RESUMO
Monocytes are peripheral leukocytes that function in innate immunity. Excessive triglyceride (TG) accumulation causes monocyte death and thus can compromise innate immunity. However, the mechanisms by which TG mediates monocyte death remain unclear to date. Thus, this study aimed to elucidate the mechanisms by which TG induces monocyte death. Results showed that TG induced monocyte death by activating caspase-3/7 and promoting poly (ADP-ribose) polymerase (PARP) cleavage. In addition, TG induced DNA damage and activated the ataxia telangiectasia mutated (ATM)/checkpoint kinase 2 and ATM-and Rad3-related (ATR)/checkpoint kinase 1 pathways, leading to the cell death. Furthermore, TG-induced DNA damage and monocyte death were mediated by caspase-2 and -8, and caspase-8 acted as an upstream molecule of caspase-2. Taken together, these results suggest that TG-induced monocyte death is mediated via the caspase-8/caspase-2/DNA damage/executioner caspase/PARP pathways. [BMB Reports 2023; 56(3): 166-171].
Assuntos
Caspase 2 , Caspase 8 , Imunidade Inata , Monócitos , Triglicerídeos , Proteínas Mutadas de Ataxia Telangiectasia/genética , Caspase 2/genética , Caspase 2/metabolismo , Caspase 3/metabolismo , Caspase 8/genética , Caspase 8/metabolismo , Proteínas de Ciclo Celular/metabolismo , Dano ao DNA , Monócitos/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Poli(ADP-Ribose) Polimerases/metabolismo , Triglicerídeos/genética , Triglicerídeos/imunologia , Imunidade Inata/imunologiaRESUMO
BACKGROUND: Data on the burden of dyslipidaemia among people with HIV undergoing antiretroviral therapy (ART) in sub-Saharan Africa are limited and little is known about the factors contributing for poor lipid profiles. The aim of this study was to determine the prevalence of dyslipidaemia and factors associated with lipid levels among HIV-infected patients receiving first-line combination ART in North Shewa, Ethiopia. METHODS: A cross-sectional study was conducted between April and December 2018 among 392 HIV-infected adults receiving first-line ART for at least six months at the ART clinic of Mehal Meda Hospital in North Shewa, Ethiopia. Blood samples were collected for determination of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c), and CD4 counts. Logistic regression analysis was used to determine factors associated with lipid abnormalities. RESULTS: The prevalence of dyslipidaemia was 59.9% (95% CI 55.0-64.7%). High TC, high TG, low HDL-c, and high LDL-c were obtained in 47.3%, 30.9%, 19.4% and 29.6%, respectively. Fifty-four participants (13.8%) had high ratio of TC/HDL-c (TC/HDL-c ratio ≥ 5). Older age was independently associated with high TC (AOR = 2.51, 95% CI 1.64-3.84), high TG (AOR = 2.95, 95% CI 1.85-4.71), low HDL-c (AOR = 2.02, 95% CI 1.17-3.50), and high LDL-c (AOR = 3.37, 95% CI 2.08-5.47). Living in an urban area (AOR = 2.61, 95% CI 1.16-6.14) and smoking (AOR = 3.61, 95% CI 1.06-12.34) were associated with low HDL-c. Participants with longer duration of ART use were more likely to have high TG (AOR = 1.86, 95% CI: 1.13-3.07), low HDL-c (AOR = 3.47, 95% CI: 1.75-6.80), and high LDL-c (AOR = 2.20, 95% CI 1.30-3.71). High BMI was independently associated with higher TC (AOR = 2.43, 95% CI 1.19-4.97), high TG (AOR = 4.17, 95% CI 2.01-8.67) and high LDL-c (AOR = 6.53, 95% CI 3.05-13.98). CONCLUSIONS: We found a high prevalence of dyslipidaemia among HIV-infected patients receiving first-line ART in North Shewa, Ethiopia. There is a need for monitoring of blood lipid levels in patients with HIV on long term first-line ART with a special attention to be focused on older age, urban residents, longer duration of ART use, high BMI and smokers.
Assuntos
Fármacos Anti-HIV/uso terapêutico , Dislipidemias/epidemiologia , Infecções por HIV/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/virologia , HDL-Colesterol/sangue , HDL-Colesterol/imunologia , LDL-Colesterol/sangue , LDL-Colesterol/imunologia , Estudos Transversais , Dislipidemias/tratamento farmacológico , Dislipidemias/imunologia , Dislipidemias/virologia , Etiópia/epidemiologia , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/imunologia , Infecções por HIV/virologia , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Prevalência , População Rural , Triglicerídeos/sangue , Triglicerídeos/imunologia , População UrbanaRESUMO
Medium-chain fatty acids (MCFAs) are the main form of Medium Chain Triglycerides (MCTs) utilized by monogastric animals. MCFAs can be directly absorbed and supply rapid energy to promote the renewal and repair of intestinal epithelial cells, maintain the integrity of intestinal mucosal barrier function, and reduce inflammation and stress. In our review, we pay more attention to the role of MCFAs on intestinal microbiota and mucosa immunity to explore MCFA's positive effect. It was found that MCFAs and their esterified forms can decrease pathogens while increasing probiotics. In addition, being recognized via specific receptors, MCFAs are capable of alleviating inflammation to a certain extent by regulating inflammation and immune-related pathways. MCFAs may also have a certain value to relieve intestinal allergy and inflammatory bowel disease (IBD). Unknown mechanism of various MCFA characteristics still causes dilemmas in the application, thus MCFAs are used generally in limited dosages and combined with short-chain organic acids (SOAs) to attain ideal results. We hope that further studies will provide guidance for the practical use of MCFAs in animal feed.
