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1.
Nat Commun ; 12(1): 1648, 2021 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-33712605

RESUMO

Cardiomyocytes undergo significant structural and functional changes after birth, and these fundamental processes are essential for the heart to pump blood to the growing body. However, due to the challenges of isolating single postnatal/adult myocytes, how individual newborn cardiomyocytes acquire multiple aspects of the mature phenotype remains poorly understood. Here we implement large-particle sorting and analyze single myocytes from neonatal to adult hearts. Early myocytes exhibit wide-ranging transcriptomic and size heterogeneity that is maintained until adulthood with a continuous transcriptomic shift. Gene regulatory network analysis followed by mosaic gene deletion reveals that peroxisome proliferator-activated receptor coactivator-1 signaling, which is active in vivo but inactive in pluripotent stem cell-derived cardiomyocytes, mediates the shift. This signaling simultaneously regulates key aspects of cardiomyocyte maturation through previously unrecognized proteins, including YAP1 and SF3B2. Our study provides a single-cell roadmap of heterogeneous transitions coupled to cellular features and identifies a multifaceted regulator controlling cardiomyocyte maturation.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Miócitos Cardíacos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fatores de Processamento de RNA/metabolismo , Fatores de Transcrição/metabolismo , Animais , Cálcio/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciação Celular , Redes Reguladoras de Genes , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Receptores Ativados por Proliferador de Peroxissomo/genética , Células-Tronco Pluripotentes/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Transcriptoma
2.
Int J Mol Sci ; 22(1)2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33406768

RESUMO

Peroxisome proliferator-activated receptors (PPARα, PPARß/δ, and PPARγ) belong to the transcription factor family, and they are highly expressed in all types of trophoblast during pregnancy. The present review discusses currently published papers that are related to the regulation of PPARs via lipid metabolism, glucose metabolism, and amino acid metabolism to affect trophoblast physiological conditions, including differentiation, maturation, secretion, fusion, proliferation, migration, and invasion. Recent pieces of evidence have proven that the dysfunctions of PPARs in trophoblast lead to several related pregnancy diseases such as recurrent miscarriage, preeclampsia, intrauterine growth restriction, and gestational diabetes mellitus. Moreover, the underlying mechanisms of PPARs in the control of these processes have been discussed as well. Finally, this review's purposes are to provide more knowledge about the role of PPARs in normal and disturbed pregnancy with trophoblast, so as to find PPAR ligands as a potential therapeutic target in the treatment and prevention of adverse pregnancy outcomes.


Assuntos
Regulação da Expressão Gênica , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Trofoblastos/fisiologia , Animais , Feminino , Humanos , Gravidez , Trofoblastos/citologia
3.
Int J Mol Sci ; 22(3)2021 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-33498245

RESUMO

Cannabinoids have shown to exert their therapeutic actions through a variety of targets. These include not only the canonical cannabinoid receptors CB1R and CB2R but also related orphan G protein-coupled receptors (GPCRs), ligand-gated ion channels, transient receptor potential (TRP) channels, metabolic enzymes, and nuclear receptors. In this review, we aim to summarize reported compounds exhibiting their therapeutic effects upon the modulation of CB1R and/or CB2R and the nuclear peroxisome proliferator-activated receptors (PPARs). Concomitant actions at CBRs and PPARα or PPARγ subtypes have shown to mediate antiobesity, analgesic, antitumoral, or neuroprotective properties of a variety of phytogenic, endogenous, and synthetic cannabinoids. The relevance of this multitargeting mechanism of action has been analyzed in the context of diverse pathologies. Synergistic effects triggered by combinatorial treatment with ligands that modulate the aforementioned targets have also been considered. This literature overview provides structural and pharmacological insights for the further development of dual cannabinoids for specific disorders.


Assuntos
Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores de Canabinoides/metabolismo , Amidoidrolases/antagonistas & inibidores , Amidoidrolases/metabolismo , Animais , Moduladores de Receptores de Canabinoides/farmacologia , Inibidores Enzimáticos/farmacologia , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Receptores Ativados por Proliferador de Peroxissomo/antagonistas & inibidores
4.
Aquat Toxicol ; 231: 105733, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33429301

