Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 1.396
Filtrar
1.
Nat Commun ; 11(1): 4765, 2020 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-32958780

RESUMO

Fatty acids (FAs) are essential nutrients, but how they are transported into cells remains unclear. Here, we show that FAs trigger caveolae-dependent CD36 internalization, which in turn delivers FAs into adipocytes. During the process, binding of FAs to CD36 activates its downstream kinase LYN, which phosphorylates DHHC5, the palmitoyl acyltransferase of CD36, at Tyr91 and inactivates it. CD36 then gets depalmitoylated by APT1 and recruits another tyrosine kinase SYK to phosphorylate JNK and VAVs to initiate endocytic uptake of FAs. Blocking CD36 internalization by inhibiting APT1, LYN or SYK abolishes CD36-dependent FA uptake. Restricting CD36 at either palmitoylated or depalmitoylated state eliminates its FA uptake activity, indicating an essential role of dynamic palmitoylation of CD36. Furthermore, blocking endocytosis by targeting LYN or SYK inhibits CD36-dependent lipid droplet growth in adipocytes and high-fat-diet induced weight gain in mice. Our study has uncovered a dynamic palmitoylation-regulated endocytic pathway to take up FAs.


Assuntos
Antígenos CD36/metabolismo , Endocitose/fisiologia , Ácidos Graxos/metabolismo , Lipoilação , Células 3T3-L1 , Aciltransferases/metabolismo , Adipócitos/metabolismo , Animais , Antígenos CD36/deficiência , Antígenos CD36/genética , Cavéolas/metabolismo , Células Cultivadas , Dieta Hiperlipídica/efeitos adversos , Humanos , Gotículas Lipídicas/metabolismo , Masculino , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mutação , Obesidade/tratamento farmacológico , Fosforilação , Transdução de Sinais , Quinase Syk/antagonistas & inibidores , Quinase Syk/metabolismo , Ganho de Peso/efeitos dos fármacos , Quinases da Família src/antagonistas & inibidores , Quinases da Família src/metabolismo
2.
PLoS One ; 15(7): e0236375, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32726331

RESUMO

BACKGROUND: Malaria in pregnancy causes maternal, fetal and neonatal morbidity and mortality, and maternal innate immune responses are implicated in pathogenesis of these complications. The effects of malaria exposure and obstetric and demographic factors on the early maternal immune response are poorly understood. METHODS: Peripheral blood mononuclear cell responses to Plasmodium falciparum-infected erythrocytes and phytohemagglutinin were compared between pregnant women from Papua New Guinea (malaria-exposed) with and without current malaria infection and from Australia (unexposed). Elicited levels of inflammatory cytokines at 48 h and 24 h (interferon γ, IFN-γ only) and the cellular sources of IFN-γ were analysed. RESULTS: Among Papua New Guinean women, microscopic malaria at enrolment did not alter peripheral blood mononuclear cell responses. Compared to samples from Australia, cells from Papua New Guinean women secreted more inflammatory cytokines tumor necrosis factor-α, interleukin 1ß, interleukin 6 and IFN-γ; p<0.001 for all assays, and more natural killer cells produced IFN-γ in response to infected erythrocytes and phytohemagglutinin. In both populations, cytokine responses were not affected by gravidity, except that in the Papua New Guinean cohort multigravid women had higher IFN-γ secretion at 24 h (p = 0.029) and an increased proportion of IFN-γ+ Vδ2 γδ T cells (p = 0.003). Cytokine levels elicited by a pregnancy malaria-specific CSA binding parasite line, CS2, were broadly similar to those elicited by CD36-binding line P6A1. CONCLUSIONS: Geographic location and, to some extent, gravidity influence maternal innate immunity to malaria.


Assuntos
Imunidade Inata/genética , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Complicações Parasitárias na Gravidez/imunologia , Adolescente , Adulto , Austrália/epidemiologia , Antígenos CD36/genética , Eritrócitos/imunologia , Eritrócitos/parasitologia , Eritrócitos/patologia , Feminino , Número de Gestações/imunologia , Humanos , Interferon gama/genética , Interferon gama/imunologia , Interleucina-6/genética , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/parasitologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/parasitologia , Leucócitos Mononucleares/patologia , Malária Falciparum/epidemiologia , Malária Falciparum/parasitologia , Pessoa de Meia-Idade , Papua Nova Guiné/epidemiologia , Plasmodium falciparum/patogenicidade , Gravidez , Complicações Parasitárias na Gravidez/parasitologia , Complicações Parasitárias na Gravidez/patologia , Linfócitos T/imunologia , Linfócitos T/parasitologia , Adulto Jovem
3.
Neurobiol Aging ; 92: 82-91, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32408056

RESUMO

Neuroinflammatory responses mediated by microglia, the resident immune cells of the central nervous system, have long been a subject of study in the field of Alzheimer's disease (AD). Microglia express a wide range of receptors that act as molecular sensors, through which they can fulfill their various functions. In this review, we first analyzed the changes in the expression levels of microglial membrane receptors SR-A, TREM2, CD36, CD33, and CR3 in aging and AD and described the different roles of these receptors in amyloid-beta clearance and inflammatory responses. Two classical hallmarks of AD are extracellular amyloid-beta deposits and intracellular aggregated phosphorylated tau. In AD, microglia reaction was initially thought to be triggered by amyloid deposits. New evidence showed it also associated with increased phosphorylation of tau. However, which first appeared and induced activated microglia is not clear. Then we summarized diverse opinions on it. Besides, as AD is tightly linked to aging, and microglia changes dramatically on aging, yet the relative impacts of both aging and microglia are less frequently considered, so at last, we discussed the roles of aging microglia in AD. We hope to provide a reference for subsequent research.


