RESUMO
Mitochondrial fatty acid oxidation (FAO) plays a pivotal role in maintaining body energy homoeostasis mainly during catabolic states. Oxidation of fatty acids requires approximately 25 proteins. Inherited defects of FAO have been identified in the majority of these proteins and constitute an important group of inborn errors of metabolism. Affected patients usually present with severe hepatopathy, cardiomyopathy and skeletal myopathy, whereas some patients may suffer acute and/or progressive encephalopathy whose pathogenesis is poorly known. In recent years growing evidence has emerged indicating that energy deficiency/disruption of mitochondrial homoeostasis is involved in the pathophysiology of some fatty acid oxidation defects (FAOD), although the exact underlying mechanisms are not yet established. Characteristic fatty acids and carnitine derivatives are found at high concentrations in these patients and more markedly during episodes of metabolic decompensation that are associated with worsening of clinical symptoms. Therefore, it is conceivable that these compounds may be toxic. We will briefly summarize the current knowledge obtained from patients and genetic mouse models with these disorders indicating that disruption of mitochondrial energy, redox and calcium homoeostasis is involved in the pathophysiology of the tissue damage in the more common FAOD, including medium-chain acyl-CoA dehydrogenase (MCAD), long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and very long-chain acyl-CoA dehydrogenase (VLCAD) deficiencies. We will also provide evidence that the fatty acids and derivatives that accumulate in these diseases disrupt mitochondrial homoeostasis. The elucidation of the toxic mechanisms of these compounds may offer new perspectives for potential novel adjuvant therapeutic strategies in selected disorders of this group.
Assuntos
Ácidos Graxos , Transtornos do Metabolismo dos Lipídeos , Mitocôndrias , Doenças Mitocondriais , Animais , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Ácidos Graxos/genética , Ácidos Graxos/metabolismo , Humanos , Transtornos do Metabolismo dos Lipídeos/genética , Transtornos do Metabolismo dos Lipídeos/metabolismo , Hepatopatias/genética , Hepatopatias/metabolismo , Camundongos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , OxirreduçãoRESUMO
Bipolar disorder (BD) is a common psychiatric mood disorder affecting more than 1-2% of the general population of different European countries. Unfortunately, there is no objective laboratory-based test to aid BD diagnosis or monitor its progression, and little is known about the molecular basis of BD. Here, we performed a comparative proteomic study to identify differentially expressed plasma proteins in various BD mood states (depressed BD, manic BD, and euthymic BD) relative to healthy controls. A total of 10 euthymic BD, 20 depressed BD, 15 manic BD, and 20 demographically matched healthy control subjects were recruited. Seven high-abundance proteins were immunodepleted in plasma samples from the 4 experimental groups, which were then subjected to proteome-wide expression profiling by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry. Proteomic results were validated by immunoblotting and bioinformatically analyzed using MetaCore. From a total of 32 proteins identified with 1.5-fold changes in expression compared with healthy controls, 16 proteins were perturbed in BD independent of mood state, while 16 proteins were specifically associated with particular BD mood states. Two mood-independent differential proteins, apolipoprotein (Apo) A1 and Apo L1, suggest that BD pathophysiology may be associated with early perturbations in lipid metabolism. Moreover, down-regulation of one mood-dependent protein, carbonic anhydrase 1 (CA-1), suggests it may be involved in the pathophysiology of depressive episodes in BD. Thus, BD pathophysiology may be associated with early perturbations in lipid metabolism that are independent of mood state, while CA-1 may be involved in the pathophysiology of depressive episodes.