RESUMO

There is increasing awareness that exposure to endocrine disrupters interferes with lipid homeostasis in vertebrates, including fish. Many of these compounds exert their action by binding to nuclear receptors, such as peroxisome proliferator-activated receptors and retinoid X receptor. This work investigates the use of fish liver cells (PLHC-1 and ZFL cells) for the screening of metabolic and lipid disrupters in the aquatic environment by assessing changes in the cell's lipidome after exposure to the model compounds, tributyltin chloride and all-trans retinoic acid. Lipid extracts, analyzed by FIA-ESI (+/-) Orbitrap, evidenced the intracellular accumulation of triglycerides and diglycerides in both cell models after exposure to 100 and 200 nM tributyltin chloride for 24 h. Exposure to 1 µM all-trans retinoic acid led to a significant accumulation of triglycerides in PLHC-1 cells, while few triglycerides were accumulated in ZFL cells. Retinoic acid (cyp26b1, cyp3a65, lrata) and lipid metabolism (fasn, scd, elovl6) related genes were up-regulated by tributyltin chloride and all-trans retinoic acid, while only all-trans retinoic acid down-regulated the expression of dgat1a. The two cell models show sensitivity and responses to tributyltin chloride and all-trans retinoic acid comparable to those previously reported in mammalian cells. These results support the use of fish liver cells as alternative models for the detection of contaminants that act as lipid disrupters in the aquatic environment.


Assuntos
Metabolismo dos Lipídeos , Tretinoína/toxicidade , Compostos de Trialquitina/toxicidade , Animais , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cyprinidae , Regulação da Expressão Gênica/efeitos dos fármacos , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipídeos/análise , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores X Retinoide/metabolismo , Poluentes Químicos da Água/toxicidade , Peixe-Zebra
5.
Metabolism ; 114: 154338, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-32791172

RESUMO

Peroxisome proliferator-activated receptors (PPARs) are fatty acid-activated transcription factors of nuclear hormone receptor superfamily that regulate energy metabolism. Currently, three PPAR subtypes have been identified: PPARα, PPARγ, and PPARß/δ. PPARα and PPARδ are highly expressed in oxidative tissues and regulate genes involved in substrate delivery and oxidative phosphorylation (OXPHOS) and regulation of energy homeostasis. In contrast, PPARγ is more important in lipogenesis and lipid synthesis, with highest expression levels in white adipose tissue (WAT). In addition to tissues regulating whole body energy homeostasis, PPARs are expressed in immune cells and have an emerging critical role in immune cell differentiation and fate commitment. In this review, we discuss the actions of PPARs in the function of the innate and the adaptive immune system and their implications in immune-mediated inflammatory conditions.


Assuntos
Imunidade/fisiologia , Inflamação/metabolismo , Metabolismo dos Lipídeos/fisiologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Linfócitos T/metabolismo , Animais , Humanos
6.
Am J Physiol Regul Integr Comp Physiol ; 320(3): R362-R376, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33356878

RESUMO

Migratory birds may benefit from diets rich in polyunsaturated fatty acids (PUFAs) that could improve exercise performance. Previous investigations suggest that different types of birds may respond differently to PUFA. We established muscle myocyte cell culture models from muscle satellite cells of a migratory passerine songbird (yellow-rumped warbler, Setophaga coronata coronata) and a nonpasserine shorebird (sanderling, Calidris alba). We differentiated and treated avian myotubes and immortalized murine C2C12 myotubes with n-3 PUFA docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), and with monounsaturated oleic acid (OA) to compare effects on aerobic performance, metabolic enzyme activities, key fatty acid (FA) transporters, and expression of peroxisome proliferator-activated receptors (PPARs). Sanderling and C2C12 myotubes increased expression of PPARs with n-3 PUFA treatments, whereas expression was unchanged in yellow-rumped warblers. Both sanderlings and yellow-rumped warblers increased expression of fatty acid transporters, whereas C2C12 cells decreased expression following n-3 PUFA treatments. Only yellow-rumped warbler myotubes increased expression of some metabolic enzymes, whereas the sanderling and C2C12 cells were unchanged. PUFA supplementation in C2C12 myotubes increased mitochondrial respiratory chain efficiency, whereas sanderlings increased proton leak-associated respiration and maximal respiration (measurements were not made in warblers). This research indicates that songbirds and shorebirds respond differently to n-3 PUFA and provides support for the hypothesis that n-3 PUFA increase the aerobic capacity of migrant shorebird muscle, which may improve overall endurance flight performance.


Assuntos
Ácidos Docosa-Hexaenoicos/farmacologia , Ácido Eicosapentaenoico/farmacologia , Metabolismo Energético/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Ácido Oleico/farmacologia , Aves Canoras/metabolismo , Animais , Comportamento Animal , Linhagem Celular , Proteínas de Transporte de Ácido Graxo/genética , Proteínas de Transporte de Ácido Graxo/metabolismo , Feminino , Voo Animal , Masculino , Camundongos , Mitocôndrias Musculares/efeitos dos fármacos , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Especificidade da Espécie
7.
Mol Med Rep ; 23(2)2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33355371

