic acid (CBDA), a major component of the fiber-type cannabis plant, exerts a variety of biological activities. We have reported that CBDA can abrogate cyclooxygenase-2 (COX-2) expression and its enzymatic activity. It is established that aberrant expression of COX-2 correlates with the degree of malignancy in breast cancer. Although the reduction of COX-2 expression by CBDA offers an attractive medicinal application, the molecular mechanisms underlying these effects have not fully been established. It has been reported that COX-2 expression is positively controlled by peroxisome proliferator-activated receptor ß/δ (PPARß/δ) in some cancerous cells, although there is "no" modulatory element for PPARß/δ on the COX-2 promoter. No previous studies have examined whether an interaction between PPARß/δ-mediated signaling and COX-2 expression exists in MDA-MB-231 cells. We confirmed, for the first time, that COX-2 expression is positively modulated by PPARß/δ-mediated signaling in MDA-MB-231 cells. CBDA inhibits PPARß/δ-mediated transcriptional activation stimulated by the PPARß/δ-specific agonist, GW501516. Furthermore, the disappearance of cellular actin stress fibers, a hallmark of PPARß/δ and COX-2 pathway activation, as evoked by the GW501516, was effectively reversed by CBDA. Activator protein-1 (AP-1)-driven transcriptional activity directly involved in the regulation of COX-2 was abrogated by the PPARß/δ-specific inverse agonists (GSK0660/ST-247). Thus, it is implicated that there is positive interaction between PPARß/δ and AP-1 in regulation of COX-2. These data support the concept that CBDA is a functional down-regulator of COX-2 through the abrogation of PPARß/δ-related signaling, at least in part, in MDA-MB-231 cells.
Assuntos
Neoplasias da Mama/enzimologia , Canabinoides/farmacologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Expressão Gênica/genética , PPAR delta/fisiologia , Feminino , Humanos , PPAR delta/agonistas , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Sulfonas/farmacologia , Tiazóis/farmacologia , Tiofenos/farmacologia , Fator de Transcrição AP-1/fisiologia , Células Tumorais CultivadasRESUMO
BACKGROUND: Although depression is the leading cause of disability worldwide, its pathophysiology is poorly understood. Our previous study showed that hippocampal peroxisome proliferator-activated receptor δ (PPARδ) overexpression displays antidepressive effect and enhances hippocampal neurogenesis during chronic stress. Herein, we further extended our curiosity to investigate whether downregulating PPARδ could cause depressive-like behaviors through downregulation of neurogenesis. METHODS: Stereotaxic injection of lentiviral vector, expressing short hairpin RNA complementary to the coding exon of PPARδ, was done into the bilateral dentate gyri of the hippocampus, and the depression-like behaviors were observed in mice. Additionally, hippocampal neurogenesis, brain-derived neurotrophic factor and cAMP response element-binding protein were measured both in vivo and in vitro. RESULTS: Hippocampal PPARδ knockdown caused depressive-like behaviors and significantly decreased neurogenesis, neuronal differentiation, levels of mature brain-derived neurotrophic factor and phosphorylated cAMP response element-binding protein in the hippocampus. In vitro study further confirmed that PPARδ knockdown could inhibit proliferation and differentiation of neural stem cells. Furthermore, these effects were mimicked by repeated systemic administration of a PPARδ antagonist, GSK0660 (1 or 3 mg/kg i.p. for 21 d). CONCLUSIONS: These findings suggest that downregulation of hippocampal PPARδ is associated with depressive behaviors in mice through an inhibitory effect on cAMP response element-binding protein/brain-derived neurotrophic factor-mediated adult neurogenesis in the hippocampus, providing new insights into the pathogenesis of depression.