Assuntos
Envelhecimento/genética , Envelhecimento/patologia , Doença de Alzheimer/etiologia , Doença de Alzheimer/patologia , Encéfalo/citologia , Encéfalo/patologia , Expressão Gênica , Microglia/patologia , Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Humanos , Inflamação , Antígeno de Macrófago 1/metabolismo , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Microglia/citologia , Fosforilação , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismo , Receptores Depuradores Classe A/genética , Receptores Depuradores Classe A/metabolismo , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/genética , Lectina 3 Semelhante a Ig de Ligação ao Ácido Siálico/metabolismo , Proteínas tau/metabolismo
4.
J Nutr ; 150(8): 2016-2022, 2020 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-32455431

RESUMO

BACKGROUND: The determinants of the intake of high-fat products are not well understood. OBJECTIVE: The aim of this study was to examine the relations between fat perception, intake of high-fat food, and body-weight status, taking into account the polymorphism of the genes that encode the proteins involved in oral fat perception. METHODS: A total of 421 participants aged 20-40 y were enrolled in Poznan, Poland, from 2016 to 2018. An ascending forced-choice triangle procedure was applied to determine fat discrimination ability. Salad dressings with varying concentrations of canola oil were used as stimuli. Genotyping of rs1761667 (CD36) rs1573611 [free fatty acid receptor 1 (FFAR1)], rs17108973 [free fatty acid receptor 4 (FFAR4)], and rs2274333 (CA6) was performed using TaqMan probes. The frequency of consumption of high-fat foods was measured using an application for mobile devices that uses the ecological momentary assessment approach. The associations were analyzed using linear regression or logistic regression, as appropriate. RESULTS: Individuals with the GG CD36 genotype were twice as likely to be fat discriminators, compared with the A allele carriers (P < 0.05). The mean total consumption of high-fat food was 45.8 (44.6, 47.0) times/wk and was not associated with fat discrimination or body-weight status. Obese and overweight subjects ate healthy high-fat food less frequently than did participants with normal body weight, at 4.53 (3.83, 5.23) versus 6.68 (5.82, 7.55) times/wk, respectively (P < 0.001). Men ate sweet high-fat food and snacks 15% less frequently than did women (P < 0.001 and P < 0.05) but consumed high-fat meat and fast food almost 40% more often than did women (P < 0.001 for both associations). CONCLUSIONS: In individuals aged 20-40 y, fat discrimination ability is associated with polymorphism of CD36 but not with the choice of high-fat food. The frequency of consumption of different types of high-fat foods varies by sex and body-weight status.


Assuntos
Antígenos CD36/genética , Antígenos CD36/metabolismo , Gorduras na Dieta , Análise de Alimentos , Polimorfismo Genético , Adulto , Anidrases Carbônicas/genética , Anidrases Carbônicas/metabolismo , Ingestão de Alimentos/genética , Comportamento Alimentar , Feminino , Genótipo , Humanos , Masculino , Receptores Acoplados a Proteínas-G/genética , Receptores Acoplados a Proteínas-G/metabolismo , Paladar/genética , Adulto Jovem
5.
Gene ; 753: 144806, 2020 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-32461018

RESUMO

BACKGROUND: The aim of the present study was to detect potential gender-specific associations between some common CD36 single nucleotide polymorphisms (SNPs) and the lipid profile, as well as the susceptibility to premature multi-vessel coronary artery heart disease (CHD) in the Han population of Northern China. METHODS: A systematic three-step study process was employed to detect associations between CD36 gene variants and blood lipid profiles, as well as premature multi-vessel CHD in a gender-specific manner. RESULTS: The current study documented the following novel findings: (I) the full population-based association study in 329 Northern Han Chinese showed that four common CD36 polymorphisms were significantly related to extreme lipid profiles, with statistically significant effects based on gender interactions (rs1049673: P = 0.001; rs7755: P = 0.008; rs3211956: P = 0.034; and rs3173798: P = 0.004); (ii) these statistically significant effects could be decomposed into statistically significant atherogenic effects in males, but non-significant non-atherogenic effects in females; (iii) the results of logistic regression analysis indicated that current smoking status, low density lipoprotein cholesterol (LDL-C) levels, and type-2 diabetes were independent risk factors for premature multi-vessel CHD phenotype (P < 0.0001). CONCLUSIONS: Four common CD36 polymorphisms (rs1049673, rs7755, rs3211956, and rs3173798) were identified to be significantly associated with extreme lipid profiles and had statistically opposite gender-specific clinical lipid profile effects. Thus, the 3'-untranslated regions (3'-UTR) CD36 SNPs could be a novel target for metabolic abnormalities in males of the Han nationality from Northern China.


