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1.
Biol Res ; 54(1): 25, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34362460

RESUMO

BACKGROUND: Peroxisome proliferator-activated receptor alpha (PPARα) is associated with diabetic retinopathy (DR), and the underlying mechanism is still unclear. Aim of this work was to investigate the mechanism of PPARα in DR. METHODS: Human retinal capillary pericytes (HRCPs) were treated with high glucose (HG) to induce DR cell model. DR mouse model was established by streptozotocin injection, and then received 5-Aza-2-deoxycytidine (DAC; DNA methyltransferase inhibitor) treatment. Hematoxylin-eosin staining was performed to assess retinal tissue damage. PPARα methylation was examined by Methylation-Specific PCR. Flow cytometry and DCFH-DA fluorescent probe was used to estimate apoptosis and reactive oxygen species (ROS). The interaction between DNA methyltransferase-1 (DNMT1) and PPARα promoter was examined by Chromatin Immunoprecipitation. Quantitative real-time PCR and western blot were performed to assess gene and protein expression. RESULTS: HG treatment enhanced the methylation levels of PPARα, and repressed PPARα expression in HRCPs. The levels of apoptotic cells and ROS were significantly increased in HRCPs in the presence of HG. Moreover, DNMT1 was highly expressed in HG-treated HRCPs, and DNMT1 interacted with PPARα promoter. PPARα overexpression suppressed apoptosis and ROS levels of HRCPs, which was rescued by DNMT1 up-regulation. In DR mice, DAC treatment inhibited PPARα methylation and reduced damage of retinal tissues. CONCLUSION: DNMT1-mediated PPARα methylation promotes apoptosis and ROS levels of HRCPs and aggravates damage of retinal tissues in DR mice. Thus, this study may highlight novel insights into DR pathogenesis.


Assuntos
DNA (Citosina-5-)-Metiltransferase 1/metabolismo , Retinopatia Diabética , PPAR alfa/genética , Retina/patologia , Animais , Apoptose , Células Cultivadas , Metilação de DNA , Diabetes Mellitus , Modelos Animais de Doenças , Humanos , Metilação , Camundongos , Regiões Promotoras Genéticas , Retina/citologia
2.
Sci Total Environ ; 790: 147990, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34380243

RESUMO

The plasticizer di(2-ethylhexyl) phthalate (DEHP) and its hydrolysate mono(2-ethylhexyl) phthalate (MEHP) are major toxicants from plastics, but their association with hormone-dependent cancers has been controversial. We treated the human ovarian cancer cell lines SKOV3 and A2780 with low concentrations of DEHP/MEHP, and found that although no significant effect on cell proliferation was observed, ovarian cancer cell migration, invasion, and epithelial-mesenchymal transition (EMT) were promoted by submicromolar MEHP but not DEHP. Next, ovarian cancer patient data from The Cancer Genome Atlas (TCGA) were obtained and subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) supported enrichment and Kaplan-Meier survival analyses, which identified PI3K/Akt pathway as a pivotal signaling pathway in ovarian cancer. We found that 500 nM MEHP treatment significantly increased PIK3CA expression, which could be reversed by the knockdown of peroxisome proliferator-activated receptor alpha (PPARα). Silencing PIK3CA significantly suppressed the MEHP-induced migration, invasion and EMT. In addition, we validated that MEHP treatment promoted phosphorylation of Akt and degradation of IκB-α, thereby activating NF-κB and enhancing NF-κB nuclear translocation. In nude mice, MEHP exposure significantly promoted the metastasis of ovarian cancer xenografts, which could be suppressed by the treatment of PPARα inhibitor GW6471. Our findings showed that low-dose MEHP promoted ovarian cancer progression through activating PI3K/Akt/NF-κB pathway, in a PPARα-dependent manner.


Assuntos
Dietilexilftalato , Neoplasias Ovarianas , Animais , Linhagem Celular Tumoral , Dietilexilftalato/análogos & derivados , Dietilexilftalato/toxicidade , Feminino , Humanos , Camundongos , Camundongos Nus , NF-kappa B , Neoplasias Ovarianas/induzido quimicamente , PPAR alfa/genética , Fosfatidilinositol 3-Quinases , Ácidos Ftálicos , Proteínas Proto-Oncogênicas c-akt
3.
Free Radic Biol Med ; 174: 249-263, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34390780

RESUMO

Alcohol metabolism in the liver simultaneously generates toxic metabolites and disrupts redox balance, but the regulatory mechanisms have not been fully elucidated. The study aimed to characterize the role of PPARα in alcohol detoxification. Hepatic PPARα and catalase levels were examined in patients with severe alcoholic hepatitis. Mouse studies were conducted to determine the effect of PPARα reactivation by Wy14,643 on alcoholic hepatotoxicity and how catalase is involved in mediating such effects. Cell culture study was conducted to determine the effect of hydrogen peroxide on cellular NAD levels. We found that the protein levels of PPARα and catalase were significantly reduced in the livers of patients with severe alcoholic hepatitis. PPARα reactivation by Wy14,643 effectively reversed alcohol-induced liver damage in mice. Global and targeted metabolites analysis revealed a fundamental role of PPARα in regulating the tryptophan-NAD pathway. Notably, PPARα activation completely switched alcohol metabolism from the CYP2E1 pathway to the catalase pathway along with accelerated alcohol clearance. Catalase knockout mice were incompetent in alcohol metabolism and hydrogen peroxide clearance and were more susceptible to alcohol-induced liver injury. Hydrogen peroxide-treated hepatocytes had a reduced size of cellular NAD pool. These data demonstrate a key role of PPARα in regulating hepatic alcohol detoxification. Catalase-mediated hydrogen peroxide removal represents an underlying mechanism of how PPARα preserves the NAD pool. The study provides a new angle of view about the PPARα-catalase pathway in combating alcohol toxicity.


Assuntos
NAD , PPAR alfa , Animais , Catalase/genética , Etanol/toxicidade , Humanos , Fígado , Camundongos , Camundongos Endogâmicos C57BL , PPAR alfa/genética
4.
Toxicol Appl Pharmacol ; 426: 115644, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34252412

RESUMO

Per- and polyfluoroalkyl substances (PFAS) are pervasive in the environment resulting in nearly universal detection in people. Human serum PFAS concentrations are strongly associated with increased serum low-density lipoprotein cholesterol (LDL-C), and growing evidence suggests an association with serum triacylglycerides (TG). Here, we tested the hypothesis that perfluorooctanoic acid (PFOA) dysregulates liver and serum triacylglycerides in human peroxisome proliferator activated receptor α (hPPARα)-expressing mice fed an American diet. Mice were exposed to PFOA (3.5 mg/L) in drinking water for 6 weeks resulting in a serum concentration of 48 ± 9 µg/ml. In male and female hPPARα mice, PFOA increased total liver TG and TG substituted with saturated and monounsaturated fatty acids. Lack of expression of PPARα alone also increased total liver TG, and PFOA treatment had little effect on liver TG in PPARα null mice. In hPPARα mice, PFOA neither significantly increased nor decreased serum TG; however, there was a modest increase in TG associated with very low-density cholesterol particles in both sexes. Intriguingly, in female PPARα null mice, PFOA significantly increased serum TG, with a similar trend in males. PFOA also modified fatty acid and TG homeostasis-related gene expression in liver, in a hPPARα-dependent manner, but not in adipose. The results of our study and others reveal the importance of context (serum concentration and genotype) in determining the effect of PFOA on lipid homeostasis.


Assuntos
Caprilatos/toxicidade , Dieta Ocidental , Dislipidemias/induzido quimicamente , Fluorcarbonetos/toxicidade , Fígado/efeitos dos fármacos , PPAR alfa/genética , Animais , Peso Corporal/efeitos dos fármacos , Dislipidemias/genética , Dislipidemias/metabolismo , Dislipidemias/patologia , Feminino , Expressão Gênica/efeitos dos fármacos , Genótipo , Lipidômica , Fígado/metabolismo , Fígado/patologia , Masculino , Camundongos Transgênicos , Tamanho do Órgão/efeitos dos fármacos , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Estados Unidos
5.
Fish Physiol Biochem ; 47(4): 1149-1164, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34142329

RESUMO

Diet-induced fatty liver is a considerable threaten to fish aquaculture due to the popularity of the high-fat diet (HFD) feeding. Our study aims to investigate the effects of flavanones from Sedum sarmentosum Bunge (FSSB) on the liver function to identify a potential treatment for HFD-induced fatty liver disease. Physiological and pathological indicators were tested in the liver of Nile tilapia (Oreochromis niloticus) and results showed parameters including lipid metabolites, redox parameters, and inflammatory factors could be adequately restored to normal level by addition of 150 mg/kg FSSB to HFD. Proteomics analysis was performed in liver tissues from tilapia with normal diet (ND), HFD, and HFD+FSSB. Totally, 51 upregulated proteins and 77 downregulated proteins were identified in HFD groups and 67 proteins of them were restored after treated with FSSB. Bioinformatics analysis showed that differentially expressed proteins (DEPs) in HFD+FSSB150 group compared with HFD group are mainly enriched in acety-CoA metabolic process, adenosine-triphosphate (ATP) biosynthetic process, lipid metabolic process, and phospholipid metabolic process. The dysregulated proteins were involved in peroxidosome proliferators-activated receptor (PPAR) signaling pathway, fat digestion and absorption, and immune system. The quantitative real-time PCR (qRT-PCR) assay further revealed that the expression of GST, PPARα, PPARγ, and multiple-inflammatory cytokines could be also reversed in HFD group under the treatment of 150 mg/kg FSSB. Our findings demonstrated FSSB is efficient for the treatment of fatty liver disease through regulation of lipid metabolism and antioxidation in Nile tilapia, providing a new treatment of non-alcoholic fatty liver disease (NAFLD) in fish aquaculture.


Assuntos
Antioxidantes/uso terapêutico , Ciclídeos , Fígado Gorduroso/tratamento farmacológico , Doenças dos Peixes/tratamento farmacológico , Flavanonas/uso terapêutico , Sedum , Animais , Antioxidantes/farmacologia , Colesterol/sangue , Ciclídeos/sangue , Ciclídeos/genética , Ciclídeos/crescimento & desenvolvimento , Dieta Hiperlipídica , Fígado Gorduroso/genética , Fígado Gorduroso/veterinária , Doenças dos Peixes/genética , Proteínas de Peixes/genética , Flavanonas/farmacologia , Glutationa Transferase/genética , Hepatócitos/efeitos dos fármacos , Hepatócitos/metabolismo , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , PPAR alfa/genética , PPAR gama/genética , Triglicerídeos/sangue
6.
Nat Commun ; 12(1): 3660, 2021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34135321

RESUMO

The mechanistic target of rapamycin complex 1 (mTORC1) integrates cellular nutrient signaling and hormonal cues to control metabolism. We have previously shown that constitutive nutrient signaling to mTORC1 by means of genetic activation of RagA (expression of GTP-locked RagA, or RagAGTP) in mice resulted in a fatal energetic crisis at birth. Herein, we rescue neonatal lethality in RagAGTP mice and find morphometric and metabolic alterations that span glucose, lipid, ketone, bile acid and amino acid homeostasis in adults, and a median lifespan of nine months. Proteomic and metabolomic analyses of livers from RagAGTP mice reveal a failed metabolic adaptation to fasting due to a global impairment in PPARα transcriptional program. These metabolic defects are partially recapitulated by restricting activation of RagA to hepatocytes, and revert by pharmacological inhibition of mTORC1. Constitutive hepatic nutrient signaling does not cause hepatocellular damage and carcinomas, unlike genetic activation of growth factor signaling upstream of mTORC1. In summary, RagA signaling dictates dynamic responses to feeding-fasting cycles to tune metabolism so as to match the nutritional state.


Assuntos
Jejum/metabolismo , Fígado/metabolismo , Proteínas Monoméricas de Ligação ao GTP/metabolismo , Transdução de Sinais , Animais , Modelos Animais de Doenças , Glucose/metabolismo , Homeostase , Humanos , Alvo Mecanístico do Complexo 1 de Rapamicina/antagonistas & inibidores , Alvo Mecanístico do Complexo 1 de Rapamicina/metabolismo , Camundongos , Proteínas Monoméricas de Ligação ao GTP/genética , Nutrientes/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Fenótipo , Proteômica , Transdução de Sinais/efeitos dos fármacos , Sirolimo/administração & dosagem , Sirolimo/farmacologia , Transcrição Genética/efeitos dos fármacos , Proteína 1 do Complexo Esclerose Tuberosa/genética , Proteína 1 do Complexo Esclerose Tuberosa/metabolismo
7.
Free Radic Biol Med ; 169: 283-293, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33892114

RESUMO

Peroxisome proliferator-activated receptor α (PPARα), a fatty acid oxidation regulator, inhibits alcohol-induced fatty liver (AFL). PPARα agonist WY-14,643 ameliorates AFL. Nicotine enhances AFL. In this study, we investigated whether PPARα activation also blocks nicotine-enhanced AFL. Mice were fed liquid diets containing ethanol in the presence or absence of nicotine, WY-14,643 was added to the above diets at 10 mg/L. The results showed that WY-14,643 blunted AFL and nicotine-enhanced AFL, which was paralleled with striking induction of PPARα target genes. However, serum ALT was dramatically increased by the ethanol/WY-14,643 feeding and was further increased by nicotine/ethanol/WY-14,643 feeding, which was confirmed by necro-inflammation and elevated oxidative stress. Interestingly, serum alcohol levels were dramatically decreased by WY-14,643. Ethanol is mainly metabolized by alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1) and catalase. ADH and CYP2E1 were not increased by WY-14,643, but catalase was induced. What is more, injection of catalase inhibitor increased serum ethanol. Decreased serum alcohol, attenuated fatty liver, and enhanced liver injury were not induced by WY-14,643 in mice lacking PPARα. In conclusion, PPARα activation by WY-14,643 attenuates alcohol/nicotine-induced fatty liver but deteriorates ethanol/nicotine-induced liver injury; WY-14,643 enhances ethanol metabolism via induction of catalase.


Assuntos
PPAR alfa , Pirimidinas , Animais , Catalase/genética , Etanol , Fígado , Camundongos , PPAR alfa/genética
8.
Aging (Albany NY) ; 13(8): 11969-11987, 2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33891564

RESUMO

Circular RNAs (circRNAs) have critical regulatory roles in tumor biology. However, their contributions in hepatocellular carcinoma (HCC) still remain enigmatic. The present study aimed to investigate the molecular mechanisms underlying the involvement of hsa_circ_0110102 in the occurrence and development of HCC. The expression level of hsa_circ_0110102 was significantly downregulated in HCC cell lines and tissues, which was associated with poor prognosis. Knockdown hsa_circ_0110102 significantly promoted cell proliferation, migration, and invasion. Moreover, the interaction between hsa_circ_0110102 and miR-580-5p was predicted and verified by luciferase assay and RNA pull-down. The findings indicated that hsa_circ_0110102 functioned as a sponge for miR-580-5p. Moreover, miR-580-5p directly bound to the 3' UTR of PPARα, which decreased the production and release of C-C chemokine ligand 2 (CCL2) in HCC cells. CCL2 could activate the cyclooxygenase-2/prostaglandin E2 (COX-2/PGE2) pathway in macrophage via FoxO1 in a p38 MAPK-dependent manner. Furthermore, the Δ256 mutant of FoxO1 showed no activation effect. These results concluded that hsa_circ_0110102 acted as a sponge for miR-580-5p and inhibited CCL2 secretion into tumor microenvironment by decrease the expression of PPARα in HCC cells, then inhibited the pro-inflammatory cytokine release from macrophages by regulating the COX-2/PGE2 pathway. In conclusion, hsa_circ_0110102 served as a potential prognostic predictor or therapeutic target for HCC.


Assuntos
Carcinoma Hepatocelular/genética , Neoplasias Hepáticas/genética , Ativação de Macrófagos/genética , MicroRNAs/metabolismo , RNA Circular/metabolismo , Idoso , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/imunologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Quimiocina CCL2/metabolismo , Ciclo-Oxigenase 2/metabolismo , Dinoprostona/metabolismo , Progressão da Doença , Regulação para Baixo , Feminino , Proteína Forkhead Box O1/metabolismo , Regulação Neoplásica da Expressão Gênica/imunologia , Técnicas de Silenciamento de Genes , Humanos , Fígado/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica/genética , Estadiamento de Neoplasias , PPAR alfa/genética , PPAR alfa/metabolismo , Prognóstico , RNA Circular/genética , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
9.
Int J Biol Macromol ; 182: 179-186, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33838185

RESUMO

Peroxisome proliferator-activated receptor α (PPARα) play a key role in the regulation of metabolic homeostasis, inflammation, cellular growth, and differentiation. To further explore the potential role of PPARα in the energy homeostasis of fatty liver hemorrhagic syndrome (FLHS), we reported the prokaryotic expression and purification of chicken PPARα subunit protein, and successfully prepared a polyclonal antibody against PPARα recombinant protein. The 987 bp PPARα subunit genes were cloned into the pEASY-T3 clone vector. Then the plasmid PCR products encoding 329 amino acids were ligated to pEASY-Blunt E2 vector and transformed into BL21 to induce expression. The recombinant PPARα subunit protein, containing His-tag, was purified by affinity column chromatography using Ni-NTA affinity column. Rabbit antiserum was generated by using the concentration of recombinant PPARα subunit protein as the antigen. The results of western blotting showed that the antiserum can specifically recognize chicken endogenous PPARα protein. Immunohistochemistry and immunofluorescence showed that the PPARα mainly existed in the nucleus of hepatocytes, renal epithelial cells and hypothalamic endocrine nerve cells. More importantly, western blotting and real-time quantitative PCR indicated that FLHS significantly decreased the expression of PPARα.


Assuntos
Anticorpos/imunologia , Fígado Gorduroso/veterinária , Hemorragia/veterinária , PPAR alfa/metabolismo , Doenças das Aves Domésticas/metabolismo , Animais , Reações Antígeno-Anticorpo , Western Blotting/métodos , Células Cultivadas , Galinhas , Fígado Gorduroso/metabolismo , Feminino , Hemorragia/metabolismo , Hepatócitos/metabolismo , Hipotálamo/metabolismo , Imuno-Histoquímica/métodos , Rim/metabolismo , PPAR alfa/genética , PPAR alfa/imunologia , Síndrome
10.
J Nutr Biochem ; 94: 108751, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33915261

RESUMO

Diets rich in mono or polyunsaturated fats have been associated with a healthy phenotype, but there is controversial evidence about coconut oil (CO), which is rich in saturated medium-chain fatty acids. Therefore, the purpose of the present work was to study whether different types of oils rich in polyunsaturated (soybean oil, SO), monounsaturated (olive oil, OO), or saturated fatty acids (coconut oil, CO) can regulate the gut microbiota, insulin sensitivity, inflammation, mitochondrial function in wild type and PPARα KO mice. The group that received SO showed the highest microbial diversity, increase in Akkermansia muciniphila, high insulin sensitivity and low grade inflammation, The OO group showed similar insulin sensitivity and insulin signaling than SO, increase in Bifidobacterium, increase in fatty acid oxidation and low grade inflammation. The CO consumption led to the lowest bacterial diversity, a 9-fold increase in the LPS concentration leading to metabolic endotoxemia, hepatic steatosis, increased lipogenesis, highest LDL-cholesterol concentration and the lowest respiratory capacity and fatty acid oxidation in the mitochondria. The absence of PPARα decreased alpha diversity and increased LPS concentration particularly in the CO group, and increased insulin sensitivity in the groups fed SO or OO. These results indicate that consuming mono or polyunsaturated fatty acids produced health benefits at the recommended intake but a high concentration of oils (three times the recommended oil intake in rodents) significantly decreased the microbial alpha-diversity independent of the type of oil.


Assuntos
Óleo de Coco/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Azeite de Oliva/farmacologia , PPAR alfa/metabolismo , Óleo de Soja/farmacologia , Animais , Bactérias/classificação , Bactérias/genética , Células Cultivadas , Biologia Computacional , DNA Bacteriano/genética , Fezes/química , Regulação da Expressão Gênica/efeitos dos fármacos , Genótipo , Intolerância à Glucose , Hepatócitos/efeitos dos fármacos , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , PPAR alfa/genética , RNA Bacteriano/genética , RNA Ribossômico 16S , Distribuição Aleatória , Receptor 4 Toll-Like/genética , Receptor 4 Toll-Like/metabolismo
11.
Am J Physiol Endocrinol Metab ; 320(5): E938-E950, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33813880

RESUMO

Elevated mitochondrial hydrogen peroxide (H2O2) emission and an oxidative shift in cytosolic redox environment have been linked to high-fat-diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle ß-oxidation flux were studied. In mice overexpressing peroxisome proliferator-activated receptor-α in muscle (MCK-PPARα), lipid-supported mitochondrial respiration, membrane potential (ΔΨm), and H2O2 production rate (JH2O2) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1-deficient, fatty-liver dystrophic mice, another model characterized by increased ß-oxidation flux and glucose intolerance. Crossing MCAT (mitochondria-targeted catalase) with MCK-PPARα mice normalized JH2O2 production, redox environment, and glucose tolerance, but surprisingly, both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high-fat diet, MCK-PPARα mice were characterized by much lower whole body, fat, and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARα in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high-fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in an attempt to restore bioenergetic homeostasis.NEW & NOTEWORTHY Prior work has suggested that mitochondrial dysfunction is an underlying cause of insulin resistance in muscle because it limits fatty acid oxidation and therefore leads to the accumulation of cytotoxic lipid intermediates. The implication has been that therapeutic strategies to accelerate ß-oxidation will be protective. The current study provides evidence that genetically increasing flux through ß-oxidation in muscle imposes reductive stress that is not beneficial but rather detrimental to metabolic regulation.


Assuntos
Catalase/genética , Intolerância à Glucose/genética , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , PPAR alfa/genética , Animais , Catalase/metabolismo , Metabolismo Energético/genética , Intolerância à Glucose/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Mitocôndrias Musculares/genética , Especificidade de Órgãos/genética , Oxirredução , Estresse Oxidativo/genética , PPAR alfa/metabolismo
12.
Ecotoxicology ; 30(5): 954-965, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33864550

RESUMO

Clofibric acid (CFA), a drug and personal care product, has been identified as ubiquitous in the aquatic system and surface water, causing pollution to the environment. In this study, after environmental (4 µg/L) levels of CFA challenge, the LvFABP, LvACS gene expressions, total haemocyte count (THC), relative enzymes (SOD1 and GST) activities in Litopenaeus vannamei were observed to decrease. In the meantime LvFATP, LvRXR expression and the level of NEFA were upregulated in L. vannamei body. LvFABP expression in vivo was knocked down by dsRNA-mediated RNA interference (RNAi), which led to significantly decreased levels of PPARα (including LvFATP, LvRXR and LvACS). When exposed to environmental CFA after 4 days, LvFABP knocked down group had a sharp upregulation of LvFATP, LvRXR, LvACS expression, GST activity and NEFA amount, following decreased THC and SOD1 activity. These results suggested that environmental concentration CFA may have some toxicological effect on L. vannamei, following fatty acids metabolism and oxidative stress responses by LvFABP via the PPARα/RXR signaling pathway, including LvFATP, LvRXR and LvACS.


Assuntos
PPAR alfa , Penaeidae , Animais , Ácido Clofíbrico , Exposição Ambiental , Ácidos Graxos , Estresse Oxidativo , PPAR alfa/genética , Transdução de Sinais
13.
Theranostics ; 11(10): 4710-4727, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754023

RESUMO

Background: Telomere shortening and dysfunction may cause metabolic disorders, tissue damage and age-dependent pathologies. However, little is known about the association of telomere-associated protein Rap1 with mitochondrial energy metabolism and cardiac aging. Methods: Echocardiography was performed to detect cardiac structure and function in Rap1+/+ and Rap1-/- mice at different ages (3 months, 12 months and 20 months). Telomere length, DNA damage, cardiac senescence and cardiomyocyte size were analyzed using the real-time PCR, Western blotting, senescence associated ß-galactosidase assay and wheat germ agglutinin staining, respectively. Western blotting was also used to determine the level of cardiac fatty acid metabolism related key enzymes in mouse and human myocardium. Chromatin immunoprecipitation assay was used to verify the direct link between p53 and PPARα. The p53 inhibitor, Pifithrin-α and PPARα activator WY14643 were utilized to identify the effects of Rap1/p53/PPARα signaling pathway. Results: Telomere was shortened concomitant with extensive DNA damage in aged Rap1-/- mouse hearts, evidenced by reduced T/S ratios and increased nuclear γH2AX. Meanwhile, the aging-associated phenotypes were pronounced as reflected by altered mitochondrial ultrastructure, enhanced senescence, cardiac hypertrophy and dysfunction. Mechanistically, acetylated p53 and nuclear p53 was enhanced in the Rap1-/- mouse hearts, concomitant with reduced PPARα. Importantly, p53 directly binds to the promoter of PPARα in mouse hearts and suppresses the transcription of PPARα. In addition, aged Rap1-/- mice exhibited reduced cardiac fatty acid metabolism. Pifithrin-α alleviated cardiac aging and enhanced fatty acid metabolism in the aged Rap1-/- mice. Activating PPARα with WY14643 in primarily cultured Rap1-/- cardiomyocytes restored maximal oxygen consumption rates. Reduced Rap1 expression and impaired p53/PPARα signaling also presented in aged human myocardium. Conclusion: In summary, Rap1 may link telomere biology to fatty acid metabolism and aging-related cardiac pathologies via modulating the p53/PPARα signaling pathway, which could represent a therapeutic target in preventing/attenuating cardiac aging.


Assuntos
Envelhecimento/genética , Cardiomegalia/genética , Senescência Celular/genética , Miócitos Cardíacos/metabolismo , PPAR alfa/genética , Proteínas de Ligação a Telômeros/genética , Proteína Supressora de Tumor p53/genética , Animais , Benzotiazóis/farmacologia , Cardiomegalia/diagnóstico por imagem , Cardiomegalia/fisiopatologia , Dano ao DNA , Ecocardiografia , Ácidos Graxos/metabolismo , Cardiopatias/diagnóstico por imagem , Cardiopatias/genética , Cardiopatias/fisiopatologia , Histonas/metabolismo , Camundongos , Camundongos Knockout , Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Cardíacas/ultraestrutura , Teste de Campo Aberto , PPAR alfa/metabolismo , Proliferadores de Peroxissomos/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais , Telômero/metabolismo , Homeostase do Telômero , Proteínas de Ligação a Telômeros/metabolismo , Tolueno/análogos & derivados , Tolueno/farmacologia , Proteína Supressora de Tumor p53/antagonistas & inibidores , Proteína Supressora de Tumor p53/metabolismo
14.
J Nutr Biochem ; 95: 108633, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33789150

RESUMO

The liver is a critical mediator of lipid and/or glucose homeostasis and is a primary organ involved in dynamic changes during feeding and fasting. Additionally, hepatic-centric pathways are prone to dysregulation during pathophysiological states including metabolic syndrome (MetS) and non-alcoholic fatty liver disease. Omics platforms and GWAS have elucidated genes related to increased risk of developing MetS and related disorders, but mutations in these metabolism-related genes are rare and cannot fully explain the increasing prevalence of MetS-related pathologies worldwide. Complex interactions between diet, lifestyle, environmental factors, and genetic predisposition jointly determine inter-individual variability of disease risk. Given the complexity of these interactions, researchers have focused on master regulators of metabolic responses incorporating and mediating the impact of multiple environmental cues. Transcription factors are DNA binding, terminal executors of signaling pathways that modulate the cellular responses to complex metabolic stimuli and are related to the control of hepatic lipid and glucose homeostasis. Among numerous hepatic transcription factors involved in regulating metabolism, three emerge as key players in transducing nutrient sensing, which are dysregulated in MetS-related perturbations in both clinical and preclinical studies: cAMP Responsive Element Binding Protein 3 Like 3 (CREB3L3), Peroxisome Proliferator Activated Receptor Alpha (PPAR), and Forkhead Box O1 (FOXO1). Additionally, these three transcription factors appear to be amenable to dietary and/or nutrient-based therapies, being potential targets of nutritional therapy. In this review we aim to describe the activation, regulation, and impact of these transcription factors in the context of metabolic homeostasis. We also summarize their perspectives in MetS and nutritional therapies.


Assuntos
Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Dieta/efeitos adversos , Metabolismo Energético , Proteína Forkhead Box O1/metabolismo , PPAR alfa/metabolismo , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/genética , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , PPAR alfa/genética
15.
Molecules ; 26(4)2021 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-33671486

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is among the leading causes of end-stage liver disease. The impaired hepatic lipid metabolism in NAFLD is exhibited by dysregulated PPARα and SREBP-1c signaling pathways, which are central transcription factors associated with lipid degradation and de novo lipogenesis. Despite the growing prevalence of this disease, current pharmacological treatment options are unsatisfactory. Genistein, a soy isoflavone, has beneficial effects on lipid metabolism and may be a candidate for NAFLD treatment. In an in vitro model of hepatic steatosis, primary human hepatocytes (PHHs) were incubated with free fatty acids (FFAs) and different doses of genistein. Lipid accumulation and the cytotoxic effects of FFAs and genistein treatment were evaluated by colorimetric and enzymatic assays. Changes in lipid homeostasis were examined by RT-qPCR and Western blot analyses. PPARα protein expression was induced in steatotic PHHs, accompanied by an increase in CPT1L and ACSL1 mRNA. Genistein treatment increased PPARα protein expression only in control PHHs, while CPTL1 and ACSL1 were unchanged and PPARα mRNA was reduced. In steatotic PHHs, genistein reversed the increase in activated SREBP-1c protein. The model realistically reflected the molecular changes in hepatic steatosis. Genistein suppressed the activation of SREBP-1c in steatotic hepatocytes, but the genistein-mediated effects on PPARα were abolished by high hepatic lipid levels.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Genisteína/farmacologia , Fígado/efeitos dos fármacos , Modelos Biológicos , Células Cultivadas , Relação Dose-Resposta a Droga , Fígado Gorduroso/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/antagonistas & inibidores , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
16.
J Physiol Biochem ; 77(2): 205-214, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33555532

RESUMO

Nowadays, the complications related to diabetes, such as nephropathy, cardiovascular problems, and aging, are highly being considered. Renal cell aging is affected by various mechanisms of inflammation, oxidative stress, and basement membrane thickening, which are significant causes of renal dysfunction in diabetes. Due to recent studies, adiponectin plays a key role in diabetes-related kidney diseases as a fat-derived hormone. In diabetes, reduced adiponectin levels are associated to renal cell aging. Oxidative stress and related signaling pathways are the main routes in which adiponectin may be effective to decline diabetes-associated aging. Therefore, adiponectin signaling in target tissues becomes one of the research areas of interest in metabolism and clinical medicine. Studies on adiponectin signaling will increase our understanding of adiponectin role in diabetes-linked diseases as well as shortening life span conditions which may guide the design of antidiabetic and anti-aging drugs.


Assuntos
Adiponectina/genética , Diabetes Mellitus Tipo 2/genética , Nefropatias Diabéticas/genética , Obesidade/tratamento farmacológico , Obesidade/genética , Receptores de Adiponectina/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Adiponectina/metabolismo , Envelhecimento , Animais , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/tratamento farmacológico , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Regulação da Expressão Gênica , Humanos , Hipoglicemiantes/uso terapêutico , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Redes e Vias Metabólicas/genética , Obesidade/metabolismo , Obesidade/patologia , Estresse Oxidativo , PPAR alfa/genética , PPAR alfa/metabolismo , Receptores de Adiponectina/metabolismo , Transdução de Sinais
17.
J Sci Food Agric ; 101(12): 5038-5048, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33570774

RESUMO

BACKGROUND: Polyphenols have the potential to reduce the risk of many metabolic disorders. Lily bulbs are rich in polyphenols; however, their effects on lipid metabolism remain unclear. This study aimed to explore the effects of lily bulbs' polyphenols (LBPs) on oxidative stress and lipid metabolism. RESULTS: A total of 14 polyphenolic compounds in LBPs were identified by high-performance liquid chromatography equipped with diode-array detection mass spectrometry. Total phenolic compound in LBPs was 53.76 ± 1.12 g kg-1 dry weight. In cellular experiments, LBPs attenuated the disruption of mitochondrial membrane potential, impeded reactive oxygen species production, alleviated oxidative stress, and reduced lipid accumulation in oleic acid induced HepG2 cells. In in vivo studies, LBPs significantly inhibited body weight gain, reduced lipid levels in serum and liver, and improved oxidative damage in a dose-dependent manner in mice fed a high-fat diet. Moreover, LBPs ameliorated hepatic steatosis and suppressed the expression of hepatic-lipogenesis-related genes (SREBP-1c, FAS, ACC1, and SCD-1) and promoted lipolysis genes (SRB1 and HL) and lipid oxidation genes (PPARα and CPT-1) in mice fed a high-fat diet. CONCLUSION: It was concluded that LBPs are a potential complementary therapeutic alternative in the development of functional foods to curb obesity and obesity-related diseases, such as metabolic syndrome. © 2021 Society of Chemical Industry.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Lilium/química , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/administração & dosagem , Raízes de Plantas/química , Polifenóis/administração & dosagem , Animais , Dieta Hiperlipídica , Fígado Gorduroso/genética , Fígado Gorduroso/metabolismo , Células Hep G2 , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos ICR , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/genética , Mitocôndrias/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
18.
Circ Res ; 128(3): 335-357, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33539225

RESUMO

RATIONALE: Diabetic cardiomyopathy (DbCM) is a major complication in type-1 diabetes, accompanied by altered cardiac energetics, impaired mitochondrial function, and oxidative stress. Previous studies indicate that type-1 diabetes is associated with increased cardiac expression of KLF5 (Krüppel-like factor-5) and PPARα (peroxisome proliferator-activated receptor) that regulate cardiac lipid metabolism. OBJECTIVE: In this study, we investigated the involvement of KLF5 in DbCM and its transcriptional regulation. METHODS AND RESULTS: KLF5 mRNA levels were assessed in isolated cardiomyocytes from cardiovascular patients with diabetes and were higher compared with nondiabetic individuals. Analyses in human cells and diabetic mice with cardiomyocyte-specific FOXO1 (Forkhead box protein O1) deletion showed that FOXO1 bound directly on the KLF5 promoter and increased KLF5 expression. Diabetic mice with cardiomyocyte-specific FOXO1 deletion had lower cardiac KLF5 expression and were protected from DbCM. Genetic, pharmacological gain and loss of KLF5 function approaches and AAV (adeno-associated virus)-mediated Klf5 delivery in mice showed that KLF5 induces DbCM. Accordingly, the protective effect of cardiomyocyte FOXO1 ablation in DbCM was abolished when KLF5 expression was rescued. Similarly, constitutive cardiomyocyte-specific KLF5 overexpression caused cardiac dysfunction. KLF5 caused oxidative stress via direct binding on NADPH oxidase (NOX)4 promoter and induction of NOX4 (NADPH oxidase 4) expression. This was accompanied by accumulation of cardiac ceramides. Pharmacological or genetic KLF5 inhibition alleviated superoxide formation, prevented ceramide accumulation, and improved cardiac function in diabetic mice. CONCLUSIONS: Diabetes-mediated activation of cardiomyocyte FOXO1 increases KLF5 expression, which stimulates NOX4 expression, ceramide accumulation, and causes DbCM.


Assuntos
Cardiomiopatias Diabéticas/metabolismo , Proteína Forkhead Box O1/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , PPAR alfa/metabolismo , Idoso , Animais , Linhagem Celular , Cardiomiopatias Diabéticas/genética , Cardiomiopatias Diabéticas/patologia , Modelos Animais de Doenças , Feminino , Proteína Forkhead Box O1/genética , Regulação da Expressão Gênica , Humanos , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Pessoa de Meia-Idade , Miócitos Cardíacos/patologia , PPAR alfa/genética , Transcrição Genética
19.
Mol Biol Rep ; 48(2): 1359-1370, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33580458

RESUMO

Hepatic steatosis is an early form of non-alcoholic fatty liver disease (NAFLD), caused by abnormal fat deposition in the hepatocytes. Conjugated linoleic acid (CLA) is a group of positional and geometric dienoic isomers of linoleic acid that attract significant attention because of its beneficial effects on chronic diseases such as cancer, obesity, and metabolic syndrome. This study examined the influence of a mixture of two main CLA isomers (CLA-mix) on lipid accumulation and lipid metabolism-related genes using HepG2 cells treated with palmitic acid (PA) as an in vitro model for hepatic steatosis. Methods and Results: HepG2 cells were treated for 24 h: control (BSA), model (BSA + PA), and treated groups (BSA-PA + non-toxic concentrations of CLA-mix). Intracellular lipid deposition, triglyceride (TG), total cholesterol (TC) and gene expression were measured by Oil-Red O staining, colorimetric assay kits and real-time PCR, respectively. CLA-mix at high concentrations had significantly decreased intracellular total lipid and TG deposition compared to the model group. However, none of the CLA-mix concentrations had a significant effect on the intracellular TC level. CLA-mix significantly increased the expression of some genes mainly regulated by PPARα but did not alter the expression of lipogenesis-related genes. Conclusions: These results demonstrate that high concentrations of CLA-mix protect against hepatic steatosis and play a role in regulating fatty acid oxidation and bile excretion through the PPARα pathway. It is suggested that the effect of different ratios of two main CLA isomers on the amount and ratio of bile compounds be investigated in future studies.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Ácidos Linoleicos Conjugados/farmacologia , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Obesidade/tratamento farmacológico , PPAR alfa/genética , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Regulação da Expressão Gênica/efeitos dos fármacos , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipogênese/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Obesidade/metabolismo , Obesidade/patologia , Oxirredução/efeitos dos fármacos , Triglicerídeos/metabolismo
20.
Sci Total Environ ; 772: 144957, 2021 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-33578161

RESUMO

Short-chain chlorinated paraffins (SCCPs) could disrupt fatty acid metabolism in male rat liver through activating rat PPARα signaling. However, whether this mode of action can translate to humans remained largely unclear. In this study, based on luciferase assays, C10-13-CPs (56.5% Cl) at concentrations greater than 1 µM (i.e., 362 µg/L) showed weak agonistic activity toward human PPARα (hPPARα) signaling. But in HepG2 cells, exposure to C10-13-CPs (56.5% Cl) at the human internal exposure level (100 µg/L) down-regulated expressions of most of the tested hPPARα target genes, which encode for enzymes that oxidize fatty acids. In line with the gene expression data, metabolomics further confirmed that exposure to four SCCP standards with varying chlorine contents at 100 µg/L significantly suppressed oxidation of fatty acids in HepG2 cells, mainly evidenced by elevations in both total fatty acids and long-chain acylcarnitines. In addition, exposure to these SCCPs also caused a shift in carbohydrate metabolism from the tricarboxylic acid cycle (TCA cycle) to aerobic glycolysis. Overall, the results revealed that SCCPs could inhibit hPPARα-mediated fatty acid oxidation, and stimulated aerobic glycolysis in HepG2 cells.


Assuntos
Hidrocarbonetos Clorados , Parafina , Animais , China , Ciclo do Ácido Cítrico , Monitoramento Ambiental , Ácidos Graxos , Glicólise , Humanos , Hidrocarbonetos Clorados/análise , Masculino , PPAR alfa/genética , Parafina/análise , Ratos
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