Assuntos
Adolescente , Adulto , Feminino , Humanos , Masculino , Adulto Jovem , Apolipoproteína A-I/sangue , Apolipoproteínas/sangue , Transtorno Bipolar/sangue , Anidrase Carbônica I/sangue , Transtornos do Metabolismo dos Lipídeos/metabolismo , Lipoproteínas HDL/sangue , Proteômica , Transtorno Bipolar/complicações , Transtorno Bipolar/diagnóstico , Bases de Dados de Proteínas , Diagnóstico Diferencial , Progressão da Doença , Regulação para Baixo , Transtorno Depressivo Maior/diagnóstico , Eletroforese em Gel Bidimensional , Immunoblotting , Imunoprecipitação , Transtornos do Metabolismo dos Lipídeos/complicações , Espectrometria de Massas/métodosRESUMO
Bipolar disorder (BD) is a common psychiatric mood disorder affecting more than 1-2% of the general population of different European countries. Unfortunately, there is no objective laboratory-based test to aid BD diagnosis or monitor its progression, and little is known about the molecular basis of BD. Here, we performed a comparative proteomic study to identify differentially expressed plasma proteins in various BD mood states (depressed BD, manic BD, and euthymic BD) relative to healthy controls. A total of 10 euthymic BD, 20 depressed BD, 15 manic BD, and 20 demographically matched healthy control subjects were recruited. Seven high-abundance proteins were immunodepleted in plasma samples from the 4 experimental groups, which were then subjected to proteome-wide expression profiling by two-dimensional electrophoresis and matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry. Proteomic results were validated by immunoblotting and bioinformatically analyzed using MetaCore. From a total of 32 proteins identified with 1.5-fold changes in expression compared with healthy controls, 16 proteins were perturbed in BD independent of mood state, while 16 proteins were specifically associated with particular BD mood states. Two mood-independent differential proteins, apolipoprotein (Apo) A1 and Apo L1, suggest that BD pathophysiology may be associated with early perturbations in lipid metabolism. Moreover, down-regulation of one mood-dependent protein, carbonic anhydrase 1 (CA-1), suggests it may be involved in the pathophysiology of depressive episodes in BD. Thus, BD pathophysiology may be associated with early perturbations in lipid metabolism that are independent of mood state, while CA-1 may be involved in the pathophysiology of depressive episodes.
Assuntos
Apolipoproteína A-I/sangue , Apolipoproteínas/sangue , Transtorno Bipolar/sangue , Anidrase Carbônica I/sangue , Transtornos do Metabolismo dos Lipídeos/metabolismo , Lipoproteínas HDL/sangue , Proteômica , Adolescente , Adulto , Apolipoproteína L1 , Transtorno Bipolar/complicações , Transtorno Bipolar/diagnóstico , Bases de Dados de Proteínas , Transtorno Depressivo Maior/diagnóstico , Diagnóstico Diferencial , Progressão da Doença , Regulação para Baixo , Eletroforese em Gel Bidimensional , Feminino , Humanos , Immunoblotting , Imunoprecipitação , Transtornos do Metabolismo dos Lipídeos/complicações , Masculino , Espectrometria de Massas/métodos , Adulto JovemRESUMO
The advances in systems biology and in the development of new technological tools in analysis, as well as in the omic sciences, among which, metabolomics, and more specifically, lipidomics, have made it possible to investigate the structural and functional complexity of lipids in biological systems. Liquid chromatography and mass spectrometry are the analytical approaches most used in lipid research. Biomedical research, with the development of specific markers for lipids, together with new software development, have both enabled the early diagnosis of several illnesses, besides the evaluation of drug activity and treatment efficacy.
Assuntos
Lipídeos/análise , Metabolômica/métodos , Biomarcadores/metabolismo , Cromatografia Líquida/métodos , Humanos , Transtornos do Metabolismo dos Lipídeos/metabolismo , Lipídeos/química , Espectrometria de Massas/métodos , Software , Biologia de SistemasRESUMO
It has been hypothesized that deviations in glucocorticoid secretion and/or action may contribute to somatic and biochemical changes observed in patients with and animal models of insulin resistance (IR). In this study, we analyzed changes in rat adrenocortical function and morphology associated with the development of IR, generated in male adult rats by the addition of 30% sucrose to the drinking water. Caloric intake, body and adipose tissue weights, and biochemical parameters associated with IR were determined. Expression levels of Star, Cyp11A1, Mc2r, Pparγ (Pparg), and Cd36 were evaluated by real-time PCR, histochemical analysis of the adrenal cortex was performed using Masson's trichrome and Sudan III staining, and corticosterone levels were measured by RIA. After 7 weeks of sucrose administration, higher serum glucose, insulin, and triglyceride levels and an altered glycemic response to an i.p. insulin test were detected. Adrenal glands showed a neutral lipid infiltration. An increase in Star, Cyp11A1, Mc2r, Pparg and Cd36 and a decrease in Mc2r levels were also found. Furthermore, sucrose-treated animals exhibited higher basal corticosterone levels and a blunted response to ACTH injection. Noteworthy, the adrenocortical (functional and histological) abnormalities were prevented in sucrose-treated rats by the simultaneous administration of an insulin-sensitizing PPARγ agonist. In conclusion, sucrose-induced IR affects adrenocortical morphology and function possibly via the generation of adipokines or lipid metabolites within the adrenal gland. These abnormalities are prevented by the administration of a PPARγ agonist by mechanisms involving both extra- and intra-adrenal effects.
