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1.
iScience ; 27(3): 109276, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38450153

RESUMO

Chronic stress episodes increase metabolic disease risk even after recovery. We propose that persistent stress detrimentally impacts hepatic metabolic reprogramming, particularly mitochondrial function. In male C57BL/6 mice chronic variable stress (Cvs) reduced energy expenditure (EE) and body mass despite increased energy intake versus controls. This coincided with decreased glucose metabolism and increased lipid ß-oxidation, correlating with EE. After Cvs, mitochondrial function revealed increased thermodynamic efficiency (ƞ-opt) of complex CI, positively correlating with blood glucose and NEFA and inversely with EE. After Cvs recovery, the metabolic flexibility of hepatocytes was lost. Reduced CI-driving NAD+/NADH ratio, and diminished methylation-related one-carbon cycle components hinted at epigenetic regulation. Although initial DNA methylation differences were minimal after Cvs, they diverged during the recovery phase. Here, the altered enrichment of mitochondrial DNA methylation and linked transcriptional networks were observed. In conclusion, Cvs rapidly initiates the reprogramming of hepatic energy metabolism, supported by lasting epigenetic modifications.

3.
Cell Mol Life Sci ; 80(4): 108, 2023 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-36988756

RESUMO

Episodes of chronic stress can result in psychic disorders like post-traumatic stress disorder, but also promote the development of metabolic syndrome and type 2 diabetes. We hypothesize that muscle, as main regulator of whole-body energy expenditure, is a central target of acute and adaptive molecular effects of stress in this context. Here, we investigate the immediate effect of a stress period on energy metabolism in Musculus gastrocnemius in our established C57BL/6 chronic variable stress (Cvs) mouse model. Cvs decreased lean body mass despite increased energy intake, reduced circadian energy expenditure (EE), and substrate utilization. Cvs altered the proteome of metabolic components but not of the oxidative phosphorylation system (OXPHOS), or other mitochondrial structural components. Functionally, Cvs impaired the electron transport chain (ETC) capacity of complex I and complex II, and reduces respiratory capacity of the ETC from complex I to ATP synthase. Complex I-OXPHOS correlated to diurnal EE and complex II-maximal uncoupled respiration correlated to diurnal and reduced nocturnal EE. Bioenergetics assessment revealed higher optimal thermodynamic efficiencies (ƞ-opt) of mitochondria via complex II after Cvs. Interestingly, transcriptome and methylome were unaffected by Cvs, thus excluding major contributions to supposed metabolic adaptation processes. In summary, the preclinical Cvs model shows that metabolic pressure by Cvs is initially compensated by adaptation of mitochondria function associated with high thermodynamic efficiency and decreased EE to manage the energy balance. This counter-regulation of mitochondrial complex II may be the driving force to longitudinal metabolic changes of muscle physiological adaptation as the basis of stress memory.


Assuntos
Diabetes Mellitus Tipo 2 , Camundongos , Animais , Diabetes Mellitus Tipo 2/metabolismo , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Fosforilação Oxidativa , Metabolismo Energético , Complexo I de Transporte de Elétrons/genética , Complexo I de Transporte de Elétrons/metabolismo , Mitocôndrias Musculares/metabolismo
5.
Nutrients ; 14(19)2022 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-36235669

RESUMO

The worldwide incidence of allergic diseases has been continuously increasing, and up to one in every five people are currently affected by these medical conditions. Although seldom fatal, allergies have a profound impact on children's growth, development, and quality of life, besides being associated with heavy healthcare costs and resource utilisation. In this context, a group of experts in nutrition, paediatric gastroenterology, allergology, and neonatology joined forces to discuss the role of infant formulas in the primary prevention of allergies in infants for whom breastfeeding is not an option and who are at risk of developing allergies. The topics discussed included the assessment of risk, the impact of the microbiota on the modulation of immune tolerance, and the added value of certain formula characteristics, namely, protein integrity (hydrolysed protein vs. intact protein) and the addition of prebiotics, probiotics, or synbiotics. This article describes the latest evidence on each of the above-mentioned points, as well as a number of recommendations made by the experts to guide counselling of parents in the choice of a formula for infants at risk of allergy. Overall, the experts highlighted family history and dysbiosis-promoting factors (namely, caesarean delivery and antibiotic use) as two of the most important risk factors for allergy development. Moreover, in line with international guidelines, the panel advocated that intact protein formula should be offered to all bottle-fed healthy infants, irrespective of their allergic risk (with the exception of short-term bottle feeding of otherwise breastfed babies in their first week of life, for whom a hydrolysed formula may be advisable). Finally, the experts agreed that the use of prebiotic-, probiotic-, or synbiotic-enriched formulas should be considered in infants at risk of developing allergies.