Assuntos
Comportamento Animal/fisiologia , Giro Denteado/metabolismo , Depressão/fisiopatologia , Neurogênese/efeitos dos fármacos , PPAR delta/fisiologia , Animais , Comportamento Animal/efeitos dos fármacos , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Proteína de Ligação a CREB/metabolismo , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Giro Denteado/efeitos dos fármacos , Depressão/induzido quimicamente , Regulação para Baixo/efeitos dos fármacos , Técnicas de Silenciamento de Genes , Masculino , Camundongos , Células-Tronco Neurais/efeitos dos fármacos , PPAR delta/genética , RNA Interferente Pequeno/farmacologia , Sulfonas/farmacologia , Tiofenos/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Impaired endothelium-dependent relaxation (EDR) is a hallmark of endothelial dysfunction. A deficiency of tetrahydrobiopterin (BH4 ) causes endothelial NOS to produce ROS rather than NO. PPARδ is an emerging target for pharmacological intervention of endothelial dysfunction. Thus, the present study examined the role of PPARδ in the regulation of dihydrofolate reductase (DHFR), a key enzyme in the BH4 salvage pathway. EXPERIMENTAL APPROACH: Gene expression was measured by using qRT-PCR and western blotting. Biopterins and ROS were determined by using HPLC. NO was measured with fluorescent dye and electron paramagnetic resonance spectroscopy. Vasorelaxation was measured by Multi Myograph System. KEY RESULTS: The PPARδ agonist GW501516 increased DHFR and BH4 levels in endothelial cells (ECs). The effect was blocked by PPARδ antagonist GSK0660. Chromatin immunoprecipitation identified PPAR-responsive elements within the 5'-flanking region of the human DHFR gene. The promoter activity was examined with luciferase assays using deletion reporters. Importantly, DHFR expression was suppressed by palmitic acid (PA, a saturated fatty acid) but increased by docosahexaenoic acid (DHA, a polyunsaturated fatty acid). GSK0660 prevented DHA-induced increased DHFR expression. Conversely, the suppressive effect of PA was mitigated by GW501516. In mouse aortae, GW501516 ameliorated the PA-impaired EDR. However, this vasoprotective effect was attenuated by DHFR siRNA or methotrexate. In EC-specific Ppard knockout mice, GW501516 failed to improve vasorelaxation. CONCLUSION AND IMPLICATIONS: PPARδ prevented endothelial dysfunction by increasing DHFR and activating the BH4 salvage pathway. These results provide a novel mechanism for the protective roles of PPARδ against vascular diseases.
Assuntos
Biopterinas/análogos & derivados , PPAR delta/fisiologia , Tetra-Hidrofolato Desidrogenase/fisiologia , Animais , Aorta/efeitos dos fármacos , Aorta/fisiologia , Biopterinas/fisiologia , Células Cultivadas , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Expressão Gênica/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , PPAR delta/agonistas , PPAR delta/antagonistas & inibidores , PPAR delta/genética , Sulfonas/farmacologia , Tetra-Hidrofolato Desidrogenase/genética , Tiazóis/farmacologia , Tiofenos/farmacologia , Artérias Torácicas/efeitos dos fármacos , Artérias Torácicas/fisiologiaRESUMO
Sirtuin 1 (SIRT1) activation reduces oxidative stress, inhibits inflammatory responses, and retards cellular senescence in endothelial cells in mouse models of diabetes. However, whether SIRT1 also plays a protective role in vascular dysfunction of diabetic and obese mice is not fully characterized. Previous work showed that peroxisome proliferator-activated receptor δ (PPARδ) is beneficial in diabetic vascular dysfunction. Whether PPARδ is involved in the beneficial effect of SIRT1 on vascular endothelial function is unknown. We used mice with overexpression of endothelial cell-specific human SIRT1 (SIRT1-Tg) and dominant-negative SIRT1 (SIRT1-mut) fed with normal chow and high fat diet to show that expression of functional SIRT1 in endothelium protects against vascular dysfunction in diet-induced obese mice. Endothelial-specific overexpression of SIRT1 improved endothelium-dependent dilation in aortas treated with risk factors including high glucose, angiotensin II, and lysophosphatidylcholine. Oral treatment with resveratrol treatment improves endothelial function in high fat diet fed wild type Ppard-wt but not in PPARδ knockout Ppard-mut mice. Experiments on isolated arteries also showed that the effect of resveratrol or SIRT1 activator CAY10602 was inhibited by PPARδ antagonist GSK0660. Resveratrol increased PPARδ transcriptional activity in endothelial cells. Results demonstrated here indicated that PPARδ contributes to the beneficial effect of SIRT1 to ameliorate endothelial dysfunction in diabetic and obese mice. These results help to understand SIRT1-based strategy for treating vascular and metabolic dysfunction in the context of obesity and insulin resistance.