Assuntos
Caprilatos/imunologia , Colite Ulcerativa/dietoterapia , Doença de Crohn/dietoterapia , Ácidos Decanoicos/imunologia , Síndrome do Intestino Irritável/dietoterapia , Ácidos Láuricos/imunologia , Ração Animal/análise , Animais , Caprilatos/administração & dosagem , Caprilatos/metabolismo , Colite Ulcerativa/imunologia , Colite Ulcerativa/microbiologia , Colite Ulcerativa/patologia , Doença de Crohn/imunologia , Doença de Crohn/microbiologia , Doença de Crohn/patologia , Citocinas/genética , Citocinas/imunologia , Ácidos Decanoicos/administração & dosagem , Ácidos Decanoicos/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Imunidade nas Mucosas/efeitos dos fármacos , Absorção Intestinal/efeitos dos fármacos , Absorção Intestinal/imunologia , Intestinos/efeitos dos fármacos , Intestinos/imunologia , Intestinos/microbiologia , Síndrome do Intestino Irritável/imunologia , Síndrome do Intestino Irritável/microbiologia , Síndrome do Intestino Irritável/patologia , Ácidos Láuricos/administração & dosagem , Ácidos Láuricos/metabolismo , NF-kappa B/genética , NF-kappa B/imunologia , Estômago/efeitos dos fármacos , Estômago/imunologia , Estômago/microbiologia , Triglicerídeos/imunologia , Triglicerídeos/metabolismoRESUMO
Lipid droplets are fat storage organelles present in most eukaryotic cells. They consist of a neutral lipid core containing mostly triglycerides and sterol esters and covered by a monolayer of phospholipids, wherein numerous proteins are embedded. In the cell, lipid droplets have a dynamic life cycle, rapidly altering their size, location, lipid and protein composition in response to environmental stimuli and cell state. Lipid droplets are primarily involved in the coordination of lipid metabolism with cellular requirements for energy production, membrane homeostasis and cell growth. However, they are also directly or indirectly engaged in signalling pathways. On the one hand, lipid droplets sequester lipids and proteins thereby limiting their availability for participation in signalling pathways. On the other hand, the lipolytic machinery provides a highly regulated, on-demand source of signalling lipids: lipids derived from their neutral lipid core, or the phospholipid monolayer, directly act as signalling mediators or are converted into ones. In fact, emerging studies suggest that these organelles are essential for various cellular stress response mechanisms, including inflammation and immunity, acting as hubs that integrate metabolic and inflammatory processes. Here, we discuss the ways in which lipid droplets regulate the availability of fatty acids for the activation of signalling pathways and for the production of polyunsaturated fatty acid-derived lipid mediators. We focus in particular on recent discoveries in immune cells and adipose tissue that have revealed an intricate relationship between lipid droplets and inflammatory signalling and may also be relevant for other tissues and various human diseases.
Assuntos
Tecido Adiposo/metabolismo , Eicosanoides/metabolismo , Gotículas Lipídicas/metabolismo , Metabolismo dos Lipídeos/genética , Fosfolipídeos/metabolismo , Triglicerídeos/metabolismo , Tecido Adiposo/imunologia , Animais , Ácidos Docosa-Hexaenoicos/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Eicosanoides/imunologia , Regulação da Expressão Gênica , Homeostase/genética , Homeostase/imunologia , Humanos , Inflamação , Lipase/genética , Lipase/imunologia , Gotículas Lipídicas/imunologia , Metabolismo dos Lipídeos/imunologia , Fosfolipases/genética , Fosfolipases/imunologia , Fosfolipídeos/imunologia , Transdução de Sinais , Receptores Toll-Like/genética , Receptores Toll-Like/imunologia , Triglicerídeos/imunologiaRESUMO
BACKGROUND: Acne vulgaris (AV) is an inflammatory skin disorder that may be associated with metabolic disorders. The relation between lipid profile in acne is not widely investigated. Chitinase-3-like protein 1 (YKL-40) has been found to be implicated in different inflammatory conditions. AIMS: We aimed at investigating the role YKL-40 in acne pathogenesis and associated dyslipidemia in acne patients. PATIENTS/METHODS: This study included 50 acne vulgaris patients and 30 matched control subjects. Serum YKL-40 in addition to lipid profile were assessed in all studied subjects. RESULTS: Serum YKL-40 level was significantly elevated in acne patients than healthy controls (P < .001). We also found a significant positive correlations between serum YKL-40, serum TGs, TC, and LDL-C (P value: .022, .001, .017 respectively) while, a significant negative correlation between serum YKL-40 and HDL-c (P value: .036) was detected. CONCLUSION: Our study results suggest that YKL-40 might have a role in AV pathogenesis. In addition, it could provide a new potential link between inflammation and dyslipidemia observed in acne patients.
