RESUMO
BACKGROUND: The adiponectin is one of the rare adipokines down-regulated with obesity and protects against obesity-related disorders. Similarly, the apolipoprotein M (apoM) is expressed in adipocytes and its expression in adipose tissue is associated with metabolic health. We compared circulating apoM with adiponectin regarding their relationship with metabolic parameters and insulin sensitivity and examined their gene expression patterns in adipocytes and in the adipose tissue. METHODS: Circulating apoM and adiponectin were examined in 169 men with overweight in a cross-sectional study, and 13 patients with obesity during a surgery-induced slimming program. Correlations with clinical parameters including the insulin resistance index (HOMA-IR) were analyzed. Multiple regression analyses were performed on HOMA-IR. The APOM and ADIPOQ gene expression were measured in the adipose tissue from 267 individuals with obesity and a human adipocyte cell line. RESULTS: Participants with type 2 diabetes had lower circulating adiponectin and apoM, while apoM was higher in individuals with dyslipidemia. Similar to adiponectin, apoM showed negative associations with HOMA-IR and hs-CRP (r < -0.2), and positive correlations with HDL markers (HDL-C and apoA-I, r > 0.3). Unlike adiponectin, apoM was positively associated with LDL markers (LDL-C and apoB100, r < 0.20) and negatively correlated with insulin and age (r < -0.2). The apoM was the sole negative determinant of HOMA-IR in multiple regression models, while adiponectin not contributing significantly. After surgery, the change in HOMA-IR was negatively associated with the change in circulating apoM (r = -0.71), but not with the change in adiponectin. The APOM and ADIPOQ gene expression positively correlated in adipose tissue (r > 0.44) as well as in adipocytes (r > 0.81). In adipocytes, APOM was downregulated by inflammatory factors and upregulated by adiponectin. CONCLUSIONS: The apoM rises as a new partner of adiponectin regarding insulin sensitivity. At the adipose tissue level, the adiponectin may be supported by apoM to promote a healthy adipose tissue. TRIAL REGISTRATION: NCT01277068, registered 13 January 2011; NCT02332434, registered 5 January 2015; and NCT00390637, registered 20 October 2006.
Assuntos
Adiponectina , Apolipoproteínas M , Resistência à Insulina , Humanos , Masculino , Apolipoproteínas M/sangue , Resistência à Insulina/fisiologia , Adiponectina/sangue , Estudos Transversais , Pessoa de Meia-Idade , Adulto , Obesidade/sangue , Obesidade/metabolismo , Feminino , Adipócitos/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/metabolismo , Biomarcadores/sangue , Tecido Adiposo/metabolismo , Apolipoproteínas/sangueRESUMO
BACKGROUND: Alcohol use disorder (AUD) courses with inflammation and cognitive decline. Apolipoproteins have emerged as novel target compounds related to inflammatory processes and cognition. METHODS: A cross-sectional study was performed on abstinent AUD patients with at least 1 month of abstinence (n = 33; 72.7% men) and healthy controls (n = 34; 47.1% men). A battery of plasma apolipoproteins (APOAI, APOAII, APOB, APOCII, APOE, APOJ, and APOM), plasma inflammatory markers (LPS, LBP), and their influence on cognition and presence of the disorder were investigated. RESULTS: Higher levels of plasma APOAI, APOB, APOE, and APOJ, as well as the proinflammatory LPS, were observed in the AUD group, irrespective of sex, whereas APOM levels were lower vs controls. Hierarchical logistic regression analyses, adjusting for covariates (age, sex, education), associated APOM with the absence of cognitive impairment in AUD and identified APOAI and APOM as strong predictors of the presence or absence of the disorder, respectively. APOAI and APOM did not correlate with alcohol abuse variables or liver status markers, but they showed an opposite profile in their associations with LPS (positive for APOAI; negative for APOM) and cognition (negative for APOAI; positive for APOM) in the entire sample. CONCLUSIONS: The HDL constituents APOAI and APOM were differentially regulated in the plasma of AUD patients compared with controls, playing divergent roles in the disorder identification and associations with inflammation and cognitive decline.