Assuntos
Hipersensibilidade Alimentar , Hipersensibilidade a Leite , Antibacterianos , Aleitamento Materno , Criança , Feminino , Hipersensibilidade Alimentar/complicações , Hipersensibilidade Alimentar/prevenção & controle , Humanos , Lactente , Fórmulas Infantis , Hipersensibilidade a Leite/prevenção & controle , Prebióticos , Prevenção Primária , Qualidade de Vida
6.
Cureus ; 14(7): e26659, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35949781

RESUMO

Background Urticaria typically involves the skin and mucosa and is characterized by the development of wheals, angioedema, or both. According to the temporal evolution of the lesions, urticaria is classified as acute (AU) or chronic (CU), depending on whether the episodes last for fewer or more than six weeks, respectively. This study aimed to characterize a group of children and adolescents with urticaria and describe its subtypes, associated comorbidities, treatment, and evolution. Methodology This retrospective, observational study included patients aged <18 years who were diagnosed with urticaria in a tertiary teaching hospital in Portugal, and followed up in a Pediatric Allergy Unit, between January 2019 and December 2021. Results A total of 43 patients, aged nine months to 16 years were included. Of these, 22 (51%) were males. AU was identified in 12 (28%) cases, chronic spontaneous urticaria in 21 (63%), and physical urticaria (to cold) in four (9%). Autoantibodies were detected in four patients with spontaneous urticaria. In 6% of patients with CU, the episodes were associated with angioedema. Most CU episodes were successfully managed with the recommended or double the recommended dose (48%) of H1 antihistamines. Three patients requiring fourfold higher than the recommended dose of H1 antihistamines remained unresponsive and were started on omalizumab. Associated autoimmune thyroiditis was diagnosed in four patients. Conclusions In this cohort of patients, urticaria was equally distributed between the genders and the first-line therapy was second-generation antihistamines, consistent with current guidelines. Universal screening for autoimmune diseases in patients with chronic spontaneous urticaria revealed four cases of thyroiditis, which supports the relevance of this approach when managing CU.

7.
Int J Mol Sci ; 23(12)2022 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-35743314

RESUMO

Alterations in mitochondrial function are an important control variable in the progression of metabolic dysfunction-associated fatty liver disease (MAFLD), while also noted by increased de novo lipogenesis (DNL) and hepatic insulin resistance. We hypothesized that the organization and function of a mitochondrial electron transport chain (ETC) in this pathologic condition is a consequence of shifted substrate availability. We addressed this question using a transgenic mouse model with increased hepatic insulin resistance and DNL due to constitutively active human SREBP-1c. The abundance of ETC complex subunits and components of key metabolic pathways are regulated in the liver of these animals. Further omics approaches combined with functional assays in isolated liver mitochondria and primary hepatocytes revealed that the SREBP-1c-forced fatty liver induced a substrate limitation for oxidative phosphorylation, inducing enhanced complex II activity. The observed increased expression of mitochondrial genes may have indicated a counteraction. In conclusion, a shift of available substrates directed toward activated DNL results in increased electron flows, mainly through complex II, to compensate for the increased energy demand of the cell. The reorganization of key compounds in energy metabolism observed in the SREBP-1c animal model might explain the initial increase in mitochondrial function observed in the early stages of human MAFLD.