Assuntos
Acne Vulgar/etiologia , Proteína 1 Semelhante à Quitinase-3/sangue , Dislipidemias/complicações , Inflamação/imunologia , Acne Vulgar/sangue , Acne Vulgar/metabolismo , Adolescente , Estudos de Casos e Controles , Proteína 1 Semelhante à Quitinase-3/imunologia , HDL-Colesterol/sangue , HDL-Colesterol/imunologia , HDL-Colesterol/metabolismo , LDL-Colesterol/sangue , LDL-Colesterol/imunologia , LDL-Colesterol/metabolismo , Dislipidemias/sangue , Dislipidemias/imunologia , Feminino , Humanos , Inflamação/sangue , Lipidômica , Masculino , Triglicerídeos/sangue , Triglicerídeos/imunologia , Triglicerídeos/metabolismo , Adulto JovemRESUMO
Recurrent pregnancy loss (RPL) is deï¬ned as three or more consecutive pregnancy losses prior to the 20th week of gestation. Exaggerated maternal immune response and oxidative stress status have been proposed as one of the main underlying mechanisms for RPL. The aim of this study was to evaluate the role of inflammatory pathway and oxidative stress imbalance in RPL patients with or without metabolic syndrome (MetS). 21 and 28 RPL patients with (RPL-MS) and without (RPL-NMS) metabolic syndrome were enrolled in this clinical study. 42 healthy women also were considered as the control group. The levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8 were evaluated by ELISA method. Additionally, the oxidative stress biomarkers including TAS, TOS, NO, CAT, SOD, AOPP, MPO were analyzed by spectrophotometry. The expression levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8, NFĸB, AP1, miR-21, miR-146-a, miR-223 were also assessed by real time PCR. The frequency of Th17 and T-reg cells was also measured by flow cytometry. Significant increase in the expression levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8, NFĸB, AP1 and miR-21 was observed in RPL-MS patients. Furthermore, significant decreased expression levels of FoxP3, miR-146-a and miR-223 was also observed in RPL-MS group. The levels of IL1ß, IL6, IL17, TNFα, CCL2, CXCL8, NO, MPO and TOS were found to be higher in RPL-MS group compared to the RPL-NMS and healthy controls. In contrast, the level of CAT and SOD in RPL-MS patients was decreased. The frequency of Th17 and Treg cells was also higher and lower in RPL-MS patients compared to the other groups, respectively. Our results support the concept that subclinical inflammatory state, oxidative stress and metabolic syndrome play a crucial role in the etiopathogenesis of RPL assisting clinicians for pregnancy consequences prediction.
Assuntos
Aborto Habitual/imunologia , Síndrome Metabólica/imunologia , Aborto Habitual/sangue , Aborto Habitual/epidemiologia , Adulto , Glicemia/análise , Glicemia/imunologia , Estudos de Casos e Controles , HDL-Colesterol/sangue , HDL-Colesterol/imunologia , Feminino , Humanos , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Síndrome Metabólica/diagnóstico , Estresse Oxidativo/imunologia , Gravidez , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo , Triglicerídeos/sangue , Triglicerídeos/imunologia , Circunferência da Cintura/imunologia , Adulto JovemAssuntos
Anticorpos Anti-Idiotípicos/sangue , Cirrose Hepática/sangue , Miócitos de Músculo Liso/imunologia , Hepatopatia Gordurosa não Alcoólica/imunologia , Adulto , Anticorpos Anti-Idiotípicos/imunologia , Bilirrubina/sangue , Bilirrubina/imunologia , Feminino , Humanos , Fígado/imunologia , Fígado/metabolismo , Fígado/patologia , Cirrose Hepática/imunologia , Cirrose Hepática/patologia , Masculino , Miócitos de Músculo Liso/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Hepatopatia Gordurosa não Alcoólica/patologia , Tempo de Protrombina , Albumina Sérica , Triglicerídeos/sangue , Triglicerídeos/imunologiaRESUMO
PURPOSE OF REVIEW: Not all of the risk of cardiovascular disease can be explained by diet and genetics, and the human microbiome, which lies at the interface of these two factors, may help explain some of the unaccounted risk. This review examines some of the well established links between the microbiome and cardiovascular health, and proposes relatively unexplored associations. RECENT FINDINGS: Byproducts of microbial metabolism are associated with health and disease: Trimethylamine N oxide is associated with atherosclerosis; whereas short-chain fatty acids are associated with decreased inflammation and increased energy expenditure. More broadly, a large number of association studies have been conducted to explore the connections between bacterial taxa and metabolic syndrome. In contrast, the relationship between the microbiome and triglycerides levels remains poorly understood. SUMMARY: We suggest that deeper understanding of the molecular mechanisms that drive linkages between the microbiome and disease can be determined by replacing 16S rRNA gene sequencing with shotgun metagenomic sequencing or other functional approaches. Furthermore, to ensure translatability and reproducibility of research findings, a combination of multiple different complementary '-omic' approaches should be employed.