Assuntos
Antígenos CD36/genética , Doença da Artéria Coronariana/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Aterosclerose/sangue , Aterosclerose/genética , Aterosclerose/patologia , Estudos de Casos e Controles , China/epidemiologia , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/epidemiologia , Doença da Artéria Coronariana/patologia , Vasos Coronários/patologia , Grupos Étnicos/genética , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Lipídeos/sangue , Lipídeos/genética , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Caracteres Sexuais
6.
Diabetes ; 69(6): 1193-1205, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32198214

RESUMO

Obesity is a risk factor for type 2 diabetes (T2D); however, not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from donors with T2D and non-T2D (ND), especially obese donors (BMI ≥30 kg/m2). Islets from obese donors with T2D had reduced insulin secretion, decreased ß-cell exocytosis, and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis, and reduced granule docking. This was accompanied by reduced expression of the exocytotic proteins SNAP25, STXBP1, and VAMP2, likely because CD36 induced downregulation of the insulin receptor substrate (IRS) proteins, suppressed the insulin-signaling phosphatidylinositol 3-kinase/AKT pathway, and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human ß-cell line EndoC-ßH1 increased IRS1 and exocytotic protein levels, improved granule docking, and enhanced insulin secretion. Our results demonstrate that ß-cells from obese donors with T2D have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit ß-cell function in T2D associated with obesity.


Assuntos
Antígenos CD36/metabolismo , Diabetes Mellitus Tipo 2/etiologia , Exocitose/fisiologia , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Obesidade/complicações , Anticorpos/farmacologia , Antígenos CD36/genética , Linhagem Celular , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Ilhotas Pancreáticas/citologia
8.
Transfusion ; 60(4): 847-854, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32129498

RESUMO

BACKGROUND: Anti-CD36s, developing after transfusion or during pregnancy, play an important role in immune-mediated bleeding disorders among Asian populations. Currently, little is known about the clinical relevance of anti-CD36. Here, we aimed to determine the frequency of CD36 deficiency in Thais by analyzing CD36 expression on cell surfaces and in plasma. STUDY DESIGN AND METHODS: The expression and deficiency of CD36 on platelets and monocytes were determined by flow cytometry. Mutations in the CD36 gene were analyzed by nucleotide sequencing. Soluble CD36 (sCD36) in plasma was quantified with enzyme-linked immunosorbent assay. RESULTS: Fifteen of 700 blood donors (2.14%) were identified as CD36 deficient. The frequencies of Type I and II CD36 deficiency were 0.43% and 1.71%, respectively. Type I individuals exhibited c.1163A > T, c.429 + 4insG, and c.1156C > T. Type II individuals exhibited c.879 T > C, c.329-330delAC, c.818 + 108delAACT, c.1125 + 13C > A, and c.1163A > T. CD36 on donor platelets (n = 685) showed a wide distribution of expression levels (mean fluorescence intensity, 16.71 ± 8.68). In the normal phenotype (n = 14), sCD36 concentration was 58.84 ± 11.68 ng/mL, which was significantly correlated with platelet CD36 expression (r2 = 0.8551). In Type II-deficient individuals (n = 6), a similar sCD36 concentration was detected (53.67 ± 8.17 ng/mL). However, sCD36 could not be detected in Type I individuals (n = 3). CONCLUSION: CD36 Type I deficiency was found, indicating the potential for immune-mediated platelet disorders in Thais. However, the underlying mutations differed from those reported in Japan and China. Interestingly, sCD36 could not be detected in plasma of Type I-deficient individuals. This finding may lead to the use of plasma to identify individuals at risk and to allow screening of large cohorts.


Assuntos
Antígenos de Superfície/análise , Doadores de Sangue , Plaquetas/imunologia , Antígenos CD36/deficiência , Plasma/imunologia , Grupo com Ancestrais do Continente Asiático , Antígenos CD36/análise , Antígenos CD36/sangue , Antígenos CD36/genética , Ensaio de Imunoadsorção Enzimática , Citometria de Fluxo , Humanos , Monócitos/imunologia , Mutação , Análise de Sequência de DNA , Tailândia/epidemiologia
9.
Nutrients ; 12(2)2020 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033224

RESUMO

Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract resulting from interactions among various factors with diet being one of the most significant. IBD-related dietary behaviors are not clearly related to taste dysfunctions. We analyzed body mass index (BMI) and perception of six taste qualities and assessed effects of specific taste genes in IBD patients and healthy subjects (HC). BMI in IBD patients was higher than in HC subjects. Taste sensitivity to taste qualities was reduced in IBD patients, except for sour taste, which was higher than in HC subjects. Genetic variations were related to some taste responses in HC subjects, but not in IBD patients. Frequencies of genotype AA and allele A in CD36 polymorphism (rs1761667) were significantly higher in IBD patients than in HC subjects. The taste changes observed could be explained by the oral pathologies and microbiome variations known for IBD patients and can justify their typical dietary behaviors. The lack of genetic effects on taste in IBD patients indicates that IBD might compromise taste so severely that gene effects cannot be observed. However, the high frequency of the non-tasting form of CD36 substantiates the fact that IBD-associated fat taste impairment may represent a risk factor for IBD.