Assuntos
Fígado Gorduroso , Resistência à Insulina , Animais , Fígado Gorduroso/metabolismo , Lipogênese/genética , Fígado/metabolismo , Camundongos , Fosforilação Oxidativa , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
8.
Biochim Biophys Acta Mol Basis Dis ; 1868(1): 166286, 2022 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-34624498

RESUMO

Chronic stress leads to post-traumatic stress disorder (PTSD) and metabolic disorders including fatty liver. We hypothesized that stress-induced molecular mechanisms alter energy metabolism, thereby promoting hepatic lipid accumulation even after a stress-free recovery period. In this context, we investigated fibroblast growth factor-21 (FGF21) as protective for energy and glucose homeostasis. FGF21 knockout mice (B6.129S6(SJL)-Fgf21tm1.2Djm; FGF21KO) and control mice (C57BL6; WT) were subjected to chronic variable stress. Mice were examined directly after acute intervention (Cvs) and long-term after 3 months of recovery (3mCvs). In WT, Cvs reduced insulin sensitivity and hepatic lipid accumulation, whilst fatty acid uptake increased. FGF21KO mice responded to Cvs with improved glucose tolerance, insulin resistance but liver triglycerides and plasma lipids were unaltered. Hepatic gene expression was specifically altered by genotype and stress e.g. by PPARa and SREBP-1 regulated genes. The stress-induced alteration of hepatic metabolism persisted after stress recovery. In hepatocytes at 3mCvs, differential gene regulation and secreted proteins indicated a genotype specific progression of liver dysfunction. Overall, at 3mCvs FGF21 was involved in maintaining mitochondrial activity, attenuating de novo lipogenesis, increased fatty acid uptake and histone acetyltransferase activity. Glucocorticoid release and binding to the FGF21 promoter may contribute to prolonged FGF21 release and protection against hepatic lipid accumulation. In conclusion, we showed that stress favors fatty liver disease and FGF21 protected against hepatic lipid accumulation after previous chronic stress loading by i) restored physiological function, ii) modulated gene expression via DNA-modifying enzymes, and iii) maintained energy metabolism.


Assuntos
Metabolismo Energético/genética , Fígado Gorduroso/genética , Fatores de Crescimento de Fibroblastos/genética , Transtornos de Estresse Pós-Traumáticos/genética , Animais , Fígado Gorduroso/metabolismo , Fígado Gorduroso/patologia , Genótipo , Glucose/metabolismo , Hepatócitos/metabolismo , Hepatócitos/patologia , Humanos , Metabolismo dos Lipídeos/genética , Lipídeos/genética , Fígado/metabolismo , Fígado/patologia , Camundongos , Camundongos Knockout , PPAR alfa/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Transtornos de Estresse Pós-Traumáticos/metabolismo , Transtornos de Estresse Pós-Traumáticos/patologia
9.
Int J Mol Sci ; 21(11)2020 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-32532003

RESUMO

Fatty liver occurs from simple steatosis with accumulated hepatic lipids and hepatic insulin resistance to severe steatohepatitis, with aggravated lipid accumulation and systemic insulin resistance, but this progression is still poorly understood. Analyses of hepatic gene expression patterns from alb-SREBP-1c mice with moderate, or aP2-SREBP-1c mice with aggravated, hepatic lipid accumulation revealed IGFBP2 as key nodal molecule differing between moderate and aggravated fatty liver. Reduced IGFBP2 expression in aggravated fatty liver was paralleled with promoter hypermethylation, reduced hepatic IGFBP2 secretion and IGFBP2 circulating in plasma. Physiologically, the decrease of IGFBP2 was accompanied with reduced fatty acid oxidation and increased de novo lipogenesis potentially mediated by IGF1 in primary hepatocytes. Furthermore, methyltransferase and sirtuin activities were enhanced. In humans, IGFBP2 serum concentration was lower in obese men with non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) compared to non-obese controls, and liver fat reduction by weight-loss intervention correlated with an increase of IGFBP2 serum levels. In conclusion, hepatic IGFBP2 abundance correlates to its circulating level and is related to hepatic energy metabolism and de novo lipogenesis. This designates IGFBP2 as non-invasive biomarker for fatty liver disease progression and might further provide an additional variable for risk prediction for pathogenesis of fatty liver in diabetes subtype clusters.


