RESUMO
SCOPE: Omega-3 polyunsaturated fatty acids (n-3 PUFA) found in fish oil activate PPAR-α, stimulate peroxisomal fatty acid (FA) ß-oxidation and prevent impairments on glucose homeostasis. METHODS AND RESULTS: Glucose metabolism and FA oxidation were studied in C57/Bl6 mice fed with diets containing either 3.6 and 31.5% fish oil or lard. To assess the effects of peroxisomal proliferation on FA oxidation independent of n-3 PUFA intake, mice were treated with the PPAR-α agonist WY-14643. n-3 PUFA-fed mice were protected from glucose intolerance and dyslipidemia compared to animals fed a lard-based high-fat diet. Most importantly, mice fed on the hyperlipidic diet based on fish oil as well as the WY-14643 treated mice showed twofold increase of odd, medium-chain, dicarboxylic acylcarnitines in the liver suggesting that not only ß-oxidation, but also α- and ω-oxidation of FA were increased. Finally, an oxidation assay using liver homogenates and palmitic acid as substrate revealed an over tenfold increased production of similar acylcarnitines, indicating that FA are their precursors. CONCLUSION: This study shows at the metabolite level that peroxisome proliferation induced either by fish oil or WY-14643 is associated with increased α- and ω-oxidation of FA producing specific acylcarnitines that can be utilized as biomarkers of peroxisomal FA oxidation.
Assuntos
Carnitina/análogos & derivados , Dieta Hiperlipídica/efeitos adversos , Gorduras Insaturadas na Dieta/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Fígado/metabolismo , Sobrepeso/metabolismo , Peroxissomos/metabolismo , Animais , Biomarcadores/química , Biomarcadores/metabolismo , Carnitina/química , Carnitina/metabolismo , Gorduras na Dieta/efeitos adversos , Gorduras Insaturadas na Dieta/efeitos adversos , Gorduras Insaturadas na Dieta/uso terapêutico , Ácidos Graxos Ômega-3/uso terapêutico , Óleos de Peixe/uso terapêutico , Regulação da Expressão Gênica/efeitos dos fármacos , Intolerância à Glucose/etiologia , Intolerância à Glucose/prevenção & controle , Hiperlipidemias/etiologia , Hiperlipidemias/prevenção & controle , Fígado/efeitos dos fármacos , Fígado/enzimologia , Masculino , Camundongos Endogâmicos C57BL , Peso Molecular , Sobrepeso/etiologia , Sobrepeso/fisiopatologia , Sobrepeso/prevenção & controle , Oxirredução , Proliferadores de Peroxissomos/farmacologia , Peroxissomos/efeitos dos fármacos , Peroxissomos/enzimologia , Pirimidinas/farmacologiaRESUMO
Obesity, type 2 diabetes, insulin resistance, dyslipidemia, cardiovascular diseases and atherosclerosis have all been associated with high levels of free fatty acid (FFA). In the present review, we suggest that FFA may act as either pro- or anti-inflammatory agents depending on the chemical structure. Saturated fatty acids (SFA) and polyunsaturated fatty acids (PUFA) significantly differ in their contributions to inflammation. While SFAs have been shown to induce inflammation, PUFAs have anti-inflammatory effects by downregulating NF-kappaB, IL-1ß, TNF-α and IL-6 despite upregulating of IL-10. It is suggested that FFA may activate Toll Like Receptor-4 (TLR4) and G protein-coupled receptors (GPCR) activating signaling pathways that promote production and release of inflammatory cytokines (IL-6 and TFN-α). Fatty acid action on TLR4, peroxisome proliferator-activated receptors (PPARs) and GPCRs are potential therapeutic targets for controlling FFA-induced inflammation. Approaches that downregulate the inflammatory properties of free fatty acid are discussed in this manuscript. In this review, some patents associated with controlling FFA effects are also reported.