Assuntos
Antígenos CD36/genética , Anidrases Carbônicas/genética , Doenças Inflamatórias Intestinais/genética , Polimorfismo Genético , Percepção Gustatória/genética , Paladar/genética , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Feminino , Frequência do Gene , Genótipo , Humanos , Doenças Inflamatórias Intestinais/complicações , Masculino , Fenótipo , Distúrbios do Paladar/genética
10.
Nat Immunol ; 21(3): 298-308, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066953

RESUMO

Depleting regulatory T cells (Treg cells) to counteract immunosuppressive features of the tumor microenvironment (TME) is an attractive strategy for cancer treatment; however, autoimmunity due to systemic impairment of their suppressive function limits its therapeutic potential. Elucidating approaches that specifically disrupt intratumoral Treg cells is direly needed for cancer immunotherapy. We found that CD36 was selectively upregulated in intrautumoral Treg cells as a central metabolic modulator. CD36 fine-tuned mitochondrial fitness via peroxisome proliferator-activated receptor-ß signaling, programming Treg cells to adapt to a lactic acid-enriched TME. Genetic ablation of Cd36 in Treg cells suppressed tumor growth accompanied by a decrease in intratumoral Treg cells and enhancement of antitumor activity in tumor-infiltrating lymphocytes without disrupting immune homeostasis. Furthermore, CD36 targeting elicited additive antitumor responses with anti-programmed cell death protein 1 therapy. Our findings uncover the unexplored metabolic adaptation that orchestrates the survival and functions of intratumoral Treg cells, and the therapeutic potential of targeting this pathway for reprogramming the TME.


Assuntos
Antígenos CD36/imunologia , Neoplasias/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/imunologia , Antígenos CD36/deficiência , Antígenos CD36/genética , Linhagem Celular Tumoral , Feminino , Homeostase/imunologia , Humanos , Imunoterapia , Metabolismo dos Lipídeos/genética , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/metabolismo , Neoplasias/patologia , PPAR beta/imunologia , Transdução de Sinais/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Microambiente Tumoral/imunologia
11.
Am J Physiol Renal Physiol ; 318(4): F911-F921, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32068459

RESUMO

The present study examined whether development of renal injury in the nondiabetic obese Dahl salt-sensitive leptin receptor mutant (SSLepRmutant) strain is associated with elevations in glomerular filtration rate and renal lipid accumulation. Baseline mean arterial pressure at 6 wk of age was similar between Dahl salt-sensitive wild-type (SSWT) and SSLepRmutant rats. However, by 18 wk of age, the SSLepRmutant strain developed hypertension, while the elevation in mean arterial pressure was not as severe in SSWT rats (192 ± 4 and 149 ± 6 mmHg, respectively). At baseline, proteinuria was fourfold higher in SSLepRmutant than SSWT rats and remained elevated throughout the study. The early development of progressive proteinuria was associated with renal hyperfiltration followed by a decline in renal function over the course of study in the SSLepRmutant compared with SSWT rats. Kidneys from the SSLepRmutant strain displayed more glomerulosclerosis and glomerular lipid accumulation than SSWT rats. Glomeruli were isolated from the renal cortex of both strains at 6 and 18 wk of age, and RNA sequencing was performed to identify genes and pathways driving glomerular injury. We observed significant increases in expression of the influx lipid transporters, chemokine (C-X-C motif) ligand 16 (Cxcl16) and scavenger receptor and fatty acid translocase (Cd36), respectively, and a significant decrease in expression of the efflux lipid transporter, ATP-binding cassette subfamily A member 2 (Abca2; cholesterol efflux regulatory protein 2), in SSLepRmutant compared with SSWT rats at 6 and 18 wk of age, which were validated by RT-PCR analysis. These data suggest an association between glomerular hyperfiltration and glomerular lipid accumulation during the early development of proteinuria associated with obesity.


Assuntos
Tecido Adiposo/metabolismo , Hemodinâmica , Hipertensão/metabolismo , Nefropatias/metabolismo , Glomérulos Renais/metabolismo , Metabolismo dos Lipídeos , Mutação , Obesidade/metabolismo , Receptores para Leptina/genética , Circulação Renal , Transportador 1 de Cassete de Ligação de ATP/genética , Transportador 1 de Cassete de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/genética , Transportadores de Cassetes de Ligação de ATP/metabolismo , Tecido Adiposo/patologia , Tecido Adiposo/fisiopatologia , Adiposidade , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Quimiocina CXCL16/genética , Quimiocina CXCL16/metabolismo , Modelos Animais de Doenças , Predisposição Genética para Doença , Taxa de Filtração Glomerular , Hipertensão/genética , Hipertensão/patologia , Hipertensão/fisiopatologia , Nefropatias/genética , Nefropatias/patologia , Nefropatias/fisiopatologia , Glomérulos Renais/patologia , Glomérulos Renais/fisiopatologia , Metabolismo dos Lipídeos/genética , Obesidade/genética , Obesidade/patologia , Obesidade/fisiopatologia , Fenótipo , Proteinúria/metabolismo , Proteinúria/patologia , Proteinúria/fisiopatologia , Ratos Endogâmicos Dahl , Cloreto de Sódio na Dieta
12.
J Endocrinol ; 244(3): 473-486, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31905167