Assuntos
Aterosclerose/microbiologia , Ácidos Graxos Voláteis/metabolismo , Microbioma Gastrointestinal/imunologia , Metabolismo dos Lipídeos/imunologia , Síndrome Metabólica/microbiologia , Metilaminas/metabolismo , Animais , Aterosclerose/genética , Aterosclerose/imunologia , Aterosclerose/patologia , Ácidos e Sais Biliares/imunologia , Ácidos e Sais Biliares/metabolismo , Carnitina/imunologia , Carnitina/metabolismo , Colina/imunologia , Colina/metabolismo , Metabolismo Energético/genética , Metabolismo Energético/imunologia , Ácidos Graxos Voláteis/imunologia , Microbioma Gastrointestinal/genética , Genômica/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Humanos , Metabolismo dos Lipídeos/genética , Síndrome Metabólica/genética , Síndrome Metabólica/imunologia , Síndrome Metabólica/patologia , Metilaminas/imunologia , Metilaminas/farmacologia , Fosfatidilcolinas/imunologia , Fosfatidilcolinas/metabolismo , RNA Ribossômico 16S/genética , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/microbiologia , Triglicerídeos/imunologia , Triglicerídeos/metabolismoRESUMO
Tolllike receptor 4 (TLR4)mediated immune and inflammatory signaling serves a pivotal role in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Our previous study demonstrated that celastrol treatment was able to improve hepatic steatosis and inhibit the TLR4 signaling cascade pathway in type 2 diabetic rats. The present study aimed to investigate the effects of celastrol on triglyceride accumulation and inflammation in steatotic HepG2 cells, and the possible mechanisms responsible for the regulation of cellular responses following TLR4 gene knockdown by small interfering RNA (siRNA) in vitro. A cell model of hepatic steatosis was prepared by exposing the HepG2 cells to free fatty acid (FFA) in the absence or presence of celastrol. Intracellular triglycerides were visualized by Oil red O staining, and the TLR4/myeloid differentiation primary response 88 (MyD88)/nuclear factorκB (NFκB) signaling cascade pathway were investigated. To directly elucidate whether TLR4 was the blocking target of celastrol upon FFA exposure, the cellular response to inflammation was determined upon transfection with TLR4 siRNA. The results revealed that celastrol significantly reduced triglyceride accumulation in the steatotic HepG2 cells, and downregulated the expression levels of TLR4, MyD88 and phosphoNFκBp65, as well as of the downstream inflammatory cytokines interleukin1ß and tumor necrosis factor α. Knockdown of TLR4 also alleviated FFAinduced inflammatory response. In addition, cotreatment with TLR4 siRNA and celastrol further attenuated the expression of inflammatory mediators. These results suggest that celastrol exerts its protective effect partly via inhibiting the TLR4mediated immune and inflammatory response in steatotic HepG2 cells.
Assuntos
Ácidos Graxos não Esterificados/efeitos adversos , Hepatopatia Gordurosa não Alcoólica/imunologia , Receptor 4 Toll-Like/imunologia , Triglicerídeos/imunologia , Triterpenos/farmacocinética , Animais , Ácidos Graxos não Esterificados/farmacologia , Células Hep G2 , Humanos , Inflamação/induzido quimicamente , Inflamação/genética , Inflamação/imunologia , Hepatopatia Gordurosa não Alcoólica/induzido quimicamente , Hepatopatia Gordurosa não Alcoólica/genética , Hepatopatia Gordurosa não Alcoólica/patologia , Triterpenos Pentacíclicos , Ratos , Receptor 4 Toll-Like/genética , Triglicerídeos/genéticaRESUMO
In addition to accumulation and metabolism of triglycerides, white adipose tissue is recognized as the active endocrine organ, whose dysfunction is associated with the development of a wide range of diseases. The secretome of adipocytes is represented by a wide range of adipokines, which vary in depot and sex-specific manner. In addition, adipokines have diverse biological effects, correlations with different metabolic features and functions. In this review, the data on biological effects, origin and the clinical significance of adipokines are discussed. The influence of adipokines on metabolism, sensitivity to insulin, vascular homeostasis, angiogenesis, repair, inflammation and immune cells are shown. Visceral adipose tissue accumulation is accompanied with adipocytes hypertrophy and overproduction of such proinflammatory and proaterogenic molecules like resistin, visfatin, vaspin, tumor necrosis factor, interleukin 6, lipocalin, glypican 4, RBP4 etc. There is a tight correlation between these adipokines level and development of insulin resistance, type 2 diabetes, cardiometabolic complications and cancer. Thus, adipokines represent a group of informative biomarkers for the diagnostics of metabolic disorders and the prediction of the outcome of the wide range of diseases. The study of the effects and mechanisms of the action of adipokines is the basis for determining new targets for therapy.