Assuntos
Alcoolismo , Apolipoproteína A-I , Apolipoproteínas M , Disfunção Cognitiva , Inflamação , Humanos , Masculino , Feminino , Apolipoproteínas M/sangue , Projetos Piloto , Disfunção Cognitiva/sangue , Disfunção Cognitiva/etiologia , Pessoa de Meia-Idade , Estudos Transversais , Inflamação/sangue , Alcoolismo/sangue , Adulto , Apolipoproteína A-I/sangue , Biomarcadores/sangue , Apolipoproteínas/sangueRESUMO
BACKGROUND: Apo (apolipoprotein) M mediates the physical interaction between high-density lipoprotein (HDL) particles and sphingosine-1-phosphate (S1P). Apo M exerts anti-inflammatory and cardioprotective effects in animal models. METHODS: In a subset of PHFS (Penn Heart Failure Study) participants (n=297), we measured apo M by Enzyme-Linked ImmunoSorbent Assay (ELISA). We also measured total S1P by liquid chromatography-mass spectrometry and isolated HDL particles to test the association between apo M and HDL-associated S1P. We confirmed the relationship between apo M and outcomes using modified aptamer-based apo M measurements among 2170 adults in the PHFS and 2 independent cohorts: the Washington University Heart Failure Registry (n=173) and a subset of TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial; n=218). Last, we examined the relationship between apo M and ≈5000 other proteins (SomaScan assay) to identify biological pathways associated with apo M in heart failure. RESULTS: In the PHFS, apo M was inversely associated with the risk of death (standardized hazard ratio, 0.56 [95% CI, 0.51-0.61]; P<0.0001) and the composite of death/ventricular assist device implantation/heart transplantation (standardized hazard ratio, 0.62 [95% CI, 0.58-0.67]; P<0.0001). This relationship was independent of HDL cholesterol or apo AI levels. Apo M remained associated with death (hazard ratio, 0.78 [95% CI, 0.69-0.88]; P<0.0001) and the composite of death/ventricular assist device/heart transplantation (hazard ratio, 0.85 [95% CI, 0.76-0.94]; P=0.001) in models that adjusted for multiple confounders. This association was present in both heart failure with reduced and preserved ejection fraction and was replicated in the Washington University cohort and a cohort with heart failure with preserved ejection fraction only (TOPCAT). The S1P and apo M content of isolated HDL particles strongly correlated (R=0.81, P<0.0001). The top canonical pathways associated with apo M were inflammation (negative association), the coagulation system (negative association), and liver X receptor/retinoid X receptor activation (positive association). The relationship with inflammation was validated with multiple inflammatory markers measured with independent assays. CONCLUSIONS: Reduced circulating apo M is independently associated with adverse outcomes across the spectrum of human heart failure. Further research is needed to assess whether the apo M/S1P axis is a suitable therapeutic target in heart failure.
Assuntos
Apolipoproteínas M/sangue , Insuficiência Cardíaca/sangue , Proteoma , Idoso , Biomarcadores/sangue , Regulação para Baixo , Feminino , Insuficiência Cardíaca/diagnóstico , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/terapia , Humanos , Lipoproteínas HDL/sangue , Lisofosfolipídeos/sangue , Masculino , Pessoa de Meia-Idade , Prognóstico , Proteômica , Ensaios Clínicos Controlados Aleatórios como Assunto , Sistema de Registros , Medição de Risco , Fatores de Risco , Esfingosina/análogos & derivados , Esfingosina/sangue , Fatores de Tempo , Estados UnidosRESUMO
OBJECTIVE: Clinical evidence has linked low HDL (high-density lipoprotein) cholesterol levels with high cardiovascular disease risk; however, its significance as a therapeutic target remains unestablished. We hypothesize that HDLs functional heterogeneity is comprised of metabolically distinct proteins, each on distinct HDL sizes and that are affected by diet. Approach and Results: Twelve participants were placed on 2 healthful diets high in monounsaturated fat or carbohydrate. After 4 weeks on each diet, participants completed a metabolic tracer study. HDL was isolated by Apo (apolipoprotein) A1 immunopurification and separated into 5 sizes. Tracer enrichment and metabolic rates for 8 HDL proteins-ApoA1, ApoA2, ApoC3, ApoE, ApoJ, ApoL1, ApoM, and LCAT (lecithin-cholesterol acyltransferase)-were determined by parallel reaction monitoring and compartmental modeling, respectively. Each protein had a unique, size-specific distribution that was not altered by diet. However, carbohydrate, when replacing fat, increased the fractional catabolic rate of ApoA1 and ApoA2 on alpha3 HDL; ApoE on alpha3 and alpha1 HDL; and ApoM on alpha2 HDL. Additionally, carbohydrate increased the production of ApoC3 on alpha3 HDL and ApoJ and ApoL1 on the largest alpha0 HDL. LCAT was the only protein studied that diet did not affect. Finally, global proteomics showed that diet did not alter the distribution of the HDL proteome across HDL sizes. CONCLUSIONS: This study demonstrates that HDL in humans is composed of a complex system of proteins, each with its own unique size distribution, metabolism, and diet regulation. The carbohydrate-induced hypercatabolic state of HDL proteins may represent mechanisms by which carbohydrate alters the cardioprotective properties of HDL.