RESUMO

Osteoarthritis (OA) is the most common form of arthritis, for which treatment options are not always satisfactory, since complete cure for OA is not yet possible. A better understanding of OA pathogenesis is thus important. The peroxisome proliferator­activated receptor (PPAR) plays a major regulatory role in lipid metabolism and energy homeostasis. This review article aimed to discuss the biological function of PPARs, and their role in regulating OA progression, as well as the therapeutic aspect of PPARs in OA. Studies indicate that PPARs regulate articular cartilage homeostasis through the modulation of various signaling pathways, and reduce the inflammatory responses in human OA cartilage. Furthermore, the deficiency of PPARs in the articular cartilage might be responsible for the acceleration of severe OA by increasing catabolic activity and suppression of chondroprotection. Therapeutic applications of PPAR­agonists can thus reduce the development of cartilage lesions by inhibiting the synthesis of various catabolic and inflammatory factors involved in the pathogenesis of OA. PPARs are thus important proteins in OA regulation, which may have significant importance in OA therapeutics.


Assuntos
Cartilagem Articular/metabolismo , Osteoartrite/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais , Animais , Cartilagem Articular/patologia , Humanos , Osteoartrite/genética , Osteoartrite/patologia , Receptores Ativados por Proliferador de Peroxissomo/genética
8.
J Ethnopharmacol ; 265: 113324, 2021 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32890714

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Fufang Xueshuantong (FXST) is a traditional Chinese patent medicine composed of Panax notoginseng (Burkill) F.H.Chen (Araliaceae), Salvia miltiorrhiza Bunge (Lamiaceae), Astragalus propinquus Schischkin (Leguminosae), and Scrophularia ningpoensis Hemsl. (Scrophulariaceae). It has been widely used for the treatment of diabetic retinopathy (DR) and exerts a positive clinical therapeutic effect. AIM OF THE STUDY: The aim of this study was to observe the effect of FXST on diabetic rat retinas and investigate its pharmacological mechanism for improving DR. METHODS: The diabetic rat model was established by intraperitoneal injection of streptozotocin. The rats were divided into a normal group, diabetic group, and FXST group. The rats in the FXST group were treated with FXST by intragastric administration for 12 weeks while other rats were given the same volume of normal saline. The haemodynamic parameters of the central retinal artery in the rats were measured by ultrasound. Haematoxylin-eosin staining was utilised to observe the pathological structural changes in the retina. The apoptosis of retinal nerve cells was detected by terminal deoxynucleotidyl transferase dUTP nick end labelling. RNA sequencing was used to screen the differentially expressed genes (DEGs), and enrichment analyses were performed. The DEGs were validated through real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR). RESULTS: The peak systolic velocity, end diastolic velocity, and mean velocity decreased while the resistance index and pulsatility index increased in the diabetic rat retinas. FXST also improved haemodynamics. In contrast with the diabetic group, FXST allayed the disorder and oedema of the retinal structure in addition to reversing the reductions in retinal thickness and retinal ganglion cell number. It also decreased the apoptosis index of retinal cells. A total of 1134 DEGs were identified by RNA sequencing in the FXST group compared to the diabetic group, including 814 upregulated genes and 320 downregulated genes. These genes were enriched in the complement and coagulation cascades as well as the peroxisome proliferator-activated receptor (PPAR) signalling pathway. Several DEGs, including PPAR gamma, perilipin 4, acyl-CoA dehydrogenase long chain, CD55 molecule, and plasminogen activator urokinase, were identified by qRT-PCR, and the results were consistent with the RNA sequencing data. CONCLUSIONS: FXST alleviates DR by improving the haemodynamics and morphological alterations of diabetic rat retinas, which are mediated by complement and coagulation cascades and the PPAR signalling pathway.


Assuntos
Diabetes Mellitus Experimental/tratamento farmacológico , Retinopatia Diabética/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Animais , Coagulação Sanguínea/efeitos dos fármacos , Ativação do Complemento/efeitos dos fármacos , Diabetes Mellitus Experimental/complicações , Retinopatia Diabética/patologia , Masculino , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Estreptozocina
9.
Int J Mol Sci ; 21(24)2020 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-33322384

RESUMO

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear hormone receptor family. They are ligand-activated transcription factors and exist in three different isoforms, PPARα (NR1C1), PPARß/δ (NR1C2), and PPARγ (NR1C3). PPARs regulate a variety of functions, including glucose and lipid homeostasis, inflammation, and development. They exhibit tissue and cell type-specific expression patterns and functions. Besides the established notion of the therapeutic potential of PPAR agonists for the treatment of glucose and lipid disorders, more recent data propose specific PPAR ligands as potential therapies for cardiovascular diseases. In this review, we focus on the knowledge of PPAR function in myocardial infarction, a severe pathological condition for which therapeutic use of PPAR modulation has been suggested.


