Evidence that CD36 is expressed on red blood cells and constitutes a novel blood group system of clinical importance.

BACKGROUND AND OBJECTIVES: Polymorphic molecules expressed on the surface of certain blood cells are traditionally categorized as blood groups and human platelet or neutrophil antigens. CD36 is widely considered a platelet antigen (Naka) and anti-CD36 can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) in CD36-negative pregnant women. CD36 is used as a marker of differentiation in early erythroid culture. During the experimental culture of CD34+ cells from random blood donors, we observed that one individual lacked CD36. We sought to investigate this observation further and determine if CD36 fulfils the International Society of Blood Transfusion criteria for becoming a blood group. MATERIALS AND METHODS: Surface markers were monitored by flow cytometry on developing cells during the erythroid culture of CD34+ cells. Genetic and flow cytometric analyses on peripheral blood cells were performed. Proteomic datasets were analysed, and clinical case reports involving anti-CD36 and foetal anaemia were scrutinized. RESULTS: Sequencing of CD36-cDNA identified homozygosity for c.1133G>T/p.Gly378Val in the CD36-negative donor. The minor allele frequency of rs146027667:T is 0.1% globally and results in abolished CD36 expression. CD36 has been considered absent from mature red blood cells (RBCs); however, we detected CD36 expression on RBCs and reticulocytes from 20 blood donors. By mining reticulocyte and RBC datasets, we found evidence for CD36-derived peptides enriched in the membrane fractions. Finally, our literature review revealed severe cases of foetal anaemia attributed to anti-CD36. CONCLUSIONS: Based on these findings, we conclude that CD36 fulfils the criteria for becoming a new blood group system and that anti-CD36 is implicated not only in FNAIT but also foetal anaemia.

Impact of the interaction between the polymorphisms and hypermethylation of the CD36 gene on a new biomarker of type 2 diabetes mellitus: circulating soluble CD36 (sCD36) in Senegalese females.

BACKGROUND: Several predisposing factors for diabetes mellitus have been identified, including cluster determinant 36 (CD36) receptor expression. We aimed to determine the effects of CD36 gene polymorphisms and hypermethylation on the plasma CD36 protein levels in type 2 diabetes. MATERIALS AND METHODS: We conducted a cross-sectional study involving 100 females (lean healthy control subjects and subjects with type 2 diabetes). This study was conducted at the Human Physiology Laboratory at the Dakar Faculty of Medicine in Senegal. Circulating sCD36 levels and DNA methyltransferase 3a levels were determined by enzyme-linked immunosorbent assay. The other biological parameters were evaluated in a biochemical laboratory. CD36 gene polymorphisms and methylation were explored by real-time polymerase chain reaction and methylation-specific polymerase chain reaction, respectively. RESULTS: sCD36 was negatively correlated with HDL-cholesterol levels (r = - 0.52 p = 0.0001) and triglyceride levels (r = - 0.36 p = 0.01) in control subjects. However, in the type 2 diabetes group, sCD36 levels were positively correlated with total cholesterol levels (r = 0.28 p = 0.04). For rs3211867, control subjects harboring the CC genotypes had significantly higher sCD36 levels than control subjects harboring the AA/AC genotype (p = 0.02); in the type 2 diabetes group, the sCD36 level was not significantly lower in subjects harboring the AA/AC genotype than in subjects harboring the CC genotype (p = 0.27). CD36 gene methylation reduced the sCD36 level in the control subjects compared to control subjects without CD36 gene methylation (p = 0.03). This difference was not significant in the type 2 diabetes group comparing subjects with diabetes with CD36 gene methylation to subjects with diabetes without CD36 gene methylation (p = 0.09). We noted a nonsignificant increase in sCD36 levels in subjects with diabetes with CD36 gene methylation compared to control subjects with CD36 gene methylation (p = 0.27). A combination of the CD36 polymorphism effect and the CD36 methylation effect did not significantly reduce sCD36 levels in subjects with type 2 diabetes. CONCLUSION: CD36 gene polymorphisms and CD36 gene methylation separately reduce sCD36 levels. Their impacts are compensated for in subjects with type 2 diabetes by an increase in sCD36 levels, the mechanism of which needs to be elucidated.

Evaluation of the expression of red blood cell CD36, interleukin-6 and interleukin-8 in sickle cell anemia pediatric patients.