Assuntos
Metabolismo Energético/fisiologia , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/genética , Hepatopatia Gordurosa não Alcoólica/metabolismo , Adulto , Animais , Peso Corporal , Estudos de Casos e Controles , Metabolismo Energético/genética , Hepatócitos/metabolismo , Humanos , Resistência à Insulina , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Proteína 2 de Ligação a Fator de Crescimento Semelhante à Insulina/metabolismo , Proteína 3 de Ligação a Fator de Crescimento Semelhante à Insulina/sangue , Fator de Crescimento Insulin-Like I/análise , Masculino , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/complicações , Obesidade/metabolismo , Obesidade/cirurgia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo
10.
Sci Rep ; 10(1): 4888, 2020 03 17.
Artigo em Inglês | MEDLINE | ID: mdl-32184434

RESUMO

Although fibrosis depicts a reparative mechanism, maladaptation of the heart due to excessive production of extracellular matrix accelerates cardiac dysfunction. The anthraquinone Rhein was examined for its anti-fibrotic potency to mitigate cardiac fibroblast-to-myofibroblast transition (FMT). Primary human ventricular cardiac fibroblasts were subjected to hypoxia and characterized with proteomics, transcriptomics and cell functional techniques. Knowledge based analyses of the omics data revealed a modulation of fibrosis-associated pathways and cell cycle due to Rhein administration during hypoxia, whereas p53 and p21 were identified as upstream regulators involved in the manifestation of cardiac fibroblast phenotypes. Mechanistically, Rhein acts inhibitory on HDAC classes I/II as enzymatic inhibitor. Rhein-mediated cellular effects were linked to the histone deacetylase (HDAC)-dependent protein stabilization of p53 under normoxic but not hypoxic conditions. Functionally, Rhein inhibited collagen contraction, indicating anti-fibrotic property in cardiac remodeling. This was accompanied by increased abundance of SMAD7, but not SMAD2/3, and consistently SMAD-specific E3 ubiquitin ligase SMURF2. In conclusion, this study identifies Rhein as a novel potent direct HDAC inhibitor that may contribute to the treatment of cardiac fibrosis as anti-fibrotic agent. As readily available drug with approved safety, Rhein constitutes a promising potential therapeutic approach in the supplemental and protective intervention of cardiac fibrosis.


Assuntos
Antraquinonas/farmacologia , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Histona Desacetilase 1/antagonistas & inibidores , Histona Desacetilase 2/antagonistas & inibidores , Adulto , Western Blotting , Cardiomiopatias/genética , Cardiomiopatias/metabolismo , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase em Tempo Real , Proteína Smad2/genética , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Proteína Smad7/genética , Proteína Smad7/metabolismo , Transcriptoma/genética , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/metabolismo
11.
Front Cell Dev Biol ; 7: 248, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31709254

RESUMO

In non-alcoholic fatty liver disease (NAFLD) caused by ectopic lipid accumulation, lipotoxicity is a crucial molecular risk factor. Mechanisms to eliminate lipid overflow can prevent the liver from functional complications. This may involve increased secretion of lipids or metabolic adaptation to ß-oxidation in lipid-degrading organelles such as mitochondria and peroxisomes. In addition to dietary factors, increased plasma fatty acid levels may be due to increased triglyceride synthesis, lipolysis, as well as de novo lipid synthesis (DNL) in the liver. In the present study, we investigated the impact of fatty liver caused by elevated DNL, in a transgenic mouse model with liver-specific overexpression of human sterol regulatory element-binding protein-1c (alb-SREBP-1c), on hepatic gene expression, on plasma lipids and especially on the proteome of peroxisomes by omics analyses, and we interpreted the results with knowledge-based analyses. In summary, the increased hepatic DNL is accompanied by marginal gene expression changes but massive changes in peroxisomal proteome. Furthermore, plasma phosphatidylcholine (PC) as well as lysoPC species were altered. Based on these observations, it can be speculated that the plasticity of organelles and their functionality may be directly affected by lipid overflow.

12.
Int J Mol Sci ; 20(10)2019 May 24.
Artigo em Inglês | MEDLINE | ID: mdl-31137678

RESUMO

Adipocyte and hepatic lipid metabolism govern whole-body metabolic homeostasis, whereas a disbalance of de novo lipogenesis (DNL) in fat and liver might lead to obesity, with severe co-morbidities. Nevertheless, some obese people are metabolically healthy, but the "protective" mechanisms are not yet known in detail. Especially, the adipocyte-derived molecular mediators that indicate adipose functionality are poorly understood. We studied transgenic mice (alb-SREBP-1c) with a "healthy" obese phenotype, and obob mice with hyperphagia-induced "sick" obesity to analyze the impact of the tissue-specific DNL on the secreted proteins, i.e., the adipokinome, of the primary adipose cells by label-free proteomics. Compared to the control mice, adipose DNL is reduced in both obese mouse models. In contrast, the hepatic DNL is reduced in obob but elevated in alb-SREBP-1c mice. To investigate the relationship between lipid metabolism and adipokinomes, we formulated the "liver-to-adipose-tissue DNL" ratio. Knowledge-based analyses of these results revealed adipocyte functionality with proteins, which was involved in tissue remodeling or metabolism in the alb-SREBP-1c mice and in the control mice, but mainly in fibrosis in the obob mice. The adipokinome in "healthy" obesity is similar to that in a normal condition, but it differs from that in "sick" obesity, whereas the serum lipid patterns reflect the "liver-to-adipose-tissue DNL" ratio and are associated with the adipokinome signature.


Assuntos
Adipocinas/metabolismo , Tecido Adiposo/metabolismo , Ácidos Graxos não Esterificados/sangue , Obesidade/metabolismo , Adipocinas/genética , Animais , Lipogênese , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Obesidade/sangue , Obesidade/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/genética
14.
Int J Mol Sci ; 19(4)2018 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-29587401

RESUMO

The key lipid metabolism transcription factor sterol regulatory element-binding protein (SREBP)-1a integrates gene regulatory effects of hormones, cytokines, nutrition and metabolites as lipids, glucose, or cholesterol via phosphorylation by different mitogen activated protein kinase (MAPK) cascades. We have previously reported the impact of SREBP-1a phosphorylation on the phenotype in transgenic mouse models with liver-specific overexpression of the N-terminal transcriptional active domain of SREBP-1a (alb-SREBP-1a) or a MAPK phosphorylation site-deficient variant (alb-SREBP-1a∆P; (S63A, S117A, T426V)), respectively. In this report, we investigated the molecular basis of the systemic observations by holistic analyses of gene expression in liver and of proteome patterns in lipid-degrading organelles involved in the pathogenesis of metabolic syndrome, i.e., peroxisomes, using 2D-DIGE and mass spectrometry. The differences in hepatic gene expression and peroxisomal protein patterns were surprisingly small between the control and alb-SREBP-1a mice, although the latter develop a severe phenotype with visceral obesity and fatty liver. In contrast, phosphorylation site-deficient alb-SREBP-1a∆P mice, which are protected from fatty liver disease, showed marked differences in hepatic gene expression and peroxisomal proteome patterns. Further knowledge-based analyses revealed that disruption of SREBP-1a phosphorylation resulted in massive alteration of cellular processes, including signs for loss of targeting lipid pathways.


Assuntos
Modelos Animais de Doenças , Fígado Gorduroso/metabolismo , Camundongos , Proteoma/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Animais , Fígado Gorduroso/genética , Deleção de Genes , Humanos , Masculino , Síndrome Metabólica/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Obesidade Abdominal/metabolismo , Peroxissomos/patologia , Fosforilação , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Transcriptoma
15.
Int J Obes (Lond) ; 42(5): 1039-1050, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29467502

RESUMO

BACKGROUND: CDH13, an atypical member of the cadherin superfamily, has been identified in adipocyte secretomes of lean mouse models. CDH13 abundance differs in mouse models according to their susceptibility to develop metabolic disorders, but the role of CDH13 in adipose tissue is unknown. METHODS: Secreted CDH13 protein levels and mRNA levels in visceral adipose tissue were determined in lean and obese mouse models. In vitro studies were performed in 3T3-L1 adipocytes to determine the role of CDH13 in adipocyte differentiation. The pathophysiological impact of visceral adipose tissue CDH13 mRNA and circulating CDH13 levels were determined in humans (normal-weight men n = 37, obese men n = 109 including n = 51 type 2 diabetes patients) and in obese patients (n = 14) pre- and post-metabolic surgery. RESULTS: This study shows that in visceral adipose tissue CDH13 protein secretion and mRNA levels were decreased in obese mouse models. Mechanistically, CDH13 affects lipid metabolism during adipogenesis but not in mature adipocytes. CDH13 knockdown during adipogenesis reduced fatty acid uptake and lipid content in developing adipocytes. Furthermore, CDH13 depletion during adipogenesis lowered the induction of PPARγ and C/EBPα expression. These observations are of pathophysiological impact since visceral adipose tissue CDH13 mRNA and circulating CDH13 levels were decreased in obese men compared to normal-weight controls. Weight loss induced by bariatric surgery restored circulating CDH13 to levels found in normal-weight controls. CONCLUSIONS: CDH13 levels in adipose tissue and the circulation are affected by obesity in mouse models and humans and are restored by weight loss in humans. CDH13 interferes with the differentiation potential of adipocytes and therefore is a marker for plasticity of fat tissue that might reflect the health status of adipose tissue.


Assuntos
Adipócitos/citologia , Tecido Adiposo/química , Caderinas/metabolismo , Diferenciação Celular/fisiologia , Obesidade/metabolismo , Adipócitos/metabolismo , Adipogenia/efeitos dos fármacos , Adipogenia/fisiologia , Tecido Adiposo/metabolismo , Adulto , Animais , Biomarcadores/análise , Biomarcadores/metabolismo , Caderinas/análise , Caderinas/genética , Caderinas/farmacologia , Diferenciação Celular/efeitos dos fármacos , Feminino , Humanos , Masculino , Camundongos , Camundongos Obesos , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/fisiopatologia , RNA Mensageiro/análise , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
18.
Proteomics Clin Appl ; 12(1)2018 01.
Artigo em Inglês | MEDLINE | ID: mdl-29068532

RESUMO

PURPOSE: Metabolic syndrome (MetS) consists of five risk factors: elevated blood pressure and fasting glucose, visceral obesity, dyslipidemia, and hypercholesterinemia. The physiological impact of lipid metabolism indicated as visceral obesity and hepatic lipid accumulation on MetS is still under debate. One major cause of disturbed lipid metabolism might be dysfunction of cellular organelles controlling energy homeostasis, i.e., mitochondria and peroxisomes. EXPERIMENTAL DESIGN: The New Zealand Obese (NZO) mouse model exhibits a polygenic syndrome of obesity, insulin resistance, triglyceridemia, and hypercholesterolemia that resembles human metabolic syndrome. We applied a multi-omics approach combining lipidomics with liver transcriptomics and top-down MS based organelle proteomics (2D-DIGE) of highly enriched mitochondria and peroxisomes in male mice, to investigate molecular mechanisms related to the impact of lipid metabolism in the pathophysiology of the metabolic syndrome. CONCLUSIONS AND CLINICAL RELEVANCE: Proteome analyses of liver organelles indicate differences in fatty acid and cholesterol metabolism, mainly influenced by PG-C1α/PPARα and other nuclear receptor mediated pathways. These results are in accordance with altered serum lipid profiles and elevated organelle functionality. These data emphasize that metabolic syndrome is accompanied with increased mitochondria and peroxisomal activity to cope with dyslipidemia and hypercholesterinemia driven hepatic lipid overflow in developing a fatty liver.


Assuntos
Fígado/metabolismo , Síndrome Metabólica/metabolismo , Mitocôndrias/metabolismo , Obesidade/metabolismo , Peroxissomos/metabolismo , Animais , Colesterol/metabolismo , Modelos Animais de Doenças , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica , Humanos , Resistência à Insulina , Metabolismo dos Lipídeos/genética , Fígado/patologia , Masculino , Síndrome Metabólica/genética , Síndrome Metabólica/patologia , Camundongos , Camundongos Obesos , Mitocôndrias/patologia , Obesidade/genética , Obesidade/patologia , PPAR alfa/genética , PPAR alfa/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/metabolismo , Peroxissomos/patologia , Proteoma/genética , Proteoma/metabolismo , Transcriptoma
19.
Arq. Asma, Alerg. Imunol ; 1(4): 427-430, out.dez.2017. ilus
Artigo em Português | LILACS | ID: biblio-1380656