Assuntos
Endotélio Vascular/efeitos dos fármacos , PPAR delta/fisiologia , Resveratrol/farmacologia , Sirtuína 1/fisiologia , Animais , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/fisiologia , Endotélio Vascular/fisiologia , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade/metabolismoRESUMO
BACKGROUND: Peroxisome proliferatorâ»activated receptor (PPAR) ß/δ, a ligand-activated transcription factor, is involved in diverse biological processes including cell proliferation, cell differentiation, inflammation and energy homeostasis. Besides its well-established roles in metabolic disorders, PPARß/δ has been linked to carcinogenesis and was reported to inhibit melanoma cell proliferation, anchorage-dependent clonogenicity and ectopic xenograft tumorigenicity. However, PPARß/δ's role in tumour progression and metastasis remains controversial. METHODS: In the present studies, the consequence of PPARß/δ inhibition either by global genetic deletion or by a specific PPARß/δ antagonist, 10h, on malignant transformation of melanoma cells and melanoma metastasis was examined using both in vitro and in vivo models. RESULTS: Our study showed that 10h promotes epithelial-mesenchymal transition (EMT), migration, adhesion, invasion and trans-endothelial migration of mouse melanoma B16/F10 cells. We further demonstrated an increased tumour cell extravasation in the lungs of wild-type mice subjected to 10h treatment and in Pparß/δ-/- mice in an experimental mouse model of blood-borne pulmonary metastasis by tail vein injection. This observation was further supported by an increased tumour burden in the lungs of Pparß/δ-/- mice as demonstrated in the same animal model. CONCLUSION: These results indicated a protective role of PPARß/δ in melanoma progression and metastasis.
Assuntos
Melanoma/genética , Metástase Neoplásica/genética , PPAR delta/fisiologia , PPAR beta/fisiologia , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal/genética , Melanoma/patologia , Camundongos , Invasividade Neoplásica/genética , Metástase Neoplásica/patologia , PPAR delta/genética , PPAR delta/metabolismo , PPAR beta/genética , PPAR beta/metabolismoRESUMO
Activation of peroxisome proliferator-activated receptor beta/delta (PPAR-ß/δ), a nuclear receptor acting as a transcription factor, was shown to be protective in various models of neurological diseases. However, there is no information about the role of PPAR-ß/δ as well as its molecular mechanisms in neonatal hypoxia-ischemia (HI). In the present study, we hypothesized that PPAR-ß/δ agonist GW0742 can activate miR-17-5p, consequently inhibiting TXNIP and ASK1/p38 pathway leading to attenuation of apoptosis. Ten-day-old rat pups were subjected to right common carotid artery ligation followed by 2.5â¯h hypoxia. GW0742 was administered intranasally 1 and 24â¯h post HI. PPAR-ß/δ receptor antagonist GSK3787 was administered intranasally 1â¯h before and 24â¯h after HI, antimir-17-5p and TXNIP CRISPR activation plasmid were administered intracerebroventricularly 24 and 48â¯h before HI, respectively. Brain infarct area measurement, neurological function tests, western blot, reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR), Fluoro-Jade C and immunofluorescence staining were conducted. GW0742 reduced brain infarct area, brain atrophy, apoptosis, and improved neurological function at 72â¯h and 4 weeks post HI. Furthermore, GW0742 treatment increased PPAR-ß/δ nuclear expression and miR-17-5p level and reduced TXNIP in ipsilateral hemisphere after HI, resulting in inhibition of ASK1/p38 pathway and attenuation of apoptosis. Inhibition of PPAR-ß/δ receptor and miR-17-5p and activation of TXNIP reversed the protective effects. For the first time, we provide evidence that intranasal administration of PPAR-ß/δ agonist GW0742 attenuated neuronal apoptosis at least in part via PPAR-ß/δ/miR-17/TXNIP pathway. GW0742 could represent a therapeutic target for treatment of neonatal hypoxic ischemic encephalopathy (HIE).