Sickle cell anemia (SCA) is a complex multisystem disease characterized by acute and chronic inflammation, with alterations in inflammatory cytokines and adhesion molecules. This case-control study was carried out to assess the levels of CD36, immature reticulocytes, interleukin (IL)-6 and IL8 in SCA patients (in crisis and the steady state) and healthy controls. It included 90 children who were 2-18 years old; 60 with SCA and 30 healthy controls. Complete blood count, total reticulocyte count, reticulocyte subpopulations, immature reticulocyte fraction (IRF), percentage of CD36-positive red blood cells (RBCs), IL-6 and IL-8 levels were evaluated. The total white blood cell (WBC) and neutrophil counts, CD36-positive RBCs percentage, IRF, IL-6 and IL-8 levels were significantly higher in crises than in the steady state (P < 0.05). We also found that patients with SCA had significantly higher reticulocyte, WBC and neutrophil counts, fetal hemoglobin, CD36-positive RBCs percentage, IRF, and IL-6 and IL-8 levels than healthy children (P < 0.05). A significant positive linear correlation was reported between IL-6 and neutrophils during crises (Spearman correlation coefficient = 0.397, P = 0.03). These findings suggest that the levels of adhesion molecules and inflammatory markers and IRF, as evidenced by CD36-positive RBCs, IL-6 and IL-8, are elevated in SCA patients, both during steady state and crises, although these elevations are more marked during crises. Further knowledge about these cytokines and adhesion molecules will help in understanding the pathogenesis and improve therapy of SCA.

Soluble Receptors Affecting Stroke Outcomes: Potential Biomarkers and Therapeutic Tools.

Soluble receptors are widely understood to be freestanding moieties formed via cleavage from their membrane-bound counterparts. They have unique structures, are found among various receptor families, and have intriguing mechanisms of generation and release. Soluble receptors' ability to exhibit pleiotropic action by receptor modulation or by exhibiting a dual role in cytoprotection and neuroinflammation is concentration dependent and has continually mystified researchers. Here, we have compiled findings from preclinical and clinical studies to provide insights into the role of soluble/decoy receptors, focusing on the soluble cluster of differentiation 36, the soluble cluster of differentiation 163, and soluble lipoprotein-related protein 1 (sCD36, sCD163, and sLRP1, respectively) and the functions they could likely serve in the management of stroke, as they would notably regulate the bioavailability of the hemoglobin and heme after red blood cell lysis. The key roles that these soluble receptors play in inflammation, oxidative stress, and the related pharmacotherapeutic potential in improving stroke outcomes are described. The precise pleiotropic physiological functions of soluble receptors remain unclear, and further scientific investigation/validation is required to establish their respective role in diagnosis and therapy.

Lack of change in serum sCD36 concentration in children with non-alcoholic fatty liver disease - A preliminary study.

PURPOSE: Non-alcoholic fatty liver disease (NAFLD) is increasingly being recognized in the pediatric population, therefore, the search for non-invasive parameters to predict progression of NAFLD is of great interest. The aim of this study was to assess serum concentration of sCD36 in children with obesity and to determine its diagnostic value in pediatric NAFLD. PATIENTS AND METHODS: The study group consisted of 50 children with obesity aged 8-17.5 years, admitted to our Department because of suspected liver pathology. Selected liver diseases were excluded in the examined group. Anthropometry, laboratory tests (including the concentration of sCD36) and liver ultrasound, were performed in all subjects. RESULTS: NAFLD was confirmed in 16 out of 50 patients with obesity. There was significantly higher activity of ALT, AST, GGT, and increased waist-hip ratio WHR in individuals with NAFLD in comparison to non-hepatopathic children with obesity. We did not find a significant difference between sCD36 concentration in patients with obesity and NAFLD and non-hepathopathic patients with obesity. We also did not find a significant difference between sCD36 concentration in children with obesity in comparison to the control group and between mild (grade 1) vs. advanced (grade ≥2) steatosis. Correlation of sCD36 concentration with anthropometric, biochemical, and bioimpedance parameters in children with obesity was confirmed only with body fat percentage. CONCLUSIONS: sCD36 is not a suitable parameter to differentiate children with NAFLD from non-hepatopathic children with obesity and controls without obesity. Further studies on a larger pediatric population are needed to confirm these findings.

Association of cardiometabolic risk status with clinical activity and damage in systemic lupus erythematosus patients: A cross-sectional study.