Assuntos
Adipócitos Brancos/metabolismo , Adipocinas/genética , Tecido Adiposo Branco/metabolismo , Doenças Cardiovasculares/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Neoplasias/metabolismo , Adipócitos Brancos/citologia , Adipócitos Brancos/imunologia , Adipocinas/imunologia , Tecido Adiposo Branco/citologia , Tecido Adiposo Branco/imunologia , Biomarcadores/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/imunologia , Doenças Cardiovasculares/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Diabetes Mellitus Tipo 2/patologia , Regulação da Expressão Gênica , Humanos , Resistência à Insulina , Metaboloma/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/patologia , Neovascularização Fisiológica/imunologia , Fatores Sexuais , Transdução de Sinais , Triglicerídeos/imunologia , Triglicerídeos/metabolismoRESUMO
Mycobacterium tuberculosis remains a global threat to human health, yet the molecular mechanisms regulating immunity remain poorly understood. Cytokines can promote or inhibit mycobacterial survival inside macrophages and the underlying mechanisms represent potential targets for host-directed therapies. Here we show that cytokine-STAT signalling promotes mycobacterial survival within macrophages by deregulating lipid droplets via ATG2 repression. In Drosophila infected with Mycobacterium marinum, mycobacterium-induced STAT activity triggered by unpaired-family cytokines reduces Atg2 expression, permitting deregulation of lipid droplets. Increased Atg2 expression or reduced macrophage triglyceride biosynthesis, normalizes lipid deposition in infected phagocytes and reduces numbers of viable intracellular mycobacteria. In human macrophages, addition of IL-6 promotes mycobacterial survival and BCG-induced lipid accumulation by a similar, but probably not identical, mechanism. Our results reveal Atg2 regulation as a mechanism by which cytokines can control lipid droplet homeostasis and consequently resistance to mycobacterial infection in Drosophila.
Assuntos
Proteínas Relacionadas à Autofagia/imunologia , Proteínas de Drosophila/imunologia , Interleucina-6/metabolismo , Infecções por Mycobacterium/imunologia , Fatores de Transcrição STAT/imunologia , Proteínas de Transporte Vesicular/imunologia , Animais , Proteínas Relacionadas à Autofagia/metabolismo , Linhagem Celular , Modelos Animais de Doenças , Resistência à Doença/imunologia , Drosophila , Proteínas de Drosophila/metabolismo , Hemócitos , Humanos , Interleucina-6/imunologia , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Infecções por Mycobacterium/microbiologia , Mycobacterium bovis/imunologia , Mycobacterium bovis/patogenicidade , Mycobacterium marinum/imunologia , Mycobacterium marinum/patogenicidade , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/patogenicidade , Cultura Primária de Células , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Triglicerídeos/imunologia , Triglicerídeos/metabolismo , Proteínas de Transporte Vesicular/metabolismo , VirulênciaRESUMO
OBJECTIVE: Mendelian randomization studies revealed a causal role for remnant cholesterol in cardiovascular disease. Remnant particles accumulate in the arterial wall, potentially propagating local and systemic inflammation. We evaluated the impact of remnant cholesterol on arterial wall inflammation, circulating monocytes, and bone marrow in patients with familial dysbetalipoproteinemia (FD). APPROACH AND RESULTS: Arterial wall inflammation and bone marrow activity were measured using 18F-FDG PET/CT. Monocyte phenotype was assessed with flow cytometry. The correlation between remnant levels and hematopoietic activity was validated in the CGPS (Copenhagen General Population Study). We found a 1.2-fold increase of 18F-FDG uptake in the arterial wall in patients with FD (n=17, age 60±8 years, remnant cholesterol: 3.26 [2.07-5.71]) compared with controls (n=17, age 61±8 years, remnant cholesterol 0.29 [0.27-0.40]; P<0.001). Monocytes from patients with FD showed increased lipid accumulation (lipid-positive monocytes: Patients with FD 92% [86-95], controls 76% [66-81], P=0.001, with an increase in lipid droplets per monocyte), and a higher expression of surface integrins (CD11b, CD11c, and CD18). Patients with FD also exhibited monocytosis and leukocytosis, accompanied by a 1.2-fold increase of 18F-FDG uptake in bone marrow. In addition, we found a strong correlation between remnant levels and leukocyte counts in the CGPS (n=103 953, P for trend 5×10-276). In vitro experiments substantiated that remnant cholesterol accumulates in human hematopoietic stem and progenitor cells coinciding with myeloid skewing. CONCLUSIONS: Patients with FD have increased arterial wall and cellular inflammation. These findings imply an important inflammatory component to the atherogenicity of remnant cholesterol, contributing to the increased cardiovascular disease risk in patients with FD.