Assuntos
Apoptose/fisiologia , Proteínas de Transporte/fisiologia , Hipóxia-Isquemia Encefálica/fisiopatologia , MicroRNAs/fisiologia , PPAR delta/fisiologia , PPAR beta/fisiologia , Animais , Apoptose/efeitos dos fármacos , Benzamidas/farmacologia , Proteínas de Transporte/antagonistas & inibidores , Proteínas de Transporte/metabolismo , Proteínas de Ciclo Celular , Infarto Cerebral/tratamento farmacológico , Infarto Cerebral/patologia , Hipóxia-Isquemia Encefálica/metabolismo , Hipóxia-Isquemia Encefálica/patologia , MAP Quinase Quinase Quinase 5/antagonistas & inibidores , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , MicroRNAs/antagonistas & inibidores , MicroRNAs/metabolismo , Neurônios/patologia , PPAR delta/agonistas , PPAR delta/antagonistas & inibidores , PPAR delta/biossíntese , PPAR beta/agonistas , PPAR beta/antagonistas & inibidores , PPAR beta/biossíntese , Ratos , Transdução de Sinais/fisiologia , Sulfonas/farmacologia , Tiazóis/farmacologia , Tiazóis/uso terapêuticoRESUMO
The hypothesis of the study was that inhibition of PPARß/δ increases glucose uptake and lactose synthesis in bovine mammary epithelial cells by reducing the expression of the glucose transporter mRNA destabiliser calreticulin. Three experiments were conducted to test the hypothesis using immortalised bovine mammary alveolar (MACT) and primary bovine mammary (PBMC) cells. In Experiment 1, the most effective dose to inhibit PPARß/δ activity among two synthetic antagonists (GSK-3787 and PT-s58) was assessed using a gene reporter assay. In Experiment 2, the effect on glucose uptake and lactose synthesis was evaluated by measuring glucose and lactose in the media and expression of related key genes upon modulation of PPARß/δ using GSK-3787, the synthetic PPARß/δ agonist GW-501516, or a combination of the two in cells cultivated in plastic. In Experiment 3, the same treatments were applied to cells cultivated in Matrigel and glucose and lactose in media were measured. In Experiment 1 it was determined that a significant inhibition of PPARß/δ in the presence or absence of fetal bovine serum was achieved with ≥ 1000 nm GSK-3787 but no significant inhibition was observed with PT-s58. In Experiment 2, inhibition of PPARß/δ had no effect on glucose uptake and lactose synthesis but they were both increased by GW-501516 in PBMC. The mRNA abundance of PPARß/δ target gene pyruvate dehydrogenase kinase 4 was increased but transcription of calreticulin was decreased (only in MACT cells) by GW-501516. Treatment with GSK-3787 did not affect the transcription of measured genes. No effects on glucose uptake or lactose synthesis were detected by modulation of PPARß/δ activity on cells cultivated in Matrigel. The above data do not provide support for the original hypothesis and suggest that PPARß/δ does not play a major role in glucose uptake and lactose synthesis in bovine mammary epithelial cells.
Assuntos
Bovinos , Glucose/metabolismo , Lactose/biossíntese , Glândulas Mamárias Animais/metabolismo , PPAR delta/fisiologia , PPAR beta/fisiologia , Animais , Benzamidas/farmacologia , Células Cultivadas , Células Epiteliais/metabolismo , Feminino , PPAR delta/antagonistas & inibidores , PPAR beta/antagonistas & inibidores , Proteínas Quinases/genética , RNA Mensageiro/análise , Sulfonas/farmacologiaRESUMO
STUDY QUESTION: What are the consequences of inhibiting mTOR, the mechanistic target of rapamycin (mTOR), and the peroxisome proliferator activated receptor gamma (PPARγ) and PPARδ pathways in the early post-implantation period on decidual function, embryo viability and feto-placental growth in the rat? SUMMARY ANSWER: mTOR inhibition from Days 7 to 9 of pregnancy in rats caused decidual PPARγ and PPARδ upregulation on Day 9 of pregnancy and resulted in embryo resorption by Day 14 of pregnancy. PPARγ and PPARδ inhibition differentially affected decidual mTOR signaling and levels of target proteins relevant to lipid histotrophic nutrition and led to reduced feto-placental weights on Day 14 of pregnancy. WHAT IS KNOWN ALREADY: Although mTOR, PPARγ and PPARδ are nutrient sensors important during implantation, the role of these signaling pathways in decidual function and how they interact in the early post-implantation period are unknown. Perilipin 2 (PLIN2) and fatty acid binding protein 4 (FABP4), two adipogenic proteins involved in lipid histotrophic nutrition, are targets of mTOR and PPAR signaling pathways in a variety of tissues. STUDY DESIGN, SIZE, DURATION: Rapamycin (mTOR inhibitor, 0.75 mg/kg, sc), T0070907 (PPARγ inhibitor, 0.001 mg/kg, sc), GSK0660 (PPARδ inhibitor, 0.1 mg/kg, sc) or vehicle was injected daily to pregnant rats from Days 7 to 9 of pregnancy and the studies were performed on Day 9 of pregnancy (n = 7 per group) or Day 14 of pregnancy (n = 7 per group). PARTICIPANTS/MATERIALS, SETTING, METHODS: On Day 9 of pregnancy, rat decidua were collected and prepared for western blot and immunohistochemical studies. On Day 14 of