Cardiometabolic status is a key factor in mortality by cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). This study evaluated the association of cardiometabolic risk status with clinical activity and damage in SLE patients. A cross-sectional study was conducted in 158 SLE patients and 123 healthy subjects (HS). Anthropometry, glucose, hs-CRP, lipid profile, oxLDL, sCD36, anti-oxLDL antibodies, and cardiometabolic indexes were evaluated. SLE patients had dyslipidemia, higher sCD36, anti-oxLDL antibodies, hs-CRP, and risk (OR > 2) to present Castelli score ≥ 4.5, HDL-C < 40 mg/dL and LDL-C ≥ 100 mg/dL. Disease evolution time was correlated with glucose and BMI, damage with TG, and clinical activity with TG, TG/HDL-C ratio, and Kannel index. Active SLE patients had risk (OR > 2) to present a Castelli score ≥ 4.5, Kannel score ≥ 3, TG/HDL-C ratio ≥ 3 and HDL-C < 40 mg/dL. In conclusion, SLE patients have high cardiometabolic risk to CVD related to disease evolution time, and clinical activity.

The effect of type 2 diabetes on CD36 expression and the uptake of oxLDL: Diabetes affects CD36 and oxLDL uptake.

We investigated whether type 2 diabetes mellitus (T2DM), a risk factor of stroke, affects the level of scavenger receptor CD36 and the uptake of its ligand, oxidized LDL (oxLDL); and whether pioglitazone, a drug that enhances CD36, promotes oxLDL uptake. Compared to normoglycemic db/+ mice, adult db/db mice showed a pronounced reduction in surface CD36 expression on myeloid cells from the blood, brain, and bone marrow as detected by flow cytometry, which correlated with elevated plasma soluble-CD36 as determined by ELISA. Increased CD36 expression was found in brain macrophages and microglia of both genotypes 7 days after ischemic stroke. In juvenile db/db mice, prior to obesity and hyperglycemia, only a mild reduction of surface CD36 was found in blood neutrophils, while all other myeloid cells showed no difference relative to the db/+ strain. In vivo, oral pioglitazone treatment for four weeks increased CD36 levels on myeloid cells in db/db mice. In vitro, uptake of oxLDL by bone marrow derived macrophages (BMDMs) of db/db mice was reduced relative to db/+ mice in normal glucose medium. OxLDL uptake inversely correlated with glucose levels in the medium in db/+ BMDMs. Furthermore, pioglitazone restored oxLDL uptake by BMDMs from db/db mice cultured in high glucose. Our data suggest that T2DM is associated with reduced CD36 on adult myeloid cells, and pioglitazone enhances CD36 expression in db/db cells. T2DM or high glucose reduces oxLDL uptake while pioglitazone enhances oxLDL uptake. Our findings provide new insight into the mechanism by which pioglitazone may be beneficial in the treatment of insulin resistance.

Vitamin D Status of Mice Deficient in Scavenger Receptor Class B Type 1, Cluster Determinant 36 and ATP-Binding Cassette Proteins G5/G8.

Classical lipid transporters are suggested to modulate cellular vitamin D uptake. This study investigated the vitamin D levels in serum and tissues of mice deficient in SR-B1 (Srb1-/-), CD36 (Cd36-/-) and ABC-G5/G8 (Abcg5/g8-/-) and compared them with corresponding wild-type (WT) mice. All mice received triple-deuterated vitamin D3 (vitamin D3-d3) for six weeks. All knockout mice vs. WT mice showed specific alterations in their vitamin D concentrations. Srb1-/- mice had higher levels of vitamin D3-d3 in the serum, adipose tissue, kidney and heart, whereas liver levels of vitamin D3-d3 remained unaffected. Additionally, Srb1-/- mice had lower levels of deuterated 25-hydroxyvitamin D3 (25(OH)D3-d3) in the serum, liver and kidney compared to WT mice. In contrast, Cd36-/- and WT mice did not differ in the serum and tissue levels of vitamin D3-d3, but Cd36-/- vs. WT mice were characterized by lower levels of 25(OH)D3-d3 in the serum, liver and kidney. Finally, Abcg5/g8-/- mice tended to have higher levels of vitamin D3-d3 in the serum and liver. Major alterations in Abcg5/g8-/- mice were notably higher levels of 25(OH)D3-d3 in the serum and kidney, accompanied by a higher hepatic mRNA abundance of Cyp27a1 hydroxylase. To conclude, the current data emphasize the significant role of lipid transporters in the uptake, tissue distribution and activation of vitamin D.

Hydrops fetalis associated with anti-CD36 antibodies in fetal and neonatal alloimmune thrombocytopenia: Possible underlying mechanism.