RESUMO

In previous preclinical studies, low (non-burning) doses of UV radiation (UVR) limited weight gain and metabolic dysfunction in mice fed with a high-fat diet. Here, we explored the effects of low-dose UVR on physical activity and food intake and mechanistic pathways in interscapular brown adipose tissue (iBAT). Young adult C57Bl/6J male mice, housed as individuals, were fed a high-fat diet and exposed to low-dose UVR (sub-oedemal, 1 kJ/m2 UVB, twice-a-week) or 'mock' treatment, with or without running wheel access (2 h, for 'moderate' physical activity) immediately after phototherapy. There was no difference in distance run in mice exposed to UVR or mock-treated over 12 weeks of exposure to running wheels (P = 0.14). UVR (alone) did not significantly affect food intake, adiposity, or signs of glucose dysfunction. Access to running wheels increased food intake (after 10 weeks, P ≤ 0.02) and reduced gonadal white adipose tissue and iBAT mass (P ≤ 0.03). Body weight and hepatic steatosis were lowest in mice exposed to UVR with running wheel access. In the iBAT of mice exposed to UVR and running wheels, elevated Atgl, Cd36, Fasn, Igf1, Pparγ, and Ucp1 mRNAs and reduced CD11c on F4-80 + MHC class II+ macrophages were observed, while renal Sglt2 mRNA levels were increased, compared to high-fat diet alone (P ≤ 0.03). Blood levels of 25-hydroxyvitamin D were not increased by exposure to UVR and/or access to running wheels. In conclusion, when combined with physical activity, low-dose UVR may more effectively limit adiposity (specifically, body weight and hepatic steatosis) and modulate metabolic and immune pathways in iBAT.


Assuntos
Tecido Adiposo Marrom/metabolismo , Tecido Adiposo Marrom/efeitos da radiação , Adiposidade/efeitos da radiação , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Ácido Graxo Sintase Tipo I/genética , Ácido Graxo Sintase Tipo I/metabolismo , Lipase/genética , Lipase/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Condicionamento Físico Animal , Corrida , Transportador 2 de Glucose-Sódio/genética , Transportador 2 de Glucose-Sódio/metabolismo , Raios Ultravioleta
13.
J Agric Food Chem ; 68(5): 1276-1285, 2020 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-31965794

RESUMO

Atherosclerosis is one of the main causes of cardiovascular diseases. Our previous study indicated that a type of peroxidase derived from foxtail millet bran (FMBP) had prominent antitumor activities. In the present study, we found that FMBP had potential antiatherosclerosis effects. The results showed that FMBP treatment strongly suppressed lipid phagocytosis in both HASMCs and THP-1 cells by 52% and 49%, respectively. Further, FMBP significantly inhibited HASMCs migration by promoting transformation of HASMCs from synthetic to contractile, leading to the decrease of lipid phagocytosis. Simultaneously, FMBP repressed lipid uptake by reducing the expression of CD36 in THP-1 cells. In addition, FMBP reduced the secretion of inflammatory factor IL-1ß by inhibiting the expression of STAT3 in THP-1 cells. Interestingly, FMBP also had the same effects in models of atherosclerosis constructed with ApoE-/- mice, including decreased aortic lesion area, repressed aortic sinus CD36 and STAT3 expression, and elevated serum HDL-C concentration. Collectively, these results indicate that FMBP has great potential in preventing the development of atherosclerosis.


Assuntos
Aterosclerose/tratamento farmacológico , Antígenos CD36/genética , Peroxidase/administração & dosagem , Proteínas de Plantas/administração & dosagem , Fator de Transcrição STAT3/genética , Setaria (Planta)/enzimologia , Animais , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/genética , Aterosclerose/metabolismo , Antígenos CD36/metabolismo , Humanos , Masculino , Camundongos , Camundongos Knockout , Fator de Transcrição STAT3/metabolismo , Setaria (Planta)/química , Células THP-1
14.
J Biochem Mol Toxicol ; 34(2): e22422, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31729780