pregnancy, the resorption rate, number of viable fetuses, crown-rump length and placental and decidual weights were determined. MAIN RESULTS AND THE ROLE OF CHANCE: Inhibition of mTOR in the early post-implantation period led to a reduction in FABP4 protein levels, an increase in PLIN2 levels and an upregulation of PPARγ and PPARδ in 9-day-pregnant rat decidua. Most embryos were viable on Day 9 of pregnancy but had resorbed by Day 14 of pregnancy. This denotes a key function of mTOR in the post-implantation period and suggests that activation of PPAR signaling was insufficient to compensate for impaired nutritional/survival signaling induced by mTOR inhibition. Inhibition of PPARγ signaling resulted in decreased decidual PLIN2 and FABP4 protein expression as well as in inhibition of decidual mTOR signaling in Day 9 of pregnancy. This treatment also reduced feto-placental growth on Day 14 of pregnancy, revealing the relevance of PPARγ signaling in sustaining post-implantation growth. Moreover, following inhibition of PPARδ, PLIN2 levels were decreased and mTOR complex 1 and 2 signaling was altered in decidua on Day 9 of pregnancy. On Day 14 of pregnancy, PPARδ inhibition caused reduced feto-placental weight, increased decidual weight and increased resorption rate, suggesting a key role of PPARδ in sustaining post-implantation development. LARGE SCALE DATA: Not applicable. LIMITATIONS, REASONS FOR CAUTION: This is an in vivo animal study and the relevance of the results for humans remains to be established. WIDER IMPLICATIONS OF THE FINDINGS: The early post-implantation period is a critical window of development and changes in the intrauterine environment may cause embryo resorption and lead to placental and fetal growth restriction. mTOR, PPARγ and PPARδ signaling are decidual nutrient sensors with extensive cross-talk that regulates adipogenic proteins involved in histotrophic nutrition and important for embryo viability and early placental and fetal development and growth. STUDY FUNDING/COMPETING INTEREST(S): Funding was provided by the Agencia Nacional de Promoción Científica y Tecnológica de Argentina (PICT 2014-411 and PICT 2015-0130), and by the International Cooperation (Grants CONICET-NIH-2014 and CONICET-NIH-2017) to A.J. and T.J. The authors have no conflicts of interest.
Assuntos
Decídua/fisiologia , PPAR delta/fisiologia , PPAR gama/fisiologia , Serina-Treonina Quinases TOR/fisiologia , Animais , Decídua/metabolismo , Desenvolvimento Embrionário , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Desenvolvimento Fetal , Imuno-Histoquímica , PPAR delta/genética , PPAR delta/metabolismo , PPAR gama/genética , PPAR gama/metabolismo , Gravidez , Ratos Wistar , Transdução de Sinais , Sirolimo/farmacologia , Serina-Treonina Quinases TOR/genética , Serina-Treonina Quinases TOR/metabolismoRESUMO
Even though recent evidence in goat mammary epithelial cells (GMEC) suggest a role of peroxisome proliferator-activated receptor delta (PPARD) in regulating lipid homeostasis, its role is not fully understood. Our hypothesis was that PPARD regulates lipid transport processes in GMEC and, thus, plays a crucial role in regulating fat formation. The PPARD was overexpressed using an adenovirus system (Ad-PPARD) with recombinant green fluorescent protein (Ad-GFP) as the control. Results revealed that overexpression of PPARD markedly upregulated the mRNA abundance of PPARD. Compared with the control (Ad-GFP+dimethyl sulfoxide), overexpression of PPARD alone had no effect on mRNA expression of CD36, SCD1, FABP4, ACSL1, and ADRP. The cultures overexpressing PPARD with the PPARD ligand GW0742 (GW) upregulated the expression of CD36, FABP3, FABP4, ACSL1, and ADRP. Overexpression of PPARD in GMEC plus GW increased the concentration of 16:1 and 18:1-trans and was associated with upregulation of SCD1. Compared with the control (Ad-GFP+dimethyl sulfoxide), the decrease of triacylglycerol concentration coupled with upregulation of genes related to lipid droplet secretion (e.g., ADRP and ACSL1) induced by PPARD overexpression suggests a role in lipid droplet (LD) secretion. Luciferase assay revealed that GW increased the ADRP promoter activity in a dose-dependent manner. Knockdown of PPARD impaired the increase of ADRP promoter activity induced by GW, whereas GW enhanced the activity of ADRP promoter in GMEC overexpressing PPARD. Data with the ADRP 5'-flanking truncated luciferase reporter suggest a core region (-1,444 to -990 bp) response element for the induction of GW. This core region contains a known PPARG response element (PPRE) at -1,003 to -990 bp. When the PPRE was mutated, the overexpression of PPARD had no effect on ADRP promoter activity. Collectively, these results reveal a novel role for PPARD in lipid homeostasis via promoting fatty acid transport and LD formation through a mechanism of direct binding to the promoter of key genes. Hence, PPARD activity may contribute to fatty acid transport and LD formation during lactation.