Assuntos
Doenças Cardiovasculares/metabolismo , Infarto do Miocárdio/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Animais , Doenças Cardiovasculares/genética , Humanos , Infarto do Miocárdio/genética , Miócitos Cardíacos/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/genética
10.
PLoS One ; 15(6): e0234726, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32559205

RESUMO

Hepatocellular carcinoma (HCC), the most malignant form of primary liver cancer, is the fourth most prevalent cause of cancer mortality globally. It was recently discovered that the dietary fermentable fiber, inulin, can reprogram the murine liver to favor HCC development in a gut microbiota-dependent manner. Determining the molecular pathways that are either over expressed or repressed during inulin-induced HCC would provide a platform of potential therapeutic targets. In the present study, we have combined analysis of the novel inulin-induced HCC murine model and human HCC samples to identify differentially expressed genes (DEGs) in hepatocarcinogenesis. Hepatic transcriptome profiling revealed that there were 674 DEGs in HCC mice compared to mice safeguarded from HCC. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis uncovered enrichment in ECM-receptor interaction, steroid hormone biosynthesis, PPAR signaling pathway, focal adhesion and protein digestion and absorption during inulin-induced HCC. Tandem mass tag based quantitative, multiplexed proteomic analysis delineated 57 differentially expressed proteins, where the over-expressed proteins were associated with cell adhesion molecules, valine, leucine and isoleucine degradation and ECM-receptor interaction. After obtaining the human orthologs of the mouse genes, we did a comparison analysis to level 3 RNA-seq data found in the Cancer Genome Atlas (TCGA) database, corresponding to human HCC (n = 361) and healthy liver (n = 50) samples. Out of the 549 up-regulated and 68 down-regulated human orthologs identified, 142 genes (137 significantly over-expressed and 5 significantly under-expressed) were associated with human HCC. Using univariate survival analysis, we found 27 over-expressed genes involved in cell-cell adhesion and cell division that were associated with poor HCC patient survival. Overall, the genetic and proteomics signatures highlight potential underlying mechanisms in inulin-induced HCC and support that this murine HCC model is human relevant.


Assuntos
Carcinoma Hepatocelular/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias Hepáticas/patologia , Animais , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/mortalidade , Moléculas de Adesão Celular/metabolismo , Modelos Animais de Doenças , Ontologia Genética , Humanos , Insulina/toxicidade , Estimativa de Kaplan-Meier , Fígado/metabolismo , Neoplasias Hepáticas/induzido quimicamente , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Proteômica , Transdução de Sinais , Receptor 5 Toll-Like/deficiência , Receptor 5 Toll-Like/genética , Transcriptoma
11.
Lipids Health Dis ; 19(1): 24, 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32035489

RESUMO

BACKGROUND: The LDL-C lowering effect of ezetimibe has been attributed primarily to increased catabolism of LDL-C via up-regulation of LDL receptor (LDLR) and decreased cholesterol absorption. Recently, ezetimibe has been demonstrated to have reverse cholesterol transport (RCT) promoting effects in mice, hamsters and humans. However, the underlying mechanisms are still not clear. The aim of this study is to investigate whether ezetimibe improves RCT-related protein expression in LDLR-/- hamsters. METHODS: A high-fat diet was used to induce a human-like hyperlipidemia in LDLR-/- hamsters. Lipid profiles were assayed by commercially available kits, and the effects of ezetimibe on lipid metabolism-related protein expression were carried out via western blot. RESULTS: Our data demonstrated that ezetimibe administration significantly reduced plasma total cholesterol (~ 51.6% reduction, P < 0.01) and triglyceride (from ~ 884.1 mg/dL to ~ 277.3 mg/dL) levels in LDLR-/- hamsters fed a high-fat diet. Ezetimibe administration (25 mg/kg/d) significantly promoted the protein expression of cholesterol 7 alpha-hydroxylase A1 (CYP7A1), LXRß and peroxisome proliferator-activated receptor (PPAR) γ; and down-regulated the protein expression of PPARα and PPARß. However, it showed no significant effect on sterol regulatory element-binding protein (SREBP)-1c, SREBP-2, proprotein convertase subtilisin/kexin type 9 (PCSK9), Niemann-Pick C1-like 1 (NPC1L1), and ATP-biding cassette (ABC) G5/G8. CONCLUSION: Ezetimibe may accelerate the transformation from cholesterol to bile acid via promoting CYP7A1 and thereby enhance RCT. As a compensatory mechanism of TG lowering, ezetimibe promoted the protein expression of PPARγ and decreased PPARα and ß. These results are helpful in explaining the lipid-lowering effects of ezetimibe and the potential compensatory mechanisms.