RESUMO

As proteínas de transferência lipídica (LTPs) são pan-alergênios responsáveis pela reatividade cruzada entre frutos, vegetais e polens. A Pru p 3 (LTP presente no pêssego) é reconhecida como marcador de gravidade na alergia alimentar. A romã e a noz são frutos relatados como causas de reações alérgicas devido à existência de LTPs. Reportamos o caso de um adolescente admitido por urticária e edema labial após ingestão de romã, com história prévia semelhante após ingestão de noz. Os testes cutâneos revelaram positividade para extratos comerciais de noz e para a polpa de romã, e foram negativos para gramíneas e pêssego. Apresentava um doseamento de imunoglobulina E (IgE) total de 87,2 UI/mL e IgE específicas (sIgE) para noz e avelã positivas. O doseamento de sIgE pelo método ISAC (immuno-solid-phase allergen chip) revelou positividade para os alergênios da avelã (Cor a 8), do pêssego (Pru p 3) e da noz (Jug r 3). Não havia história de reação alérgica à ingestão de pêssego. O caso questiona a relevância da sensibilização ao Pru p 3 em doentes não alérgicos ao pêssego, e se este será o único marcador de reação cruzada com a romã.


Lipid transfer proteins (LTPs) are pan-allergens that are responsible for cross-reactivity between fruits, vegetables, and pollen. Pru p 3, the LTP present in the peach, is recognized as a marker of severity in food allergy. Pomegranate and walnut have been reported to be involved in allergic reactions due to the existence of LTPs. We report the case of a teenager admitted with rash and swollen lips after the ingestion of pomegranate, and reporting a similar reaction in the past after ingesting walnut. Skin tests showed positive results for commercial extracts of walnut and pomegranate pulp, and were negative for grass and peach. The total immunoglobulin E (IgE) was 87.2 IU/mL and specific IgE (sIgE) testing for walnut and hazelnut was positive. sIgE determination using the ISAC method (immuno-solid-phase allergen chip) was positive for hazelnut (Cor A 8), peach (Pru p 3) and walnut (Jug r3). There was no history of allergic reaction after the ingestion of peach. The present case questions the relevance of Pru p 3 in patients who are not allergic to peach, and whether this is the only cross-reactive marker with pomegranate.


Assuntos
Humanos , Adolescente , Urticária , Proteínas , Punica granatum , Lábio , Imunoglobulina E , Testes Cutâneos , Alérgenos , Ingestão de Alimentos , Hipersensibilidade Alimentar , Frutas
20.
Int J Mol Sci ; 18(9)2017 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-28885548

RESUMO

The group of adipokines comprises hundreds of biological active proteins and peptides released from adipose tissue. Alterations of those complex protein signatures are suggested to play a crucial role in the pathophysiology of multifactorial, metabolic diseases. We hypothesized that also the pathophysiology of type-2-diabetes is linked to the dysregulation of the adipocyte secretome. To test this, we investigated mouse models with monogenic defects in leptin signaling which are susceptible to adipositas (C57BL/6 Cg-Lepob (obob)) or adipositas with diabetes (C57BL/KS Cg-Leprdb (dbdb)) according to their genetic background. At the age of 17 weeks, visceral fat was obtained and primary murine adipocytes were isolated to harvest secretomes. Quantitative proteome analyses (LC-ESI-MS/MS) identified more than 800 potential secreted proteins. The secretome patterns revealed significant differences connected to the pathophysiology of obese mice. Pathway analyses indicated that these differences focus on exosome modelling, but failed to provide more precise specifications. To investigate the relationship of secretome data to insulin sensitivity, we examined the content of diabetogenic lipids, i.e., diacylglycerols (DAGs), identified as key players in lipid-induced insulin resistance. In contrast to obob mice, fat tissue of dbdb mice showed elevated DAG content, especially of DAG species with saturated fatty acid C16:0 and C18:0, while unsaturated fatty acid C16:1 were only changed in obob. Furthermore, DAG signatures of the models specifically correlate to secreted regulated adipokines indicating specific pathways. In conclusion, our data further support the concept that the fat tissue is an endocrine organ that releases bioactive factors corresponding to adipose tissue health status.


Assuntos
Adipocinas/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Obesidade/metabolismo , Proteômica , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Animais , Biomarcadores , Análise por Conglomerados , Modelos Animais de Doenças , Metabolismo dos Lipídeos , Masculino , Espectrometria de Massas , Camundongos , Camundongos Obesos , Proteoma , Proteômica/métodos
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