OBJECTIVES: In the present study, we asked whether anti-CD36 antibodies impair the maturation of erythropoietic stem cells to mature red blood cells (RBCs), leading to anaemia and hydrops fetalis (HF). BACKGROUND: Recent studies have shown the importance of anti-CD36 antibodies in the development of Fetal/Neonatal Alloimmune Thrombocytopenia (FNAIT). In comparison to other types of antibody-mediated FNAIT, anti-CD36 antibodies are frequently associated with anaemia and HF. As mature RBCs do not express CD36, the reason for this phenomenon is currently not fully understood. MATERIAL AND METHODS: A case of FNAIT with signs of HF was characterised in this study. Maternal anti-CD36 antibodies were isolated by an absorption/elution approach. We cultured haematopoietic stem cells (HSCs) with purified anti-CD36 antibodies, and the formation of burst-forming unit-erythroid and colony-forming unit-erythroid (CFU-E/BFU-E) cells was analysed. Apoptosis of HSCs was also investigated. RESULTS: Analysis of the mother showed type-1 CD36 deficiency. Anti-CD36 antibodies were found in maternal serum, as well as on fetal platelets, by ELISA, and the specificity of these antibodies was further substantiated by flow cytometry. In comparison to control IgG, incubation of HSCs with purified anti-CD36 antibodies led to a significant reduction in CFU-E/BFU-E cell formation, and this result was associated with an increased number of apoptotic CD34+ erythroid/myeloid precursor cells. Administration of intra-uterine transfusion with washed RBCs was effective in improving fetal anaemia. CONCLUSIONS: Anti-CD36 antibodies may cause anaemia and trigger HF through apoptosis of CD34+ erythroid/myeloid precursor cells. However, the contribution of other cells must also be taken into account.

The Role of CD36 in Type 2 Diabetes Mellitus: ß-Cell Dysfunction and Beyond.

Impaired ß-cell function is the key pathophysiology of type 2 diabetes mellitus, and chronic exposure of nutrient excess could lead to this tragedy. For preserving ß-cell function, it is essential to understand the cause and mechanisms about the progression of ß-cells failure. Glucotoxicity, lipotoxicity, and glucolipotoxicity have been suggested to be a major cause of ß-cell dysfunction for decades, but not yet fully understood. Fatty acid translocase cluster determinant 36 (CD36), which is part of the free fatty acid (FFA) transporter system, has been identified in several tissues such as muscle, liver, and insulin-producing cells. Several studies have reported that induction of CD36 increases uptake of FFA in several cells, suggesting the functional interplay between glucose and FFA in terms of insulin secretion and oxidative metabolism. However, we do not currently know the regulating mechanism and physiological role of CD36 on glucolipotoxicity in pancreatic ß-cells. Also, the downstream and upstream targets of CD36 related signaling have not been defined. In the present review, we will focus on the expression and function of CD36 related signaling in the pancreatic ß-cells in response to hyperglycemia and hyperlipidemia (ceramide) along with the clinical studies on the association between CD36 and metabolic disorders.

Frequency of CD36 deficiency in Thais analyzed by quantification of CD36 on cell surfaces and in plasma.

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.

Tanshinone IIA prevents platelet activation and down-regulates CD36 and MKK4/JNK2 signaling pathway.

BACKGROUND: Tanshinone IIA (TS IIA), a multi-pharmaceutical compound from traditional Chinese herb, is effective for treatment of atherothrombosis. However, the underlying mechanisms of TS IIA-mediated anti-platelet activation effect are still poorly understood. As shown in our previous study, platelet-derived microvesicles (PMVs) generated in response to oxidant insult could activate CD36/mitogen-activated protein kinase kinase 4/Jun N-terminal kinase 2 (CD36/MKK4/JNK2) signals and lead to platelet activation. The present study aims to investigate the effect of TS IIA on platelet activation and the possible mechanisms. METHODS: The production of PMVs induced by Interleukin 6 (IL-6) was detected by flow cytometry. We performed activating studies of platelets with PMVs derived from IL-6-treated platelets (IL-6-PMVs) in vitro. Sometimes, platelet suspensions were incubated with serial concentrations of TS IIA for 15 min before being stimulated with IL-6-PMVs. Expression of platelet integrin αIIbß3 and CD36 was detected by flow cytometry. Phosphorylation of MKK4 and JNK were detected by immunoblotting. RESULTS: Here we demonstrated firstly that TS IIA could prevent platelet activation induced by PMVs and down-regulates CD36 and MKK4/JNK2 signaling pathway. CD36 may be the target of atherosclerosis (AS)-related thrombosis. CONCLUSIONS: This study showed the possible mechanisms of TS IIA-mediated anti-platelet activation and may provide a new strategy for the treatment of AS-related thrombosis by targeting platelet CD36.

Characteristics of circulating endothelial cells obtained from non-ST-segment elevation myocardial infarction patients with additional diastolic dysfunction of left ventricle observed in echocardiography.

BACKGROUND: Circulating endothelial cells (CEC) may be used to find new strategies for the early di-agnosis of cardiovascular diseases. The major objective of the project is to broaden knowledge of CEC biology by determining their phenotypic characteristics. The additional aim is to clarify whether on the basis of these information it is possible to identify the origin of CEC release (from various cardiovascular compartments). METHODS: Circulating endothelial cells were collected from arterial blood prior to angiography, as well as from arterial and venous blood obtained after angiography/coronary angioplasty, from 18 patients with non-ST-segment elevation myocardial infarction (NSTEMI). CECs were quantified by flow cytometry and defined as Syto16 (dye)+, CD45dim/neg, CD31+ and CD146+. The additional CD36+ was establish as a marker of endothelial cells released from small vessels of the microcirculation. RESULTS: The total number of CECs increased significantly after the percutaneous transluminal coronary angioplasty (PTCA) in the arterial system. Number of CECs isolated at similar time points (after invasive procedure) did not differ significantly between arteries and veins, but the number of CD36+ CECs after coronary angioplasty was significantly higher in the venous system, than in the arterial system. CONCLUSIONS: The number of CD36+ in artery samples obtained after coronary angioplasty (PTCA) had tendency to be decreased (in comparison to the sample obtained before angiography). It was major difference between those who had PTCA performed vs. those who had not.

Plasma CD36 and Incident Diabetes: A Case-Cohort Study in Danish Men and Women.

BACKGROUND: Membrane CD36 is a fatty acid transporter implicated in the pathogenesis of metabolic disease. We aimed to evaluate the association between plasma CD36 levels and diabetes risk and to examine if the association was independent of adiposity among Danish population. METHODS: We conducted a case-cohort study nested within the Danish Diet, Cancer and Health study among participants free of cardiovascular disease, diabetes and cancer and with blood samples and anthropometric measurements (height, weight, waist circumference, and body fat percentage) at baseline (1993 to 1997). CD36 levels were measured in 647 incident diabetes cases that occurred before December 2011 and a total of 3,515 case-cohort participants (236 cases overlap). RESULTS: Higher plasma CD36 levels were associated with higher diabetes risk after adjusting for age, sex and other lifestyle factors. The hazard ratio (HR) comparing high versus low tertile of plasma CD36 levels was 1.36 (95% confidence interval [CI], 1.00 to 1.86). However, the association lost its significance after further adjustment for different adiposity indices such as body mass index (HR, 1.23; 95% CI, 0.87 to 1.73), waist circumference (HR, 1.21; 95% CI, 0.88 to 1.68) or body fat percentage (HR, 1.20; 95% CI, 0.86 to 1.66). Moreover, raised plasma CD36 levels were moderately associated with diabetes risk among lean participants, but the association was not present among overweight/obese individuals. CONCLUSION: Higher plasma CD36 levels were associated with higher diabetes risk, but the association was not independent of adiposity. In this Danish population, the association of CD36 with diabetes risk could be either mediated or confounded by adiposity.

Correlations of degree of coronary artery stenosis with blood lipid, CRP, Hcy, GGT, SCD36 and fibrinogen levels in elderly patients with coronary heart disease.