RESUMO

M1 macrophages serve one edge as proinflammatory and M2 macrophages serve the other edge as an anti-inflammatory macrophage. It appears that a related "switch" in macrophage morphology may also happen in the course of atherosclerosis, which has not yet been elucidated. An atherogenic diet (AD) was given to rats, and induction of macrophage differentiation and the nuclear localization of nuclear factor-kappa B (NFκB) were investigated by Western blot and immunofluorescence. Chemokines were analyzed using an antibody array with 32 target proteins. M2 macrophage transformation was confirmed in diosgenin-treated aorta by immunofluorescence and was validated in vitro using THP-1 cells. MAC387 (macrophage marker) and NFκBp65 (inflammatory hub) were upregulated in oxidatively-modified low-density lipoprotein (OxyLDL) and AD-induced condition. Macrophage differentiation, which induced the formation of inflammatory mediators, was not significantly suppressed by the inhibition of NFκB using dexamethasone. M1 macrophage polarization was identified in OxyLDL-induced monocytes, which are proinflammatory in nature, whereas M2 macrophage polarization was noticed in diosgenin-treated monocytes, which exhibit anti-inflammatory properties. M1-and M2-specific chemokines were analyzed using chemokine antibody array. Furthermore, the expression of proinflammatory macrophage (M1) was noticed in AD-induced aorta and anti-inflammatory macrophage (M2) was observed in diosgenin-treated aorta. This is the first report where, unifying the mechanism of diosgenin as aan nti-atherosclerotic and the expression of M1 and M2 specific chemokines is shown by downregulating NFκB and not by preventing the differentiation of monocyte into a macrophage, but by allowing macrophage to differentiate into M2, which aids in preventing the atherosclerotic progression.


Assuntos
Aorta/metabolismo , Aterosclerose/metabolismo , Polaridade Celular , Citocinas/metabolismo , Diosgenina/farmacologia , Macrófagos/metabolismo , Extratos Vegetais/farmacologia , Fator de Transcrição RelA/metabolismo , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/genética , Antígenos de Diferenciação Mielomonocítica/metabolismo , Aterosclerose/tratamento farmacológico , Aterosclerose/prevenção & controle , Antígenos CD36/genética , Antígenos CD36/metabolismo , Diferenciação Celular/efeitos dos fármacos , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/metabolismo , Dexametasona/farmacologia , Dieta Aterogênica/efeitos adversos , Dioscorea/química , Diosgenina/uso terapêutico , Humanos , Lipoproteínas LDL/farmacologia , Masculino , Monócitos/metabolismo , Extratos Vegetais/uso terapêutico , Ratos , Transdução de Sinais/efeitos dos fármacos , Células THP-1 , Fator de Transcrição RelA/antagonistas & inibidores , Fator de Transcrição RelA/genética
15.
Artigo em Inglês | MEDLINE | ID: mdl-31678516

RESUMO

SR-B1 belongs to the class B scavenger receptor, or CD36 super family. SR-B1 and CD36 share an affinity for a wide array of ligands. Although they exhibit similar ligand binding specificity, SR-B1 and CD36 have some very specific lipid transport functions. Whereas SR-B1 primarily facilitates the selective delivery of cholesteryl esters (CEs) and cholesterol from HDL particles to the liver and non-placental steroidogenic tissues, as well as participating in cholesterol efflux from cells, CD36 primarily mediates the uptake of long-chain fatty acids in high fatty acid-requiring organs such as the heart, skeletal muscle and adipose tissue. However, CD36 also mediates cholesterol efflux and facilitates selective lipoprotein-CE delivery, although less efficiently than SR-B1. Interestingly, the ability or efficiency of SR-B1 to mediate fatty acid uptake has not been reported. In this paper, using overexpression and siRNA-mediated knockdown of SR-B1, we show that SR-B1 possesses the ability to facilitate fatty acid uptake. Moreover, this function is not blocked by BLT-1, a specific chemical inhibitor of HDL-CE uptake activity of SR-B1, nor by sulfo-N-succinimidyl oleate, which inhibits fatty acid uptake by CD36. Attenuated fatty acid uptake was also observed in primary adipocytes isolated from SR-B1 knockout mice. In conclusion, facilitation of fatty acid uptake is an additional function that is mediated by SR-B1.


Assuntos
Adipócitos/metabolismo , Ácidos Graxos/metabolismo , Receptores Depuradores Classe B/metabolismo , Adipócitos/efeitos dos fármacos , Animais , Antígenos CD36/antagonistas & inibidores , Antígenos CD36/genética , Antígenos CD36/metabolismo , Células Cultivadas , Ésteres do Colesterol/metabolismo , HDL-Colesterol/metabolismo , Ciclopentanos/farmacologia , Técnicas de Silenciamento de Genes , Metabolismo dos Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Knockout , Ácidos Oleicos/farmacologia , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Receptores Depuradores Classe B/antagonistas & inibidores , Receptores Depuradores Classe B/genética , Succinimidas/farmacologia , Tiossemicarbazonas/farmacologia
16.
Artigo em Inglês | MEDLINE | ID: mdl-31863970

RESUMO

Scavenger receptor class B type I (SR-BI) mediates the selective uptake of cholesteryl esters (CE) from high-density lipoproteins (HDL). An impaired SR-BI function leads to hyperalphalipoproteinemia with elevated levels of cholesterol transported in the HDL fraction. Accumulation of cholesterol in apolipoprotein B (apoB)-containing lipoproteins has been shown to alter skin lipid composition and barrier function in mice. To investigate whether these hypercholesterolemic effects on the skin also occur in hyperalphalipoproteinemia, we compared skins of wild-type and SR-BI knockout (SR-BI-/-) mice. SR-BI deficiency did not affect the epidermal cholesterol content and induced only minor changes in the ceramide subclasses. The epidermal free fatty acid (FFA) pool was, however, enriched in short and unsaturated chains. Plasma CE levels strongly correlated with epidermal FFA C18:1 content. The increase in epidermal FFA coincided with downregulation of cholesterol and FFA synthesis genes, suggesting a compensatory response to increased flux of plasma cholesterol and FFAs into the skin. Importantly, the SR-BI-/- epidermal lipid barrier showed increased permeability to ethyl-paraminobenzoic acid, indicating an impairment of the barrier function. In conclusion, increased HDL-cholesterol levels in SR-BI-/- mice can alter the epidermal lipid composition and lipid barrier function similarly as observed in hypercholesterolemia due to elevated levels of apoB-containing lipoproteins.