Assuntos
Tratamento Farmacológico , Ácidos Graxos não Esterificados/fisiologia , Inflamação/fisiopatologia , Transdução de Sinais/fisiologia , Animais , Ácidos Graxos Insaturados/farmacologia , Humanos , Inflamação/induzido quimicamente , Mediadores da Inflamação/metabolismo , Patentes como Assunto , Receptores Ativados por Proliferador de Peroxissomo/efeitos dos fármacos , Proliferadores de Peroxissomos/farmacologia , Receptores Acoplados a Proteínas G/efeitos dos fármacos , Receptores Acoplados a Proteínas G/fisiologia , Transdução de Sinais/efeitos dos fármacos , Receptor 4 Toll-Like/antagonistas & inibidores , Receptor 4 Toll-Like/fisiologiaRESUMO
Alzheimer disease is a neurodegenerative process that leads to severe cognitive impairment as a consequence of selective death of neuronal populations. The molecular pathogenesis of Alzheimer disease involves the participation of the beta-amyloid peptide (Abeta) and oxidative stress. We report here that peroxisomal proliferation attenuated Abeta-dependent toxicity in hippocampal neurons. Pretreatment with Wy-14.463 (Wy), a peroxisome proliferator, prevent the neuronal cell death and neuritic network loss induced by the Abeta peptide. Moreover, the hippocampal neurons treated with this compound, showed an increase in the number of peroxisomes, with a concomitant increase in catalase activity. Additionally, we evaluate the Wy protective effect on beta-catenin levels, production of intracellular reactive oxygen species, cytoplasmic calcium uptake, and mitochondrial potential in hippocampal neurons exposed to H(2) O(2) and Abeta peptide. Results show that the peroxisomal proliferation prevents beta-catenin degradation, reactive oxygen species production, cytoplasmic calcium increase, and changes in mitochondrial viability. Our data suggest, for the first time, a direct link between peroxisomal proliferation and neuroprotection from Abeta-induced degenerative changes.
Assuntos
Peptídeos beta-Amiloides/farmacologia , Morte Celular/efeitos dos fármacos , Hipocampo/citologia , Neurônios/fisiologia , Proliferadores de Peroxissomos/farmacologia , Peroxissomos/fisiologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Animais , Cálcio/metabolismo , Catalase/genética , Catalase/metabolismo , Expressão Gênica/efeitos dos fármacos , Hipocampo/embriologia , Peróxido de Hidrogênio/farmacologia , Camundongos , Camundongos Transgênicos , Mitocôndrias/fisiologia , Neuritos/fisiologia , Neurônios/efeitos dos fármacos , Neurônios/ultraestrutura , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , PPAR alfa/genética , PPAR alfa/fisiologia , Peroxissomos/efeitos dos fármacos , Peroxissomos/ultraestrutura , Pirimidinas/farmacologia , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , beta Catenina/metabolismoRESUMO
BACKGROUND: Niemann-Pick type C (NP-C) disease is a lysosomal storage disorder. It is possible that peroxisomes are also modified and their alterations can be an early event in the process of the disease. As the use of peroxisomal inducers restores the original function of the organelle, the importance of peroxisomes is further emphasized and can suggest future therapeutic interventions. METHODS: We treated fibroblast cultures from NP-C patients and normal individuals with 200 and 400 micromol/l clofibrate and evaluated its action on intracellular cholesterol content that was determined by filipin staining and quantitative measurement of unesterified cholesterol. RESULTS: The fibroblasts from NP-C patients that did not receive any drug presented a pattern of intense perinuclear fluorescence associated with the accumulation of unesterified cholesterol which was not observed in normal fibroblasts. Comparing the NP-C fibroblasts that were incubated with clofibrate and the same cells without this treatment, there were no changes in cholesterol content by filipin staining, but normal fibroblasts after incubation with this drug showed a slight increase in its cholesterol content. However, unesterified cholesterol was significantly increased in both cells treated with clofibrate when compared to untreated cells. CONCLUSIONS: Clofibrate is probably not useful for treatment of NP-C patients because it seems to contribute to an increase the cholesterol in the cells of these individuals.
Assuntos
Colesterol/metabolismo , Clofibrato/farmacologia , Fibroblastos/metabolismo , Doenças de Niemann-Pick/metabolismo , Proliferadores de Peroxissomos/farmacologia , Estudos de Casos e Controles , Células Cultivadas , Esterificação , Fibroblastos/efeitos dos fármacos , Fibroblastos/ultraestrutura , Filipina/química , Humanos , Doenças de Niemann-Pick/patologia , Coloração e Rotulagem/métodosRESUMO
We demonstrated a neutral Mg-ATPase activity in human peroxisomal membranes. To establish the precise experimental conditions for detection of this ATPase, both cytochemical and biochemical characterizations were first carried out in liver peroxisomes from control and cipofibrate-treated rats. The results demonstrated an Mg-ATPase reaction in both normal and proliferated peroxisomes. The nucleotidase activity, with marked preference for ATP, was sensitive to the inhibitors N-ethylmaleimide and 7-chloro-4-nitro-benzo-2-oxadiazole (NBDCl). An ultrastructural cytochemical analysis was developed to evaluate the peroxisomal localization, which localized the reaction product to the peroxisomal membrane. These characteristics can help to differentiate the peroxisomal ATPase from the activity found in mitochondria and endoplasmic reticulum. The conditions established for detecting the rat peroxisomal ATPase were then applied to human peroxisomes isolated from liver and skin fibroblasts in culture. A similar Mg-ATPase activity was readily shown, both cytochemically and biochemically, in the membranes of human peroxisomes. These results, together with previous evidence, strongly support the presence of a specific ATPase in the human peroxisomal membrane. This ATPase may play a crucial role in peroxisome biogenesis.