OBJECTIVE: To explore the correlations between the degree of coronary artery stenosis with blood lipid, C-reactive protein (CRP), homocysteine (Hcy), gamma-glutamyl transpeptidase (GGT), soluble cluster determinant 36 (sCD36), and fibrinogen (Fib) levels in elderly patients with coronary heart disease. PATIENTS AND METHODS: The Gensini scores for the coronary artery stenosis were analyzed in patients with single-vessel, double-vessel, and multi-vessel coronary artery diseases in observation group and normal people in control group. Changes in blood lipid-associated parameters, including total cholesterol (TC), triacylglycerol (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C), CRP, Hcy, GGT, sCD36, and Fib were compared between the two groups. The correlations between the Gensini score with changes of the blood-associated parameters, CRP, Hcy, GGT, sCD36, and Fib were analyzed. Finally, univariate and multivariate logistic regression analyses were conducted to determine the risk factors for coronary artery stenosis in elderly patients with coronary heart disease. RESULTS: The Gensini score was significantly higher in coronary heart disease patients with multi-vessel, double-vessel, and single-vessel coronary artery diseases compared with that in normal people (p<0.05). The levels of the blood lipid-associated parameters TC, TG, and LDL-C in observation group were substantially higher than those in control group (p<0.05), and the level of HDL-C was notably lower than that in control group (p<0.05). Subjects in observation group had markedly higher levels of CRP, Hcy, GGT, sCD36, and Fib than control group (p<0.05). The Gensini score for the degree of coronary artery stenosis was positively correlated with the levels of the blood lipid-associated parameters TC and TG, CRP, Hcy, GGT, sCD36, and Fib (p<0.05) and negatively associated with the level of HDL-C (p<0.05). Blood lipid-associated parameters, CRP, Hcy, GGT, sCD36, and Fib were the independent risk factors for coronary artery stenosis in elderly patients with coronary heart disease patients. CONCLUSIONS: The elevations of blood lipid, CRP, Hcy, GGT, sCD36, and Fib levels are closely associated with coronary artery stenosis, and serve as the independent risk factors for coronary artery stenosis.

Plasma sCD36 as non-circadian marker of chronic circadian disturbance in shift workers.

Shift work induces chronic circadian disturbance, which might result in increased health risks, including cardio-metabolic diseases. Previously, we identified sCD36 as a potential non-circadian biomarker of chronic circadian disturbance in mice. The aim of the current study (n = 232 individuals) was to identify whether sCD36 measured in plasma can be used as a non-circadian marker of chronic circadian disturbance in humans, which would allow its use to measure the effects of interventions and monitoring in large-scale studies. We compared levels of plasma sCD36 of day workers with recent (< 2 years) and experienced (> 5 years) night-shift workers within the Klokwerk study. We detected no differences in sCD36 levels between day workers and recent or experienced night-shift workers, measured during a day or afternoon shift. In addition, sCD36 levels measured directly after a night shift were not different from sCD36 levels measured during day or afternoon shifts, indicating no acute effect of night shifts on sCD36 levels in our study. In summary, our study does not show a relation between night-shift work experience (recent or long-term) and plasma levels of sCD36. Since we do not know if and for which time span night-shift work is associated with changes in sCD36 levels, and our study was relatively small and cross-sectional, further evidence for an association between chronic circadian disruption and this candidate biomarker sCD36 should be gathered from large cohort studies.

Oral fatty acid taste sensitivity in healthy young individuals of both sexes is related to body mass index and soluble CD36 serum levels / La sensibilidad oral a ácidos grasos en jóvenes sanos de ambos sexos está relacionada con el índice de masa corporal y los niveles séricos de sCD36

Introduction: CD36 is a membrane protein that functions as a lingual receptor for lipids. The soluble CD36 fraction (sCD36) may correlate oral fatty acid fat taste sensitivity to body mass index (BMI) and adiposity. Objectives: to determine if the oral fatty acid taste sensitivity in healthy young individuals of both sexes is related to serum sCD36 levels, adiposity and BMI. Methods: a cross-sectional study was conducted in 72 healthy young individuals (18-25 years). Serum sCD36 was quantified for all subjects. Oral fatty acid taste sensitivity was determined using an ascending series of the three-alternate forced choice methodology. Additionally, BMI was calculated using anthropometry, and adiposity was determined by bioelectric impedance analysis. Results: there was a positive correlation between BMI and the oral fatty acid taste sensitivity threshold (r = 0.277, p < 0.05) and a negative correlation between BMI and serum sCD36 levels (r = -0.035, p < 0.01). Adiposity negatively correlated with the sCD36 levels only in women (r = -0.359, p < 0.05). The threshold for oral sensitivity to fatty acids in overweight individuals was 1.0 (IQR 1.16) mM vs 0.2 (IQR 0.29) mM in healthy weight individuals (p < 0.05), while sCD36 levels were 26.1 pg/ml (IQR 32.9) and 77.97 pg/ml (IQR 560.66) in overweight and normal weight individuals, respectively (p < 0.05). Conclusions: BMI positively correlates with the oral sensitivity threshold of fatty acids and negatively correlates with serum sCD36 levels. The threshold of oral sensitivity to fatty acids was significantly higher in overweight subjects, while sCD36 levels were significantly higher in the group of normal weight individuals