Assuntos
Dieta Hiperlipídica , Carboidratos da Dieta/administração & dosagem , Gorduras Insaturadas na Dieta/administração & dosagem , Lipoproteínas HDL/sangue , Proteoma , Apolipoproteína A-I/sangue , Apolipoproteína A-II/sangue , Apolipoproteína C-III/sangue , Apolipoproteína L1/sangue , Apolipoproteínas E/sangue , Apolipoproteínas M/sangue , Clusterina/sangue , Feminino , Humanos , Lipoproteínas HDL/química , Masculino , Fosfatidilcolina-Esterol O-Aciltransferase/sangueRESUMO
PURPOSE OF REVIEW: In 2011, the crystal structure of apolipoprotein M (apoM) and its capacity to bind sphingosine-1-phosphate (S1P) was characterized. Since then, a variety of studies has increased our knowledge on apoM biology and functionality. From being an unknown and hardly significant player in overall metabolism, apoM has gained significant interest. RECENT FINDINGS: Key discoveries in the last 2 years have indicated that the apoM/S1P complex has important roles in lipid metabolism (affecting triglyceride turnover), inflammation (a marker of severe sepsis and potentially providing anti-inflammatory signaling) and kidney biology (potential to protect against immunoglobulin A nephropathy). SUMMARY: Several studies suggest a potential for apoM/S1P as biomarkers for inflammation, sepsis and nephropathy. Also, a novel chaperone is characterized and could have potential as a drug for treatment in inflammation and nephropathy.
Assuntos
Apolipoproteínas M/metabolismo , Rim/patologia , Metabolismo dos Lipídeos , Lisofosfolipídeos/metabolismo , Esfingosina/análogos & derivados , Animais , Apolipoproteínas M/sangue , Humanos , Inflamação/metabolismo , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia , Esfingosina/metabolismoRESUMO
apoM is a minor HDL apolipoprotein and carrier for sphingosine-1-phosphate (S1P). HDL apoM and S1P concentrations are inversely associated with atherosclerosis progression in rodents. We evaluated associations between plasma concentrations of S1P, plasma concentrations of apoM, and HDL apoM levels with prevalent subclinical atherosclerosis and mortality in the African American-Diabetes Heart Study participants (N = 545). Associations between plasma S1P, plasma apoM, and HDL apoM with subclinical atherosclerosis and mortality were assessed using multivariate parametric, nonparametric, and Cox proportional hazards models. At baseline, participants' median (25th percentile, 75th percentile) age was 55 (49, 62) years old and their coronary artery calcium (CAC) mass score was 26.5 (0.0, 346.5). Plasma S1P, plasma apoM, and HDL apoM were not associated with CAC. After 64 (57.6, 70.3) months of follow-up, 81 deaths were recorded. Higher concentrations of plasma S1P [odds ratio (OR) = 0.14, P = 0.01] and plasma apoM (OR = 0.10, P = 0.02), but not HDL apoM (P = 0.89), were associated with lower mortality after adjusting for age, sex, statin use, CAC, kidney function, and albuminuria. We conclude that plasma S1P and apoM concentrations are inversely and independently associated with mortality, but not CAC, in African Americans with type 2 diabetes after accounting for conventional risk factors.