Assuntos
Artérias/imunologia , Arterite/imunologia , Colesterol/imunologia , Hiperlipoproteinemia Tipo III/imunologia , Imunidade Celular , Lipoproteínas/imunologia , Triglicerídeos/imunologia , Idoso , Artérias/diagnóstico por imagem , Artérias/metabolismo , Arterite/sangue , Arterite/diagnóstico por imagem , Células da Medula Óssea/imunologia , Células da Medula Óssea/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Colesterol/sangue , Dinamarca , Feminino , Fluordesoxiglucose F18 , Células-Tronco Hematopoéticas/imunologia , Células-Tronco Hematopoéticas/metabolismo , Humanos , Hiperlipoproteinemia Tipo III/sangue , Hiperlipoproteinemia Tipo III/diagnóstico por imagem , Integrinas/imunologia , Integrinas/metabolismo , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Monócitos/metabolismo , Fenótipo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Compostos Radiofarmacêuticos , Transdução de Sinais , Triglicerídeos/sangueRESUMO
GPIHBP1, an endothelial cell protein, binds LPL in the interstitial spaces and shuttles it to its site of action inside blood vessels. For years, studies of human GPIHBP1 have been hampered by an absence of useful antibodies. We reasoned that monoclonal antibodies (mAbs) against human GPIHBP1 would be useful for 1) defining the functional relevance of GPIHBP1's Ly6 and acidic domains to the binding of LPL; 2) ascertaining whether human GPIHBP1 is expressed exclusively in capillary endothelial cells; and 3) testing whether GPIHBP1 is detectable in human plasma. Here, we report the development of a panel of human GPIHBP1-specific mAbs. Two mAbs against GPIHBP1's Ly6 domain, RE3 and RG3, abolished LPL binding, whereas an antibody against the acidic domain, RF4, did not. Also, mAbs RE3 and RG3 bound with reduced affinity to a mutant GPIHBP1 containing an Ly6 domain mutation (W109S) that abolishes LPL binding. Immunohistochemistry studies with the GPIHBP1 mAbs revealed that human GPIHBP1 is expressed only in capillary endothelial cells. Finally, we created an ELISA that detects GPIHBP1 in human plasma. That ELISA should make it possible for clinical lipidologists to determine whether plasma GPIHBP1 levels are a useful biomarker of metabolic or vascular disease.
Assuntos
Anticorpos Monoclonais/imunologia , Lipase Lipoproteica/imunologia , Receptores de Lipoproteínas/imunologia , Triglicerídeos/metabolismo , Animais , Sítios de Ligação/imunologia , Linhagem Celular , Drosophila , Células Endoteliais/enzimologia , Células Endoteliais/imunologia , Humanos , Lipase Lipoproteica/antagonistas & inibidores , Lipase Lipoproteica/isolamento & purificação , Camundongos , Receptores de Lipoproteínas/genética , Triglicerídeos/imunologiaRESUMO
Postprandial triglyceride-rich lipoproteins (TRLs) lead to a complex series of events that are potentially oxidative and inflammatory. The main goal of this study was to characterize the influence of postprandial TRLs with different fatty acid compositions (mainly SFAs, MUFAs or MUFAs plus omega-3 PUFAs) on oxidative and inflammatory markers in RPE cells, which play a pivotal role in age-related macular degeneration (AMD). Compared to TRL-SFAs, TRL-MUFAs and TRL-MUFAs plus omega-3 PUFAs decreased the production of ROS and nitrite, and the gene expression and secretion of IL-1ß, IL-6, TNF-α, IFNγ and VEGF. For the first time we show that postprandial TRLs are metabolic entities able to induce RPE oxidative stress and inflammation in a fatty acid-dependent manner, TRL-SFAs â TRL-MUFAs = TRL-MUFAs plus omega-3 PUFAs. These exciting findings open new opportunities for developing novel nutritional strategies with olive oil as the principal dietary source of oleic acid to prevent the development and progression of AMD.
Assuntos
Anti-Inflamatórios/imunologia , Células Epiteliais/imunologia , Ácidos Graxos/imunologia , Degeneração Macular/imunologia , Retina/imunologia , Anti-Inflamatórios/metabolismo , Linhagem Celular , Células Epiteliais/metabolismo , Ácidos Graxos/química , Ácidos Graxos/metabolismo , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Lipoproteínas/imunologia , Degeneração Macular/metabolismo , Período Pós-Prandial/imunologia , Espécies Reativas de Oxigênio/imunologia , Retina/metabolismo , Triglicerídeos/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Toll-like receptors (TLRs) are activated by inflammatory stimuli and influence endothelial functions, contributing to the pathogenesis of atherosclerosis. We investigate the influence of polymorphisms in the genes encoding toll-like receptor 2 (TLR2) and 4 (TLR4) and endothelial adhesion molecules on polycystic ovary syndrome (PCOS) and its interaction with obesity. Ten single nucleotide polymorphisms were genotyped in 305 women with PCOS and 166 non-hyperandrogenic control women. In obese women, TLR2 S450S and ICAM1 K469E polymorphisms differently influenced metabolic variables and PCOS, respectively. Irrespective of PCOS, variant alleles of TLR2 S450S increased triglycerides, fasting insulin levels, and insulin resistance in obese women. TLR2 S450S interacted with obesity and PCOS on androstenedione levels, mutant alleles were associated with increased androstenedione concentrations in all women, with the exception of obese patients with PCOS (P=0.034). Regarding ICAM1 K469E, homozygosis for K469 alleles was more frequent in PCOS, but only in obese women (P=0.014). K469 alleles were also related to increased body mass index (P=0.017) and diastolic blood pressure (P=0.034). Moreover, ICAM1 K469E interacted with obesity and PCOS on serum triglyceride levels (P=0.019) and with PCOS on serum sex hormone-binding globulin concentrations (P=0.006). In conclusion, TLR2 S450S and ICAM1 K469E polymorphisms may be associated with PCOS and metabolic comorbidities in obese women.
Assuntos
Alelos , Molécula 1 de Adesão Intercelular/imunologia , Obesidade/genética , Síndrome do Ovário Policístico/genética , Polimorfismo Genético , Receptor 2 Toll-Like/genética , Adulto , Substituição de Aminoácidos , Androstenodiona/sangue , Androstenodiona/genética , Androstenodiona/imunologia , Feminino , Humanos , Insulina/sangue , Insulina/genética , Insulina/imunologia , Molécula 1 de Adesão Intercelular/sangue , Molécula 1 de Adesão Intercelular/genética , Obesidade/sangue , Obesidade/complicações , Obesidade/imunologia , Síndrome do Ovário Policístico/sangue , Síndrome do Ovário Policístico/complicações , Síndrome do Ovário Policístico/imunologia , Receptor 2 Toll-Like/sangue , Receptor 2 Toll-Like/imunologia , Triglicerídeos/sangue , Triglicerídeos/genética , Triglicerídeos/imunologiaRESUMO
Abundant reports have shown that there is a strong relationship between C3 and C3a-desArg levels, adipose tissue, and risk factors for cardiovascular disease, metabolic syndrome and diabetes. The data indicate that complement components, particularly C3, are involved in lipid metabolism. The C3 fragment, C3a-desArg, functions as a hormone that has insulin-like effects and facilitates triglyceride metabolism. Adipose tissue produces and regulates the levels of complement components, which promotes generation of inflammatory initiators such as the anaphylatoxins C3a and C5a. The anaphylatoxins trigger a cyto/chemokine response in proportion to the amount of adipose tissue present, and induce inflammation and mediate metabolic effects such as insulin resistance. These observations support the concept that complement is an important participant in lipid metabolism and in obesity, contributing to the metabolic syndrome and to the low-grade inflammation associated with obesity.
Assuntos
Tecido Adiposo/imunologia , Doenças Cardiovasculares/imunologia , Complemento C3a/imunologia , Diabetes Mellitus/imunologia , Metabolismo dos Lipídeos/imunologia , Síndrome Metabólica/imunologia , Obesidade/imunologia , Tecido Adiposo/metabolismo , Tecido Adiposo/patologia , Apolipoproteínas/genética , Apolipoproteínas/imunologia , Apolipoproteínas/metabolismo , Doenças Cardiovasculares/genética , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/patologia , Complemento C3a/genética , Complemento C3a/metabolismo , Complemento C5a/genética , Complemento C5a/imunologia , Complemento C5a/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/patologia , Regulação da Expressão Gênica , Humanos , Resistência à Insulina/imunologia , Síndrome Metabólica/genética , Síndrome Metabólica/metabolismo , Síndrome Metabólica/patologia , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Receptores de Complemento/genética , Receptores de Complemento/imunologia , Receptores de Complemento/metabolismo , Fatores de Risco , Triglicerídeos/genética , Triglicerídeos/imunologia , Triglicerídeos/metabolismoRESUMO
OBJECTIVE: To investigate the frequency association between resistin gene polymorphism with its circulating levels, metabolic risk factor and insulin resistance in adult women. DESIGN: Totally 615 subjects were enrolled for the study, 305 women were with metabolic syndrome and 310 women were without metabolic syndrome according to NCEP-ATP III criteria. Fasting circulatory level of resistin, insulin, plasma glucose and lipid profiles were estimated along with calculation of insulin resistance. Resistin 420C/G promoter region polymorphism was done by RFLP method. RESULTS: Variant genotype (CC vs CG+GG) (p<0.001: OR=2.22: 95% CI=1.60-3.10) of 420C/G resistin gene polymorphism was less frequently observed in control population. Further dividing subjects into two groups according to absence (Resistin -1) or presence (Resistin-2) of the G allele, significantly high levels of triglyceride (p<0.001), plasma glucose (p=0.012), systolic blood pressure (p<0.001), diastolic blood pressure (p<0.001), waist hip ratio (p<0.001), body mass index (p<0.001) and resistin (p<0.001), were observed in resistin-2 group. CONCLUSION: Present study shows that 420C/G polymorphism of resistin gene directly correlated to its high circulating level and metabolic risk factors, specifically markers of obesity and atherosclerosis, so it may have an important role in the development of metabolic syndrome and cardio metabolic diseases.
Assuntos
Alelos , Síndrome Metabólica/genética , Polimorfismo de Fragmento de Restrição , Regiões Promotoras Genéticas , Resistina/genética , Adulto , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/imunologia , Pressão Sanguínea , Feminino , Humanos , Síndrome Metabólica/sangue , Síndrome Metabólica/imunologia , Obesidade/sangue , Obesidade/genética , Obesidade/imunologia , Resistina/sangue , Resistina/imunologia , Fatores de Risco , Triglicerídeos/sangue , Triglicerídeos/imunologiaRESUMO
BACKGROUND: Chronic HIV infection is associated with increased risk of cardiovascular disease caused by atherosclerosis. Oxidized forms of low-density lipoprotein (LDL) are present in atherosclerotic lesions and constitute major epitopes for natural antibodies. IgM has been shown to be protective against atherosclerosis, whereas the role of corresponding IgG is less clear. The objective of this study was to determine if HIV + individuals have disturbed levels of IgM and IgG directed against oxidized forms of LDL as compared to HIV- individuals. METHODS: Ninety-one HIV + patients and 92 HIV- controls were included in this retrospective study. Circulating levels of IgG and IgM directed against two forms of oxidized LDL; copper oxidized (OxLDL) and malondialdehyde modified (MDA-LDL), total IgM and IgG, C-reactive protein (CRP), soluble CD14, and apolipoproteins A1 and B were determined. RESULTS: HIV + individuals had slightly lower levels of IgM against MDA-LDL and higher levels of IgG against MDA-LDL, OxLDL, and total IgG, than HIV- controls. Anti-MDA-LDL and Anti-OxLDL IgG displayed a positive correlation with viral load and a negative correlation with the CD4+ T-cell count. HIV + individuals also displayed elevated CRP and soluble CD14 levels compared to HIV- individuals, but there were no correlations between CRP or soluble CD14 and specific antibodies. CONCLUSIONS: HIV infection is associated with higher levels of IgG including specific IgG against oxidized forms of LDL, and lower IgM against the same epitope. In addition to dyslipidemia, immune activation, HIV-replication and an accumulation of risk factors for atherosclerosis, this adverse antibody profile may be of major importance for the increased risk of cardiovascular disease in HIV + individuals.
Assuntos
Infecções por HIV/imunologia , HIV-1/imunologia , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Lipoproteínas LDL/imunologia , Adulto , Idoso , Estudos de Casos e Controles , Colesterol/sangue , Colesterol/imunologia , Feminino , Infecções por HIV/sangue , Infecções por HIV/epidemiologia , Humanos , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Triglicerídeos/sangue , Triglicerídeos/imunologia , Adulto JovemRESUMO
OBJECTIVE: Although the human adenovirus 36 (Ad-36) is associated with obesity and relative hypolipidemia, its role in pediatric weight loss treatment response is uncertain. Therefore, the primary study objective was to determine whether Ad-36 antibody (AB) status was associated with response to a pediatric weight loss program. The secondary objective was to assess the association between Ad-36 AB status and baseline lipid values. METHODS: Participants included 73 youth aged 10-17 years in a residential camp-based weight loss program. The study examined differences in baseline lipid values between Ad-36 AB+ and AB- youth as well as differences in response to treatment, including indices of body size and fitness. RESULTS: At baseline, results showed that Ad-36 AB+ youth evidenced significantly lower levels of total cholesterol and triglycerides than Ad-36 AB- youth (all p < 0.05). After 4 weeks of treatment, the Ad-36 AB+ youth showed a smaller reduction in BMI percentile than the Ad-36 AB- youth (p < 0.05), a difference of about 0.48 kg. CONCLUSION: Ad-36 AB status showed a weak association with treatment response, but was associated with a better lipid profile. Ad-36 AB status should be assessed in studies of pediatric obesity treatment and prevention.
Assuntos
Adenovírus Humanos/imunologia , Anticorpos Antivirais/sangue , Índice de Massa Corporal , Lipídeos/sangue , Obesidade Infantil/imunologia , Redução de Peso/imunologia , Programas de Redução de Peso , Adolescente , Criança , Colesterol/sangue , Colesterol/imunologia , Feminino , Humanos , Lipídeos/imunologia , Masculino , Obesidade Infantil/sangue , Obesidade Infantil/terapia , Triglicerídeos/sangue , Triglicerídeos/imunologiaRESUMO
Human pathogen group A streptococcus (GAS) has developed mechanisms to subvert innate immunity. We recently reported that the secreted esterase produced by serotype M1 GAS (SsE(M1)) reduces neutrophil recruitment by targeting platelet-activating factor (PAF). SsE(M1) and SsE produced by serotype M28 GAS (SsE(M28)) have a 37% sequence difference. This study aims at determining whether SsE(M28) is also a PAF acetylhydrolase and participates in innate immune evasion. We also examined whether SsE evolved to target PAF by characterizing the PAF acetylhydrolase (PAF-AH) activity and substrate specificity of SsE(M1), SsE(M28), SeE, the SsE homologue in Streptococcus equi, and human plasma PAF-AH (hpPAF-AH). PAF incubated with SsE(M28) or SeE was converted into lyso-PAF. SsE(M1) and SsE(M28) had kcat values of 373 s(-1) and 467 s(-1), respectively, that were ≥ 30-fold greater than that of hpPAF-AH (12 s(-1)). The comparison of SsE(M1), SsE(M28), and hpPAF-AH in kcat and Km in hydrolyzing triglycerides, acetyl esters, and PAF indicates that the SsE proteins are more potent hydrolases against PAF and have high affinity for PAF. SsE(M28) possesses much lower esterase activities against triglycerides and other esters than SsE(M1) but have similar potency with SsE(M1) in PAF hydrolysis. Deletion of sse(M28) in a covS deletion mutant of GAS increased neutrophil recruitment and reduced skin infection, whereas in trans expression of SsE(M28) in GAS reduced neutrophil infiltration and increased skin invasion in subcutaneous infection of mice. These results suggest that the SsE proteins evolved to target PAF for enhancing innate immune evasion and skin invasion.