Introducción: CD36 es una proteína de membrana que funciona como receptor lingual para lípidos. La fracción soluble del CD36 (sCD36) podría correlacionar la sensibilidad gustativa a los ácidos grasos orales con el índice de masa corporal (IMC) y con la adiposidad. Objetivos: determinar si la sensibilidad gustativa a ácidos grasos orales se relaciona con los niveles séricos de sCD36, la adiposidad y el IMC en jóvenes de ambos sexos. Métodos: estudio transversal en 72 adultos jóvenes (18-25 años). Se cuantificaron los niveles séricos de sCD36 para todos los sujetos. Se determinó la sensibilidad gustativa a los ácidos grasos orales usando la prueba triangular discriminatoria de concentraciones escaladas. Adicionalmente, se calculó el IMC usando antropometría y se determinó la adiposidad por análisis de bioimpedancia. Resultados: se encontró correlación positiva entre el IMC y el umbral de sensibilidad gustativa a los ácidos grasos orales (r = 0,277, p < 0,05) y una correlación negativa entre el IMC y los niveles séricos de sCD36 (r = -0,035, p < 0,01). La adiposidad, solo en mujeres se correlacionó negativamente con los niveles de sCD36 (r = -0,359, p < 0,05). El umbral para la sensibilidad gustativa a ácidos grasos orales en sujetos con sobrepeso fue 1,0 (IQR 1,16) mM vs. 0,2 (IQR 0,29) mM en sujetos con peso normal (p < 0,05), mientras que los niveles séricos de sCD36 fueron de 26,1 pg/ml (IQR 32,9) en sujetos con sobrepeso y 77,97 pg/ml (IQR 560,66) en sujetos con peso normal, respectivamente (p < 0,05). Conclusiones: el IMC se correlaciona positivamente con el umbral para la sensibilidad oral a los ácidos grasos y negativamente se correlaciona con los niveles séricos de sCD36. El umbral de sensibilidad oral a los ácidos grasos fue significativamente mayor en sujetos con sobrepeso, mientras que los niveles de sCD36 fueron significativamente más altos en el grupo de sujetos con peso normal

Oral fatty acid taste sensitivity in healthy young individuals of both sexes is related to body mass index and soluble CD36 serum levels.

INTRODUCTION: Introduction: CD36 is a membrane protein that functions as a lingual receptor for lipids. The soluble CD36 fraction (sCD36) may correlate oral fatty acid fat taste sensitivity to body mass index (BMI) and adiposity. Objectives: to determine if the oral fatty acid taste sensitivity in healthy young individuals of both sexes is related to serum sCD36 levels, adiposity and BMI. Methods: a cross-sectional study was conducted in 72 healthy young individuals (18-25 years). Serum sCD36 was quantified for all subjects. Oral fatty acid taste sensitivity was determined using an ascending series of the three-alternate forced choice methodology. Additionally, BMI was calculated using anthropometry, and adiposity was determined by bioelectric impedance analysis. Results: there was a positive correlation between BMI and the oral fatty acid taste sensitivity threshold (r = 0.277, p < 0.05) and a negative correlation between BMI and serum sCD36 levels (r = -0.035, p < 0.01). Adiposity negatively correlated with the sCD36 levels only in women (r = -0.359, p < 0.05). The threshold for oral sensitivity to fatty acids in overweight individuals was 1.0 (IQR 1.16) mM vs 0.2 (IQR 0.29) mM in healthy weight individuals (p < 0.05), while sCD36 levels were 26.1 pg/ml (IQR 32.9) and 77.97 pg/ml (IQR 560.66) in overweight and normal weight individuals, respectively (p < 0.05). Conclusions: BMI positively correlates with the oral sensitivity threshold of fatty acids and negatively correlates with serum sCD36 levels. The threshold of oral sensitivity to fatty acids was significantly higher in overweight subjects, while sCD36 levels were significantly higher in the group of normal weight individuals.