Assuntos
Colesterol 7-alfa-Hidroxilase/metabolismo , Ezetimiba/farmacologia , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores de LDL/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Western Blotting , Colesterol/metabolismo , Cricetinae , Dieta Hiperlipídica , Metabolismo dos Lipídeos/efeitos dos fármacos , Receptores de LDL/deficiência , Receptores de LDL/genética
12.
Nanotoxicology ; 14(3): 326-340, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31909642

RESUMO

Potential health hazards of nanomaterials on male reproductive system have received raising concerns. Even though Mn3O4 nanoparticles (Mn3O4-NPs) is highly effective in clinical diagnostic and therapeutic applications of human disease, its potential toxic effect on the male reproductive system has not been reported. In this study, the testis damage and fertility decrease of male rats were conducted to testify the experimental reproductive injury induced by Mn3O4-NPs. After repeated tail vein injection with 10 mg/kg/week Mn3O4-NPs for 0, 60 and 120 days, Mn3O4-NPs accumulated in the testes resulted in oxidative stress and disorder of normal serum sex hormones. Experiments in vivo and in vitro indicated that mitochondria-mediated cell apoptosis were triggered via oxidative stress, demonstrated by the upregulation of malondialdehyde (MDA) and the depolarization of mitochondrial membrane potential. Notably, Mn3O4-NPs significantly resulted in a reduction of the quantity/quality of sperm and finally caused astonishing fertility decrease. Our preliminary result implied that the application of Mn3O4-NPs could be a double-edged sword and careful consideration should be given to the clinical uses.


Assuntos
Fertilidade/efeitos dos fármacos , Nanopartículas/toxicidade , Óxidos/toxicidade , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Testículo/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Humanos , Masculino , Compostos de Manganês/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Nanopartículas/química , Estresse Oxidativo/efeitos dos fármacos , Óxidos/química , Ratos , Ratos Sprague-Dawley , Transdução de Sinais , Testículo/metabolismo , Testículo/patologia
13.
Nutrients ; 12(2)2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31973165

RESUMO

It is well recognized that whole-body fatty acid (FA) oxidation remains increased for several hours following aerobic endurance exercise, even despite carbohydrate intake. However, the mechanisms involved herein have hitherto not been subject to a thorough evaluation. In immediate and early recovery (0-4 h), plasma FA availability is high, which seems mainly to be a result of hormonal factors and increased adipose tissue blood flow. The increased circulating availability of adipose-derived FA, coupled with FA from lipoprotein lipase (LPL)-derived very-low density lipoprotein (VLDL)-triacylglycerol (TG) hydrolysis in skeletal muscle capillaries and hydrolysis of TG within the muscle together act as substrates for the increased mitochondrial FA oxidation post-exercise. Within the skeletal muscle cells, increased reliance on FA oxidation likely results from enhanced FA uptake into the mitochondria through the carnitine palmitoyltransferase (CPT) 1 reaction, and concomitant AMP-activated protein kinase (AMPK)-mediated pyruvate dehydrogenase (PDH) inhibition of glucose oxidation. Together this allows glucose taken up by the skeletal muscles to be directed towards the resynthesis of glycogen. Besides being oxidized, FAs also seem to be crucial signaling molecules for peroxisome proliferator-activated receptor (PPAR) signaling post-exercise, and thus for induction of the exercise-induced FA oxidative gene adaptation program in skeletal muscle following exercise. Collectively, a high FA turnover in recovery seems essential to regain whole-body substrate homeostasis.


Assuntos
Tecido Adiposo/metabolismo , Exercício Físico/fisiologia , Ácidos Graxos/farmacocinética , Músculo Esquelético/metabolismo , Nutrientes/farmacocinética , Proteínas Quinases Ativadas por AMP/metabolismo , Disponibilidade Biológica , Carnitina O-Palmitoiltransferase/metabolismo , Glucose/metabolismo , Glicogênio/metabolismo , Homeostase , Humanos , Hidrólise/efeitos dos fármacos , Lipase Lipoproteica/metabolismo , Lipoproteínas VLDL/metabolismo , Oxirredução/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Transdução de Sinais , Triglicerídeos/metabolismo
14.
Mol Biol Rep ; 47(2): 1045-1056, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31741264