Assuntos
Córtex Suprarrenal/metabolismo , Sacarose Alimentar/farmacologia , Resistência à Insulina/fisiologia , Transtornos do Metabolismo dos Lipídeos/prevenção & controle , PPAR gama/agonistas , Tiazolidinedionas/farmacologia , Córtex Suprarrenal/patologia , Hormônio Adrenocorticotrópico/farmacologia , Animais , Corticosterona/sangue , Ingestão de Energia/efeitos dos fármacos , Ingestão de Energia/fisiologia , Hormônios/farmacologia , Hipoglicemiantes/farmacologia , Insulina/sangue , Insulina/farmacologia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Transtornos do Metabolismo dos Lipídeos/patologia , Masculino , PPAR gama/metabolismo , Ratos , Ratos Wistar , Rosiglitazona , Triglicerídeos/sangueRESUMO
Accumulation of long-chain 3-hydroxy fatty acids is the biochemical hallmark of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and mitochondrial trifunctional protein (MTP) deficiencies. These disorders are clinically characterized by neurological symptoms, such as convulsions and lethargy, as well as by cardiomyopathy and muscle weakness. In the present work we investigated the in vitro effect of 3-hydroxydodecanoic (3HDA), 3-hydroxytetradecanoic (3HTA) and 3-hydroxypalmitic (3HPA) acids, which accumulate in these disorders, on important oxidative stress parameters in cerebral cortex of young rats in the hope to clarify the mechanisms leading to the brain damage found in patients affected by these disorders. It was first verified that these compounds significantly induced lipid peroxidation, as determined by increased thiobarbituric acid-reactive substances levels. In addition, carbonyl formation was significantly increased and sulfhydryl content decreased by 3HTA and 3HPA, which indicates that these fatty acids elicit protein oxidative damage. 3HTA and 3HPA also diminished the reduced glutathione (GSH) levels, without affecting nitrate and nitrite production. Finally, we observed that the addition of the antioxidants and free radical scavengers trolox and deferoxamine (DFO) was able to partially prevent lipid oxidative damage, whereas DFO fully prevented the reduction on GSH levels induced by 3HTA. Our present data showing that 3HDA, 3HTA and 3HPA elicit oxidative stress in rat brain indicate that oxidative damage may represent an important pathomechanism involved in the neurologic symptoms manifested by patients affected by LCHAD and MTP deficiencies.
Assuntos
3-Hidroxiacil-CoA Desidrogenases/deficiência , Encefalopatias Metabólicas/metabolismo , Encéfalo/metabolismo , Transtornos do Metabolismo dos Lipídeos/metabolismo , Complexos Multienzimáticos/deficiência , Ácidos Mirísticos/toxicidade , Estresse Oxidativo/fisiologia , Ácidos Palmíticos/toxicidade , Animais , Encéfalo/efeitos dos fármacos , Encefalopatias Metabólicas/induzido quimicamente , Ácidos Decanoicos/metabolismo , Ácidos Decanoicos/toxicidade , Ácidos Graxos/metabolismo , Ácidos Graxos/toxicidade , Transtornos do Metabolismo dos Lipídeos/induzido quimicamente , 3-Hidroxiacil-CoA Desidrogenase de Cadeia Longa , Masculino , Proteína Mitocondrial Trifuncional , Ácidos Mirísticos/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ácidos Palmíticos/metabolismo , Ratos , Ratos WistarRESUMO
BACKGROUND: different etiologies are related to tinnitus including metabolic disorders (blood glucose and lipids). AIM: the aim of this study was compare tinnitus severity by self-report measures pre and post nutritional intervention, using the Tinnitus Handicap Inventory. METHOD: participants of this study were twenty one male and female subjects, with ages ranging from 40 to 82 years. Inclusion criteria involved the presence of tinnitus and metabolic disorder diagnosed by laboratory exams. All subjects were submitted to a nutritional intervention program. Audiological evaluation and the Tinnitus Handicap Inventory were applied pre and post intervention. RESULTS: when comparing the presence of tinnitus pre and post intervention, data analysis indicates statistical difference concerning tinnitus sensation - 71.5 percent of the individuals referred less impact of tinnitus in daily activities. CONCLUSION: an important difference was observed concerning tinnitus influence in subject's life by self-report measures. A direct relation between tinnitus and metabolic disorders in cases related with this symptom was verified.
TEMA: diferentes etiologias estão relacionadas com a presença de zumbido, incluindo doenças metabólicas (glicêmicas e lipídicas). OBJETIVO: comparar o grau de severidade do zumbido por meio de medidas de auto-análise em sujeitos com alterações metabólicas pré e pós-intervenção nutricional, utilizando o Questionário de Gravidade do Zumbido. MÉTODO: vinte e um sujeitos, homens e mulheres, com idade entre 40 e 82 anos, participaram deste estudo. Critérios de inclusão abrangeram a presença de zumbido e de alteração metabólica diagnosticada por meio de exames laboratoriais. Todos os sujeitos foram submetidos a um programa de intervenção nutricional. A avaliação audiológia e o questionário de gravidade de zumbido foram aplicados pré e pós-intervenção. RESULTADOS: comparando os resultados pré e pós-intervenção os dados mostram uma diferença estatisticamente significante com relação à sensação do zumbido em 71,5 por cento dos sujeitos, os quais referiram menor impacto do zumbido nas atividades diárias. CONCLUSÃO: uma importante diferença foi observada com relação à influência do zumbido na vida do sujeito quando utilizadas as medidas de auto-análise. Verificou-se uma relação direta entre zumbido e alterações metabólicas em casos relacionados a estes sintomas.
Assuntos
Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Metabolismo de Glucose/complicações , Transtornos do Metabolismo dos Lipídeos/complicações , Zumbido/etiologia , Transtornos do Metabolismo de Glucose/dietoterapia , Transtornos do Metabolismo de Glucose/metabolismo , Transtornos do Metabolismo dos Lipídeos/dietoterapia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Fatores de TempoRESUMO
BACKGROUND: Different etiologies are related to tinnitus including metabolic disorders (blood glucose and lipids). AIM: The aim of this study was compare tinnitus severity by self-report measures pre and post nutritional intervention, using the Tinnitus Handicap Inventory. METHOD: Participants of this study were twenty one male and female subjects, with ages ranging from 40 to 82 years. Inclusion criteria involved the presence of tinnitus and metabolic disorder diagnosed by laboratory exams. All subjects were submitted to a nutritional intervention program. Audiological evaluation and the Tinnitus Handicap Inventory were applied pre and post intervention. RESULTS: When comparing the presence of tinnitus pre and post intervention, data analysis indicates statistical difference concerning tinnitus sensation--71.5% of the individuals referred less impact of tinnitus in daily activities. CONCLUSION: An important difference was observed concerning tinnitus influence in subject's life by self-report measures. A direct relation between tinnitus and metabolic disorders in cases related with this symptom was verified.
Assuntos
Transtornos do Metabolismo de Glucose/complicações , Transtornos do Metabolismo dos Lipídeos/complicações , Zumbido/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Transtornos do Metabolismo de Glucose/dietoterapia , Transtornos do Metabolismo de Glucose/metabolismo , Humanos , Transtornos do Metabolismo dos Lipídeos/dietoterapia , Transtornos do Metabolismo dos Lipídeos/metabolismo , Masculino , Pessoa de Meia-Idade , Fatores de TempoRESUMO
Thyroid hormone affects in a myriad of biological processes such as development, growth, and metabolic control. Triiodothyronine (T3) is the biologically active form of thyroid hormone that acts through nuclear receptors, TRalpha and TRbeta, regulating gene expression. Given that the distribution of these receptors is heterogeneous amongst the different tissues, it is not surprising that some physiological effects of T3 are isoform specific. For example, while TRalpha is the dominant receptor in the brain and skeletal system and mediates most of the synergism between T3 and the sympathetic signaling pathway in the heart, TRbeta is abundant in liver and is probably the isoform that mediates most of the T3 effects on lipid metabolism. Thus, it makes sense to develop compounds that selectively act on either one of the TRs, allowing for the activation of specific T3-dependent pathways. This article reviews the recent progress made in this area, focusing on the physiological effects of compounds that lower serum cholesterol and decrease fat mass, as they spare skeletal muscle and bone masses, as well as the heart. The available studies indicate that achieving selective activation of different TR-mediated pathways is a promising strategy for treating lipid disorders and obesity.