Assuntos
Ácidos Graxos/metabolismo , Cabras/metabolismo , Gotículas Lipídicas/metabolismo , Glândulas Mamárias Animais/metabolismo , PPAR delta/fisiologia , Animais , Transporte Biológico , Células Cultivadas , Células Epiteliais/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Cabras/genética , Lactação/genética , PPAR delta/genética , PPAR gama/genética , PPAR gama/metabolismo , Perilipina-2/genética , Perilipina-2/metabolismo , RNA Mensageiro/metabolismo , Triglicerídeos/metabolismo , Regulação para CimaRESUMO
BACKGROUND: Bariatric surgery remains the most effective treatment for reducing adiposity and eliminating type 2 diabetes; however, the mechanism(s) responsible have remained elusive. Peroxisome proliferator-activated receptors (PPAR) encompass a family of nuclear hormone receptors that upon activation exert control of lipid metabolism, glucose regulation and inflammation. Their role in adipose tissue following bariatric surgery remains undefined. MATERIALS AND METHODS: Subcutaneous adipose tissue biopsies and serum were obtained and evaluated from time of surgery and on postoperative day 7 in patients randomized to Roux-en-Y gastric bypass (n=13) or matched caloric restriction (n=14), as well as patients undergoing vertical sleeve gastrectomy (n=33). Fat samples were evaluated for changes in gene expression, protein levels, ß-oxidation, lipolysis and cysteine oxidation. RESULTS: Within 7 days, bariatric surgery acutely drives a change in the activity and expression of PPARγ and PPARδ in subcutaneous adipose tissue thereby attenuating lipid storage, increasing lipolysis and potentiating lipid oxidation. This unique metabolic alteration leads to changes in downstream PPARγ/δ targets including decreased expression of fatty acid binding protein (FABP) 4 and stearoyl-CoA desaturase-1 (SCD1) with increased expression of carnitine palmitoyl transferase 1 (CPT1) and uncoupling protein 2 (UCP2). Increased expression of UCP2 not only facilitated fatty acid oxidation (increased 15-fold following surgery) but also regulated the subcutaneous adipose tissue redoxome by attenuating protein cysteine oxidation and reducing oxidative stress. The expression of UCP1, a mitochondrial protein responsible for the regulation of fatty acid oxidation and thermogenesis in beige and brown fat, was unaltered following surgery. CONCLUSIONS: These results suggest that bariatric surgery initiates a novel metabolic shift in subcutaneous adipose tissue to oxidize fatty acids independently from the beiging process through regulation of PPAR isoforms. Further studies are required to understand the contribution of this shift in expression of PPAR isoforms to weight loss following bariatric surgery.
Assuntos
Cirurgia Bariátrica , Diabetes Mellitus Tipo 2/prevenção & controle , Metabolismo dos Lipídeos/fisiologia , Obesidade Mórbida/cirurgia , PPAR delta/fisiologia , Gordura Subcutânea/metabolismo , Adulto , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Immunoblotting , Lipólise/fisiologia , Masculino , Obesidade Mórbida/metabolismo , Resultado do Tratamento , Proteína Desacopladora 2/metabolismoRESUMO
The PPARs are a subfamily of three ligand-inducible transcription factors, which belong to the superfamily of nuclear hormone receptors. In mammals, the PPAR subfamily consists of three members: PPAR-α, PPAR-ß/δ and PPAR-γ. PPARs control the expression of a large number of genes involved in metabolic homeostasis, lipid, glucose and energy metabolism, adipogenesis and inflammation. PPARs regulate a large number of metabolic pathways that are implicated in the pathogenesis of metabolic diseases such as metabolic syndrome, Type 2 diabetes mellitus, nonalcoholic fatty liver disease and cardiovascular disease. The aim of this review is to provide up-to-date information about the biochemical and metabolic actions of PPAR-ß/δ and PPAR-γ, the therapeutic potential of their agonists currently under clinical development and the cardiovascular disease outcome of clinical trials of PPAR-γ agonists, pioglitazone and rosiglitazone.
Assuntos
Doenças Cardiovasculares/tratamento farmacológico , PPAR delta/agonistas , PPAR delta/fisiologia , PPAR gama/agonistas , PPAR gama/fisiologia , PPAR beta/agonistas , PPAR beta/fisiologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Humanos , Síndrome Metabólica/tratamento farmacológico , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Pioglitazona , Rosiglitazona , Tiazolidinedionas/uso terapêuticoRESUMO
Peroxisome proliferator-activated receptor δ (Pparδ) is a nuclear receptor that plays critical roles in lipid metabolism, glucose metabolism, and cell growth and differentiation. Several recent studies have shown that Pparδ promotes blastocyst hatching in vitro. However, the mechanism by which it promotes preimplantation embryonic development in vitro remains unclear. In this study, oocytes and parthenotes were treated with a specific agonist of PPARδ, GW501516. The activation of PPARδ had no effect on oocyte maturation for 1 µM and 10 µM GW501516 compared with the control group. Additionally, the PPARδ agonist did not affect blastocyst formation (77.79 ± 3.59% [10 µM], 79.00 ± 5.53% [50 µM], and 79.64 ± 6.00% [100 µM] vs. 81.69 ± 2.61% [control]). However, the blastocyst hatching rate was significantly greater for parthenotes treated with 10 and 50 µM agonist, and did not differ between those treated with 100 µM agonist and the control group (61.80 ± 3.03% [10 µM], 65.10 ± 5.25% [50 µM], and 38.85 ± 7.45% [100 µM] vs. 41.77 ± 10.88% [0 µM]). Activation of PPARδ also increased blastocyst quality and cell number, as well as ATP production. There were no clear differences in mitochondrial membrane potential, mitochondrion copy number, or glucose consumption between the treatment and control groups. However, PPARδ activation enhanced lipid accumulation via Fabp3 and Fabp5. Fatty acid oxidation also increased in response to treatment with the agonist via the rate-limiting gene Cpt2. Reactive oxygen species were modified and REDOX maintenance-related gene expression increased significantly in GW501516-exposed blastocysts. In addition, the activation of PPARδ resulted in changes in miRNA content. After treatment with the PPARδ agonist, miR-99 increased and miR-32 decreased. These data showed that PPARδ has a positive impact on blastocyst hatching via the regulation of lipid metabolism.
Assuntos
Blastocisto/metabolismo , Ácidos Graxos/metabolismo , PPAR delta/fisiologia , Animais , Blastocisto/efeitos dos fármacos , Desenvolvimento Embrionário , Proteínas de Ligação a Ácido Graxo/metabolismo , Expressão Gênica , Glucose/metabolismo , Potencial da Membrana Mitocondrial , Mitocôndrias/metabolismo , Oxirredução , Suínos , Tiazóis/farmacologiaRESUMO
The nuclear receptor factor peroxisome proliferator-activated receptor (PPARß/δ) can regulate its target genes by transcriptional activation or repression through both ligand-dependent and independent mechanism as well as by interactions with other transcription factors. PPARß/δ exerts essential regulatory functions in intermediary metabolism that have been elucidated in detail, but clearly also plays a role in inflammation, differentiation, apoptosis and other cancer-associated processes, which is, however, mechanistically only partly understood. Consistent with these functions clinical associations link the expression of PPARß/δ and its target genes to an unfavorable outcome of several human cancers. However, the available data do not yield a clear picture of PPARß/δ's role in cancer-associated processes and are in fact partly controversial. This article provides an overview of this research area and discusses the role of PPARß/δ in cancer in light of the complex mechanisms of its transcriptional regulation and its potential as a druggable anti-cancer target.