RESUMO

Inflammation can deregulate the testicular functions of steroidogenesis and spermatogenesis, consequently contributing to male infertility. Animals and cells treated with lipopolysaccharide (LPS) exhibit infection- and inflammation-induced testicular dysfunction. However, the precise mechanisms affecting steroidogenesis and spermatogenesis in response to LPS-treatment remain poorly understood. We isolated distinct testicular cells including spermatocytes, round spermatids and late spermatids to analyze distribution of peroxisome proliferator-activated receptor (PPAR) family, plays central roles in the regulation of metabolism. Our results suggested Pparα/Pparγ mRNA was highly expressed in late spermatids, while Pparß mRNA was highly expressed in round spermatids. To analyze the effect of LPS on testicular cells, we established an LPS infection model using primary Sertoli cells and testicular cell lines (TM4, GC2 and MLTC1). We observed that PPARγ and SIRT1 were concentrated in the nuclear region and that the mRNA expression levels of antioxidative enzymes (Cat and Homx1) and PPARγ were upregulated in primary Sertoli cells after LPS-treatment. Moreover, luciferase reporter gene assays of the testicular cell lines revealed that the activity of the PPAR response element (PPRE) was significantly increased. Importantly, the transcriptional activity of the androgen response element was significantly reduced, whereas activity of estrogen response element was strongly induced in LPS-treated TM4 cells, consistent with the RT-PCR results. Meanwhile, the qRT-PCR results revealed that the LPS-induced upregulation of Ar mRNA in MLTC1 cells and Erß mRNA in TM4 cells were significantly recovered after treatment with the specific PPARγ-antagonist GW9662. In addition, we also found that LPS induced alterations in enzymes involved in steroidogenesis in testicular cell lines. Taken together, our results revealed that LPS may induce PPAR transcriptional activity to disturb estrogen/androgen receptor expression and impair steroidogenesis and ROS metabolism in testicular cells.


Assuntos
Espermatogênese/genética , Testículo/efeitos dos fármacos , Testículo/metabolismo , Androgênios/metabolismo , Animais , Estrogênios/metabolismo , Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hormônios Esteroides Gonadais/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/metabolismo , PPAR gama/metabolismo , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Receptores Androgênicos/metabolismo , Receptores Estrogênicos/metabolismo , Células de Sertoli/efeitos dos fármacos , Células de Sertoli/metabolismo , Espermátides/metabolismo , Espermatócitos/metabolismo
15.
Theriogenology ; 142: 251-259, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31711690

RESUMO

Our objective was to elucidate differences in endometrial mRNA expressions of interferon-stimulated genes (ISG15, CTSL1, RSAD2, SLC2A1, CXCL10, and SLC27A6), peroxisome proliferator activated receptors (PPARA, PPARD, and PPARG), retinoic acid receptors (RXRA, RXRB, and RXRG), and mucin 1 (MUC1) in repeat breeder cows, with or without subclinical endometritis (RB + SE and RB, respectively) and normal cows on day 16 post-ovulation (n = 4 cows per group). The CXCL10 and SLC27A6 mRNA abundances were greater for normal cows compared to RB and RB + SE cows (P < 0.05 and P < 0.01 respectively) whereas ISG15 and SLC2A1 mRNA abundances were greater for normal cows compared to RB + SE (P < 0.05). The SLC27A6 mRNA abundances were greater for RB versus RB + SE (P < 0.01). Similarly, PPARD, PPARG, RXRA and RXRG mRNA abundances were greater for normal cows compared to RB and RB + SE (P < 0.01 and P < 0.05, respectively). Abundances of PPARD, PPARG, RXRA and RXRG mRNA were greater for RB versus RB + SE (P < 0.05) and MUC1 was lower in abundance in normal cows compared to RB or RB + SE (P < 0.05). Key predicted molecular functions were binding, signal transducer and transporter; key biological processes were cellular, localization and metabolic; key cellular components were cell part, membrane and organelle components; and key protein classes were nucleic acid binding, receptor, and transcription factors. Gene networking analysis highlighted interactions and pathways involving PAPRs, RXRs, and MUC1, notably among PPARD, PPARG, and MUC1. In conclusion, endometrial mRNA expressions of ISGs (CXCL10 and SLC27A6), PPAR isomers (PPARD and PPARG), and RXRs (RXRA and RXRG) were in lower abundances, whereas MUC1 expression was more abundant in RB or RB + SE compared to normal cows on day 16. In addition, ISG15 and SLC2A1 genes were less abundant in RB + SE versus RB or normal cows. Altered expression of these uterine genes and associated potential impairment in embryo elongation and implantation may promote embryonic loss in repeat breeder cows. Furthermore, interactions among PPARD, PPARG and MUC1 may be therapeutically exploitable.


Assuntos
Bovinos/genética , Endometrite/genética , Endométrio/metabolismo , Ovulação/genética , Transcriptoma , Animais , Cruzamento , Bovinos/metabolismo , Doenças dos Bovinos/genética , Doenças dos Bovinos/metabolismo , Doenças dos Bovinos/patologia , Citocinas/genética , Citocinas/metabolismo , Endometrite/metabolismo , Endometrite/patologia , Endometrite/veterinária , Endométrio/patologia , Feminino , Perfilação da Expressão Gênica , Mucina-1/genética , Mucina-1/metabolismo , Ovulação/metabolismo , Paridade/fisiologia , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Gravidez , Receptores X Retinoide/genética , Receptores X Retinoide/metabolismo , Ubiquitinas/genética , Ubiquitinas/metabolismo
16.
Food Chem Toxicol ; 135: 110886, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31626838