Assuntos
Proteínas de Transferência de Ésteres de Colesterol/deficiência , Epiderme/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Ácido 4-Aminobenzoico/farmacocinética , Animais , Apolipoproteínas B/metabolismo , Antígenos CD36/genética , Proteínas de Transferência de Ésteres de Colesterol/genética , Proteínas de Transferência de Ésteres de Colesterol/metabolismo , Ésteres do Colesterol/sangue , Ésteres do Colesterol/metabolismo , Epiderme/patologia , Ácidos Graxos Insaturados/metabolismo , Feminino , Lecitinas/genética , Lecitinas/metabolismo , Erros Inatos do Metabolismo Lipídico/genética , Erros Inatos do Metabolismo Lipídico/patologia , Camundongos , Camundongos Endogâmicos C57BL
17.
Life Sci ; 239: 117000, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31654747

RESUMO

AIMS: ß2-glycoprotein I/anti-ß2-glycoprotein I antibody complex (ß2/aß2) could promote oxLDL-induced endothelial inflammation through Toll-like receptor 4 (TLR4), therefore accelerates atherosclerosis in patients with anti-phospholipid syndrome (APS). However, effects of ß2/aß2 and TLR4 on oxLDL-induced CD36 activation in macrophages remain to be elucidated and are currently under investigation. MATERIALS AND METHODS: THP-1 macrophages with or without the pre-treatment of TAK-242, a TLR4 inhibitor, were treated with RPMI 1640, oxLDL, oxLDL+ß2/aß2 or oxLDL + LPS.CD36 expression and subsequent intracellular lipid accumulation, cholesterol-transportation-related proteins (ACAT1, ABCG1 and ABCA1) expression, inflammatory cytokines (IL-1ß, TNF-α and IL-6) secretion, focal adhesion kinases (FAK) activation and matrix metalloproteinases (MMP-2 and MMP-9) expression by these THP-1 macrophages were evaluated. Moreover, effects of TLR4 on oxLDL+ß2/aß2-induced peroxisome proliferators-activated receptor-γ (PPAR-γ) expression and CD36 translocation have also been observed. KEY FINDINGS: Compared with oxLDL-treated ones, CD36 expression, intracellular lipid accumulation and FAK activation were inhibited, whereas the levels of inflammatory cytokines and MMPs were upregulated in THP-1 macrophages treated with oxLDL+ß2/aß2 (p < 0.05). Moreover, observed differences between oxLDL-treated and oxLDL+ß2/aß2-treated THP-1 macrophages could be reversed by TAK-242 pre-treatment (p < 0.05). Furthermore, oxLDL+ß2/aß2 promoted PPAR-γ expression and CD36 cytoplasmic translocation in THP-1 macrophages, these effects could also be attenuated by TAK-242 (p < 0.05). SIGNIFICANCE: Through a TLR4 dependent manner, ß2/aß2 inhibited oxLDL-induced CD36 expression, lipid accumulation and FAK activation, while promoted inflammatory cytokines and MMPs expression in THP-1 macrophages, indicating the novel dual roles played by ß2/aß2 in APS-related atherosclerosis.


Assuntos
Antígenos CD36/genética , Lipoproteínas LDL/farmacologia , Macrófagos/efeitos dos fármacos , beta 2-Glicoproteína I/antagonistas & inibidores , beta 2-Glicoproteína I/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Colesterol/metabolismo , Citocinas/metabolismo , Quinase 1 de Adesão Focal/metabolismo , Humanos , Macrófagos/metabolismo , Metaloproteinases da Matriz/metabolismo , PPAR gama/biossíntese , Sulfonamidas/farmacologia , Receptor 4 Toll-Like/antagonistas & inibidores , beta 2-Glicoproteína I/imunologia
18.
Bull Exp Biol Med ; 167(5): 653-655, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31641985

RESUMO

Expression of CD11, CD29, CD36, and DC-STAMP molecules by macrophages was analyzed in in vitro experiments. These molecules mediate cell fusion, one of the mechanisms underlying the formation of multinuclear macrophages. Macrophages were obtained from intact and BCG-infected male BALB/c mice. In intact cultures, multinuclear macrophages appeared primarily due to amitotic division of cell nuclei, while in macrophage cultures from infected mice, the process of cell fusion predominated. In intact macrophage cultures, bi- and multinuclear cells expressed primarily CD29 and CD36. In cultures from infected mice, macrophages expressing CD29 and DC-STAMP predominated, but bi- and multinuclear macrophages expressing CD11 and CD36 predominated over mononuclear ones. The study of macrophage fusion mechanism can be useful for understanding of this biological phenomenon as the mechanisms of delivery of M. tuberculosis and lysosomotropic anti-tuberculosis drugs into tuberculous granulomas to suppress M. tuberculosis persisting in macrophages and reduce the destructive potential of granulomas.