INTRODUCCIÓN: Introducción: CD36 es una proteína de membrana que funciona como receptor lingual para lípidos. La fracción soluble del CD36 (sCD36) podría correlacionar la sensibilidad gustativa a los ácidos grasos orales con el índice de masa corporal (IMC) y con la adiposidad. Objetivos: determinar si la sensibilidad gustativa a ácidos grasos orales se relaciona con los niveles séricos de sCD36, la adiposidad y el IMC en jóvenes de ambos sexos. Métodos: estudio transversal en 72 adultos jóvenes (18-25 años). Se cuantificaron los niveles séricos de sCD36 para todos los sujetos. Se determinó la sensibilidad gustativa a los ácidos grasos orales. Adicionalmente, se calculó el IMC usando antropometría y se determinó la adiposidad por análisis de bioimpedancia. Resultados: se encontró correlación positiva entre el IMC y el umbral de sensibilidad gustativa a los ácidos grasos orales (r = 0,277, p < 0,05) y una correlación negativa entre el IMC y los niveles séricos de sCD36 (r = −0,035, p < 0,01). La adiposidad, solo en mujeres se correlacionó negativamente con los niveles de sCD36 (r = −0,359, p < 0,05). El umbral para la sensibilidad gustativa a ácidos grasos orales en sujetos con sobrepeso fue 1,0 (IQR 1,16) mM vs. 0,2 (IQR 0,29) mM en sujetos con peso normal (p < 0,05), mientras que los niveles séricos de sCD36 fueron de 26,1 pg/ml (IQR 32,9) en sujetos con sobrepeso y 77,97 pg/ml (IQR 560,66) en sujetos con peso normal, respectivamente (p < 0,05). Conclusiones: el IMC se correlaciona positivamente con el umbral para la sensibilidad oral a los ácidos grasos y negativamente se correlaciona con los niveles séricos de sCD36. El umbral de sensibilidad oral a los ácidos grasos fue significativamente mayor en sujetos con sobrepeso, mientras que los niveles de sCD36 fueron significativamente más altos en el grupo de sujetos con peso normal.

Circulating exosomes deliver free fatty acids from the bloodstream to cardiac cells: Possible role of CD36.

Regulation of circulating free fatty acid (FFA) levels and delivery is crucial to maintain tissue homeostasis. Exosomes are nanomembranous vesicles that are released from diverse cell types and mediate intercellular communication by delivering bioactive molecules. Here, we sought to investigate the uptake of FFAs by circulating exosomes, the delivery of FFA-loaded exosomes to cardiac cells and the possible role of the FFA transporter CD36 in these processes. Circulating exosomes were purified from the serum of healthy donors after an overnight fast (F) or 20 minutes after a high caloric breakfast (postprandial, PP). Western blotting, Immunogold Electron Microscopy and FACS analysis of circulating exosomes showed that CD36 was expressed under both states, but was higher in postprandial-derived exosomes. Flow cytometry analysis showed that circulating exosomes were able to take-up FFA directly from serum. Importantly, preincubation of exosomes with a blocking CD36 antibody significantly impeded uptake of the FFA analogue BODIPY, pointing to the role of CD36 in FFA exosomal uptake. Finally, we found that circulating exosomes could delivery FFA analogue BODIPY into cardiac cells ex vivo and in vivo in a mice model. Overall, our results suggest a novel mechanism in which circulating exosomes can delivery FFAs from the bloodstream to cardiac tissue. Further studies will be necessary to understand this mechanism and, in particular, its potential involvement in metabolic pathologies such as obesity, diabetes and atherosclerosis.

Free Fatty Acids Rewire Cancer Metabolism in Obesity-Associated Breast Cancer via Estrogen Receptor and mTOR Signaling.

Obesity is a risk factor for postmenopausal estrogen receptor alpha (ERα)-positive (ER+) breast cancer. Molecular mechanisms underlying factors from plasma that contribute to this risk and how these mechanisms affect ERα signaling have yet to be elucidated. To identify such mechanisms, we performed whole metabolite and protein profiling in plasma samples from women at high risk for breast cancer, which led us to focus on factors that were differentially present in plasma of obese versus nonobese postmenopausal women. These studies, combined with in vitro assays, identified free fatty acids (FFA) as circulating plasma factors that correlated with increased proliferation and aggressiveness in ER+ breast cancer cells. FFAs activated both the ERα and mTOR pathways and rewired metabolism in breast cancer cells. Pathway preferential estrogen-1 (PaPE-1), which targets ERα and mTOR signaling, was able to block changes induced by FFA and was more effective in the presence of FFA. Collectively, these data suggest a role for obesity-associated gene and metabolic rewiring in providing new targetable vulnerabilities for ER+ breast cancer in postmenopausal women. Furthermore, they provide a basis for preclinical and clinical trials where the impact of agents that target ERα and mTOR signaling cross-talk would be tested to prevent ER+ breast cancers in obese postmenopausal women. SIGNIFICANCE: These findings show that obesity-associated changes in certain blood metabolites rewire metabolic programs in cancer cells, influence mammary epithelial cell tumorigenicity and aggressiveness, and increase breast cancer risk.