RESUMO

Diabetes mellitus has become a worldwide concern in recent years. In this study, the effect of Holothuria leucospilota polysaccharide (HLP) on type 2 diabetes mellitus (T2DM) was investigated in Goto-Kakizaki (GK) rats. The results showed that HLP significantly improved glucose intolerance and regulated blood lipid and hormone levels (p < 0.05). Pathological analysis showed that HLP repaired the impairments of the pancreas and colon in diabetic rats. In addition, a high dose of HLP (200 mg/kg) significantly upregulated the gene expression of peroxisome proliferator-activated receptor-α (PPAR-α), peroxisome proliferator-activated receptor-γ (PPAR-γ), phosphoinositide 3-kinase (PI3K), protein kinase B (PKB/AKT), glucose transporter-4 (GLUT4) and anti-apoptotic (Bcl-2), and downregulated the mRNA levels of pro-apoptotic (Bax) and cluster of differentiation 36 (CD36) in diabetic rats (p < 0.05). Furthermore, HLP treatment increased the short-chain fatty acid-producing bacteria and decreased the opportunistic bacterial pathogen in the feces of diabetic rats. These results demonstrated that HLP has the potential to ameliorate T2DM in GK rats.


Assuntos
Diabetes Mellitus Experimental/microbiologia , Diabetes Mellitus Tipo 2/microbiologia , Microbioma Gastrointestinal/efeitos dos fármacos , Polissacarídeos/farmacologia , Adiponectina/metabolismo , Animais , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Peptídeo 1 Semelhante ao Glucagon/metabolismo , Insulina/metabolismo , Leptina/metabolismo , Lipídeos/sangue , Masculino , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Pepinos-do-Mar , Transdução de Sinais
17.
Horm Behav ; 117: 104609, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31647920

RESUMO

The objective of this study was to investigate the role of palmitoylethanolamide (PEA) in the regulation of energy homeostasis in goldfish (Carassius auratus). We examined the effects of acute or chronic intraperitoneal treatment with PEA (20 µg·g-1 body weight) on parameters related to food intake and its regulatory mechanisms, locomotor activity, glucose and lipid metabolism, and the possible involvement of transcription factors and clock genes on metabolic changes in the liver. Acute PEA treatment induced a decrease in food intake at 6 and 8 h post-injection, comparable to that observed in mammals. This PEA anorectic effect in goldfish could be mediated through interactions with leptin and NPY, as PEA increased hepatic expression of leptin aI and reduced hypothalamic expression of npy. The PEA chronic treatment reduced weight gain, growth rate, and locomotor activity. The rise in glycolytic potential together with the increased potential of glucose to be transported into liver suggests an enhanced use of glucose in the liver after PEA treatment. In addition, part of glucose may be exported to be used in other tissues. The activity of fatty acid synthase (FAS) increased after chronic PEA treatment, suggesting an increase in the hepatic lipogenic capacity, in contrast with the mammalian model. Such lipogenic increment could be linked with the PEA-induction of REV-ERBα and BMAL1 found after the chronic treatment. As a whole, the present study shows the actions of PEA in several compartments related to energy homeostasis and feeding behavior, supporting a regulatory role for this N-acylethanolamine in fish.


Assuntos
Metabolismo Energético/efeitos dos fármacos , Etanolaminas/farmacologia , Carpa Dourada/metabolismo , Homeostase/efeitos dos fármacos , Ácidos Palmíticos/farmacologia , Amidas , Animais , Peso Corporal/efeitos dos fármacos , Proteínas CLOCK/genética , Proteínas CLOCK/metabolismo , Ingestão de Alimentos/efeitos dos fármacos , Ingestão de Alimentos/fisiologia , Etanolaminas/administração & dosagem , Regulação da Expressão Gênica/efeitos dos fármacos , Hipotálamo/efeitos dos fármacos , Hipotálamo/metabolismo , Injeções Intraperitoneais , Leptina/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Ácidos Palmíticos/administração & dosagem , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Ganho de Peso/efeitos dos fármacos
18.
Cells ; 9(1)2019 12 21.
Artigo em Inglês | MEDLINE | ID: mdl-31877771

RESUMO

Non-alcoholic fatty liver disease (NAFLD) affects one-third of the population worldwide, of which a substantial number of patients suffer from non-alcoholic steatohepatitis (NASH). NASH is a severe condition characterized by steatosis and concomitant liver inflammation and fibrosis, for which no drug is yet available. NAFLD is also generally conceived as the hepatic manifestation of the metabolic syndrome. Consequently, well-established drugs that are indicated for the treatment of type 2 diabetes and hyperlipidemia are thought to exert effects that alleviate the pathological features of NASH. One class of these drugs targets peroxisome proliferator-activated receptors (PPARs), which are nuclear receptors that play a regulatory role in lipid metabolism and inflammation. Therefore, PPARs are now also being investigated as potential anti-NASH druggable targets. In this paper, we review the mechanisms of action and physiological functions of PPARs and discuss the position of the different PPAR agonists in the therapeutic landscape of NASH. We particularly focus on the PPAR agonists currently under evaluation in clinical phase II and III trials. Preclinical strategies and how refinement and optimization may improve PPAR-targeted anti-NASH drug testing are also discussed. Finally, potential caveats related to PPAR agonism in anti-NASH therapy are stipulated.


Assuntos
Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Chalconas/farmacologia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Desenvolvimento de Medicamentos , Fígado Gorduroso , Humanos , Hipoglicemiantes/farmacologia , Inflamação/patologia , Fígado/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Receptores Ativados por Proliferador de Peroxissomo/agonistas , Fenilpropionatos/farmacologia , Pioglitazona/farmacologia , Propionatos/farmacologia , Pirróis/farmacologia
19.
Molecules ; 25(1)2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31861504

RESUMO

Oxidation of fatty acids uses l-carnitine to transport acyl moieties to mitochondria in a so-called carnitine shuttle. The process of ß-oxidation also takes place in cancer cells. The majority of carnitine comes from the diet and is transported to the cell by ubiquitously expressed organic cation transporter novel family member 2 (OCTN2)/solute carrier family 22 member 5 (SLC22A5). The expression of SLC22A5 is regulated by transcription factors peroxisome proliferator-activated receptors (PPARs) and estrogen receptor. Transporter delivery to the cell surface, as well as transport activity are controlled by OCTN2 interaction with other proteins, such as PDZ-domain containing proteins, protein phosphatase PP2A, caveolin-1, protein kinase C. SLC22A5 expression is altered in many types of cancer, giving an advantage to some of them by supplying carnitine for ß-oxidation, thus providing an alternative to glucose source of energy for growth and proliferation. On the other hand, SLC22A5 can also transport several chemotherapeutics used in clinics, leading to cancer cell death.


Assuntos
Carnitina/metabolismo , Neoplasias/metabolismo , Membro 5 da Família 22 de Carreadores de Soluto/metabolismo , Transporte Biológico , Regulação Neoplásica da Expressão Gênica , Humanos , Mitocôndrias/metabolismo , Oxirredução , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Receptores Estrogênicos/metabolismo
20.
BMC Genomics ; 20(1): 863, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31729950

RESUMO

BACKGROUND: Intramuscular fat (IMF) is one of the most important factors positively associated with meat quality. Triglycerides (TGs), as the main component of IMF, play an essential role in muscle lipid metabolism. This transcriptome analysis of pectoralis muscle tissue aimed to identify functional genes and biological pathways likely contributing to the extreme differences in the TG content of broiler chickens. RESULTS: The study included Jingxing-Huang broilers that were significantly different in TG content (5.81 mg/g and 2.26 mg/g, p < 0.01) and deposition of cholesterol also showed the same trend. This RNA sequencing analysis was performed on pectoralis muscle samples from the higher TG content group (HTG) and the lower TG content group (LTG) chickens. A total of 1200 differentially expressed genes (DEGs) were identified between two groups, of which 59 DEGs were related to TG and steroid metabolism. The HTG chickens overexpressed numerous genes related to adipogenesis and lipogenesis in pectoralis muscle tissue, including the key genes ADIPOQ, CD36, FABP4, FABP5, LPL, SCD, PLIN1, CIDEC and PPARG, as well as genes related to steroid biosynthesis (DHCR24, LSS, MSMO1, NSDHL and CH25H). Additionally, key pathways related to lipid storage and metabolism (the steroid biosynthesis and peroxisome proliferator activated receptor (PPAR) signaling pathway) may be the key pathways regulating differential lipid deposition between HTG group and LTG group. CONCLUSIONS: This study showed that increased TG deposition accompanying an increase in steroid synthesis in pectoralis muscle tissue. Our findings of changes in gene expression of steroid biosynthesis and PPAR signaling pathway in HTG and LTG chickens provide insight into genetic mechanisms involved in different lipid deposition patterns in pectoralis muscle tissue.


Assuntos
Proteínas Aviárias/genética , Colesterol/biossíntese , Metabolismo dos Lipídeos/genética , Carne/análise , Músculos Peitorais/metabolismo , Transcriptoma , Triglicerídeos/biossíntese , Tecido Adiposo/metabolismo , Animais , Proteínas Aviárias/classificação , Proteínas Aviárias/metabolismo , Galinhas , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Receptores Ativados por Proliferador de Peroxissomo/genética , Receptores Ativados por Proliferador de Peroxissomo/metabolismo , Análise de Sequência de RNA , Transdução de Sinais , Esteroides/biossíntese
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