Assuntos
Vacina BCG/administração & dosagem , Antígenos CD11/genética , Antígenos CD36/genética , Integrina beta1/genética , Macrófagos/microbiologia , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Animais , Antígenos CD11/imunologia , Antígenos CD36/imunologia , Fusão Celular , Núcleo Celular/ultraestrutura , Expressão Gênica , Integrina beta1/imunologia , Macrófagos/imunologia , Macrófagos/patologia , Masculino , Proteínas de Membrana/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Proteínas do Tecido Nervoso/imunologia , Cultura Primária de Células
19.
Int J Mol Sci ; 20(20)2019 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-31658592

RESUMO

The microneme organelles of Toxoplasma gondii tachyzoites release protein complexes (MICs), including one composed of the transmembrane protein MIC6 plus MIC1 and MIC4. In this complex, carbohydrate recognition domains of MIC1 and MIC4 are exposed and interact with terminal sialic acid and galactose residues, respectively, of host cell glycans. Recently, we demonstrated that MIC1 and MIC4 binding to the N-glycans of Toll-like receptor (TLR) 2 and TLR4 on phagocytes triggers cell activation and pro-inflammatory cytokine production. Herein, we investigated the requirement for TLR2 heterodimerization and co-receptors in MIC-induced responses, as well as the signaling molecules involved. We used MICs to stimulate macrophages and HEK293T cells transfected with TLR2 and TLR1 or TLR6, both with or without the co-receptors CD14 and CD36. Then, the cell responses were analyzed, including nuclear factor-kappa B (NF-κB) activation and cytokine production, which showed that (1) only TLR2, among the studied factors, is crucial for MIC-induced cell activation; (2) TLR2 heterodimerization augments, but is not critical for, activation; (3) CD14 and CD36 enhance the response to MIC stimulus; and (4) MICs activate cells through a transforming growth factor beta-activated kinase 1 (TAK1)-, mammalian p38 mitogen-activated protein kinase (p38)-, and NF-κB-dependent pathway. Remarkably, among the studied factors, the interaction of MIC1 and MIC4 with TLR2 N-glycans is sufficient to induce cell activation, which promotes host protection against T. gondii infection.


Assuntos
Moléculas de Adesão Celular/química , Moléculas de Adesão Celular/metabolismo , Dimerização , Proteínas de Protozoários/química , Proteínas de Protozoários/metabolismo , Receptor 2 Toll-Like/química , Receptor 2 Toll-Like/metabolismo , Toxoplasma/metabolismo , Animais , Antígenos CD36/genética , Antígenos CD36/metabolismo , Citocinas/análise , Feminino , Técnicas de Silenciamento de Genes , Células HEK293 , Humanos , Receptores de Lipopolissacarídeos/genética , Receptores de Lipopolissacarídeos/metabolismo , MAP Quinase Quinase Quinases/metabolismo , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Células RAW 264.7 , Transdução de Sinais , Receptor 1 Toll-Like/metabolismo , Receptor 6 Toll-Like/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo
20.
Nat Commun ; 10(1): 3981, 2019 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-31484922

RESUMO

The diverse expression pattern of CD36 reflects its multiple cellular functions. However, the roles of CD36 in colorectal cancer (CRC) remain unknown. Here, we discover that CD36 expression is progressively decreased from adenomas to carcinomas. CD36 loss predicts poor survival of CRC patients. In CRC cells, CD36 acts as a tumor suppressor and inhibits aerobic glycolysis in vitro and in vivo. Mechanically, CD36-Glypcian 4 (GPC4) interaction could promote the proteasome-dependent ubiquitination of GPC4, followed by inhibition of ß-catenin/c-myc signaling and suppression of downstream glycolytic target genes GLUT1, HK2, PKM2 and LDHA. Moreover, disruption of CD36 in inflammation-induced CRC model as well as ApcMin/+ mice model significantly increased colorectal tumorigenesis. Our results reveal a CD36-GPC4-ß-catenin-c-myc signaling axis that regulates glycolysis in CRC development and may provide an intervention strategy for CRC prevention.


Assuntos
Antígenos CD36/genética , Neoplasias Colorretais/genética , Regulação Neoplásica da Expressão Gênica , Glicólise/genética , Glipicanas/genética , Proteínas Proto-Oncogênicas c-myc/genética , beta Catenina/genética , Idoso , Animais , Antígenos CD36/metabolismo , Células CACO-2 , Carcinogênese/genética , Linhagem Celular Tumoral , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/terapia , Feminino , Perfilação da Expressão Gênica/métodos , Glipicanas/metabolismo , Células HCT116 , Células HT29 , Humanos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-myc/metabolismo , Terapêutica com RNAi/métodos , Transdução de Sinais/genética , Ubiquitinação , Ensaios Antitumorais Modelo de Xenoenxerto/métodos , beta Catenina/metabolismo
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA