RESUMO
Early-life nutrition plays a critical role in fetal growth and development. Food intake absence and excess are the two main types of energy malnutrition that predispose to the appearance of diseases in adulthood, according to the hypothesis of 'developmental origins of health and disease'. Epidemiological data have shown an association between early-life malnutrition and the metabolic syndrome in later life. Evidence has also demonstrated that nutrition during this period of life can affect the development of the immune system through epigenetic mechanisms. Thus, epigenetics has an essential role in the complex interplay between environmental factors and genetics. Altogether, this leads to the inflammatory response that is commonly seen in non-alcoholic fatty liver disease (NAFLD), the hepatic manifestation of the metabolic syndrome. In conjunction, DNA methylation, covalent modification of histones and the expression of non-coding RNA are the epigenetic phenomena that affect inflammatory processes in the context of NAFLD. Here, we highlight current understanding of the mechanisms underlying developmental programming of NAFLD linked to epigenetic modulation of the immune system and environmental factors, such as malnutrition.
Assuntos
Epigênese Genética , Sistema Imunitário/fisiologia , Fígado/patologia , Desnutrição/complicações , Fenômenos Fisiológicos da Nutrição Materna , Hepatopatia Gordurosa não Alcoólica/etiologia , Estado Nutricional , Carcinoma Hepatocelular/etiologia , Metilação de DNA , Feminino , Histonas , Humanos , Inflamação/etiologia , Síndrome Metabólica/etiologia , MicroRNAs , Gravidez , Efeitos Tardios da Exposição Pré-NatalRESUMO
The aim of this work was to evaluate the effects of a diet depleted of amino acids (protein-free diet, or PFD), as well as the supplementation with methionine (PFD+Met), on the antioxidant status of the female mouse liver. With this purpose, cytosolic protein spots from two-dimensional non-equilibrium pH gel electrophoresis were identified by several procedures, such as mass spectrometry, Western blot, gel matching and enzymatic activity. PFD decreased the contents of catalase (CAT), peroxiredoxin I (Prx-I), and glutathione peroxidase (GPx) by 67%, 37% and 45%, respectively. Gene expression analyses showed that PFD caused a decrease in CAT (-20%) and GPx (-30%) mRNA levels but did not change that of Prx-I. It was also found that, when compared to a normal diet, PFD increased the liver contents of both reactive oxygen species (+50%) and oxidized protein (+88%) and decreased that of glutathione (-45%). Supplementation of PFD with Met prevented these latter effects to varying degrees, whereas CAT, Prx-I and GPx mRNA levels resulted unmodified. Present results suggest that dietary amino acid deprivation deranges the liver antioxidant defences, and this can be, in part, overcome by supplementation with Met.
Assuntos
Dieta com Restrição de Proteínas/efeitos adversos , Metionina/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Animais , Catalase/metabolismo , Citosol/metabolismo , Feminino , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Fígado/metabolismo , Camundongos , Carbonilação Proteica , RNA Mensageiro/metabolismo , Espécies Reativas de Oxigênio/metabolismoRESUMO
Protein malnutrition occurs when there is insufficient protein to meet metabolic demands. Previous works have indicated that cycles of protein fasting/refeeding enhance the incidence of early lesions during chemical carcinogenesis in rat liver. The general objective of this work was to study the effect of aminoacids (Aa) deprivation on the proliferation and survival of hepatocytes, to understand its possible involvement in the generation of pre-neoplastic stages in the liver. Lack of Aa in the culture medium of an immortalized mice hepatocyte cell line induced loss in cell viability, correlating with apoptosis. However, a subpopulation of cells was able to survive, which showed a more proliferative phenotype and resistance to apoptotic stimuli. Escaping to Aa deprivation-induced death is coincident with an activated mTOR signaling and higher levels of phospho-AKT and phospho-ERKs, which correlated with increased activation of EGFR/SRC pathway and overexpression of EGFR ligands, such as TGF-α and HB-EGF. Lack of Aa induced a rapid increase in reactive oxygen species (ROS) production. However, cells that survived showed an enhancement in the levels of reduced glutathione and a higher expression of γ-GCS, the regulatory enzyme of glutathione synthesis, which can be interpreted as an adaptation of the cells to counteract the oxidative stress. In conclusion, results presented in this paper indicate that it is possible to isolate a subpopulation of hepatocytes that are able to grow in the absence of Aa, showing higher capacity to proliferate and survive, reminiscent of a preneoplastic phenotype.
Assuntos
Aminoácidos/deficiência , Transformação Celular Neoplásica , Hepatócitos/fisiologia , Fígado/patologia , Animais , Caspase 3/metabolismo , Linhagem Celular Transformada , Proliferação de Células , Sobrevivência Celular , Meios de Cultura/química , Ativação Enzimática , Ensaios Enzimáticos , Camundongos , Oxirredução , Estresse Oxidativo , Fosfoproteínas/metabolismo , Fosforilação , Lesões Pré-Cancerosas/induzido quimicamente , Desnutrição Proteico-Calórica/induzido quimicamente , Transdução de Sinais , SirolimoRESUMO
The effect of frequent protein malnutrition on liver function has not been intensively examined. Thus, the effects of alternating 5 days of a protein and amino acid-free diet followed by 5 days of a complete diet repeated three times (3 PFD-CD) on female mouse liver were examined. The expression of carbonic anhydrase III (CAIII), fatty acid synthase (FAS), glyceraldehyde 3-phosphate dehydrogenase (GAPDH) and glutathione S-transferase P1 (GSTP1) in liver were assessed by proteomics, reverse transcriptase-polymerase chain reaction and Northern blotting. The activities of liver GSTs, glutathione reductase (GR) and catalase (CAT), as well as serum glutamic-oxaloacetic transaminase (SGOT) and glutamic-pyruvic transaminase (SGPT) were also tested. Additionally, oxidative damage was examined by measuring of protein carbonylation and lipid peroxidation. Liver histology was examined by light and electron microscopy. Compared with control mice, 3 PFD-CD increased the content of FAS protein (+90%) and FAS mRNA (+30%), while the levels of CAIII and CAIII mRNAs were decreased (-48% and -64%, respectively). In addition, 3 PFD-CD did not significantly change the content of GSTP1 but produced an increase in its mRNA level (+20%), while it decreased the activities of both CAT (-66%) and GSTs (-26%). After 3 PFD-CD, liver protein carbonylation and lipid peroxidation were increased by +55% and +95%, respectively. In serum, 3 PFD-CD increased the activities of both SGOT (+30%) and SGPT (+61%). In addition, 3 PFD-CD showed a histological pattern characteristic of hepatic damage. All together, these data suggest that frequent dietary amino acid deprivation causes hepatic metabolic and ultrastructural changes in a fashion similar to precancerous or cancerous conditions.
Assuntos
Proteínas Alimentares/administração & dosagem , Fígado/metabolismo , Fígado/patologia , Desnutrição/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Alanina Transaminase/sangue , Alanina Transaminase/efeitos dos fármacos , Alanina Transaminase/metabolismo , Animais , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/efeitos dos fármacos , Aspartato Aminotransferases/metabolismo , Anidrase Carbônica III/efeitos dos fármacos , Anidrase Carbônica III/metabolismo , Catalase/efeitos dos fármacos , Catalase/metabolismo , Ácido Graxo Sintases/efeitos dos fármacos , Ácido Graxo Sintases/metabolismo , Feminino , Glutationa Peroxidase/efeitos dos fármacos , Glutationa Peroxidase/metabolismo , Glutationa Redutase/efeitos dos fármacos , Glutationa Redutase/metabolismo , Glutationa Transferase/efeitos dos fármacos , Glutationa Transferase/metabolismo , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/efeitos dos fármacos , Gliceraldeído 3-Fosfato Desidrogenase (NADP+)/metabolismo , Peroxidação de Lipídeos , Fígado/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Carbonilação Proteica/efeitos dos fármacosRESUMO
The aim of the present study was to determine whether the central serotoninergic pathway (5HT) plays any stimulatory/inhibitory role in endotoxin-stimulated hypothalamo-pituitary-adrenal (HPA) axis function in the male rat. For this purpose, animals inhibited or not of central 5HT synthesis were injected with vehicle alone or containing endotoxin (LPS) and killed 2 h later. The results indicate that the inhibition of the 5HT pathway did not modify the LPS-induced hypoglycemia but that significantly reduced ACTH release in plasma. Although the inhibition of 5HT did not modify the CRH-ergic system, it diminished hypothalamic vasopressin (AVP) content in basal condition. After LPS injection, rats inhibited of 5HT synthesis showed a significant activation of the hypothalamic AVP-ergic system whereas control rats did not. These data clearly indicate that decreased HPA axis function after 5HT inhibition could be partially compensated by the facilitation of the AVP neuronal activity.