Assuntos
Apolipoproteínas M/sangue , Negro ou Afro-Americano , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/mortalidade , Lisofosfolipídeos/sangue , Esfingosina/análogos & derivados , Biomarcadores/sangue , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Esfingosina/sangue , Taxa de SobrevidaRESUMO
OBJECTIVE: ApoM (apolipoprotein M) binds primarily to high-density lipoprotein before to be exchanged with apoB (apolipoprotein B)-containing lipoproteins. Low-density lipoprotein (LDL) receptor-mediated clearance of apoB-containing particles could influence plasma apoM kinetics and decrease its antiatherogenic properties. In humans, we aimed to describe the interaction of apoM kinetics with other components of lipid metabolism to better define its potential benefit on atherosclerosis. APPROACH AND RESULTS: Fourteen male subjects received a primed infusion of 2H3-leucine for 14 hours, and analyses were performed by liquid chromatography-tandem mass spectrometry from the hourly plasma samples. Fractional catabolic rates and production rates within lipoproteins were calculated using compartmental models. ApoM was found not only in high-density lipoprotein (59%) and LDL (4%) but also in a non-lipoprotein-related compartment (37%). The apoM distribution was heterogeneous within LDL and non-lipoprotein-related compartments according to plasma triglycerides (r=0.86; P<0.001). The relationships between sphingosine-1-phosphate and apoM were confirmed in all compartments (r range, 0.55-0.89; P<0.05). ApoM fractional catabolic rates and production rates were 0.16±0.07 pool/d and 0.14±0.06 mg/kg per day in high-density lipoprotein and 0.56±0.10 pool/d and 0.03±0.01 mg/kg per day in LDL, respectively. Fractional catabolic rates of LDL-apoM and LDL-apoB100 were correlated (r=0.55; P=0.042). Significant correlations were found between triglycerides and production rates of LDL-apoM (r=0.73; P<0.004). CONCLUSIONS: In humans, LDL kinetics play a key role in apoM turnover. Plasma triglycerides act on both apoM and sphingosine-1-phosphate distributions between lipoproteins. These results confirmed that apoM could be bound to high-density lipoprotein after secretion and then quickly exchanged with a non-lipoprotein-related compartment and to LDL to be slowly catabolized.
Assuntos
Apolipoproteínas M/sangue , Deutério/administração & dosagem , Leucina/administração & dosagem , Adolescente , Adulto , Cromatografia Líquida de Alta Pressão , Cromatografia Líquida , Humanos , Infusões Intravenosas , Cinética , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lisofosfolipídeos/sangue , Masculino , Pessoa de Meia-Idade , Ligação Proteica , Proteólise , Esfingosina/análogos & derivados , Esfingosina/sangue , Triglicerídeos/sangue , Adulto JovemRESUMO
BACKGROUND The aim of this study was to observe apolipoprotein M (ApoM) level in obese patients and to explore its correlation with inflammatory factors. MATERIAL AND METHODS A total number of 96 participants were recruited and divided into 2 groups: the control group (or healthy group) whose participants had normal body weight (n=58), and the obese group with all its participants diagnosed with obesity (n=38). Data on blood pressure, body weight, height, body mass index, diastolic function of brachial artery endothelium, fasting venous blood glucose, blood lipids, plasmatic ApoM, interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), fasting insulin, and adiponectin levels were collected for both groups. RESULTS In the obese group, the levels of plasmatic ApoM, high-density lipoprotein cholesterol (HDL-C), and plasmatic adiponectin were significantly (p<0.05) decreased compared to the control group, and the levels of IL-6, TNF-α, CRP, and fasting insulin were significantly increased (p<0.05) compared to the control group. For the obese group, plasmatic ApoM level was positively correlated with HDL-C level and negatively correlated with levels of IL-6, TNF-α, CRP, insulin, and insulin resistance index. However, no significant correlations were revealed between plasmatic ApoM and the diastolic function of brachial artery endothelium, adiponectin level, blood pressure, and blood glucose level. CONCLUSIONS Obese patients showed significantly lower plasmatic ApoM levels than people with normal body weight, and ApoM level showed a strong correlation with CRP, TNF-α, and IL-6 levels, which indicated that ApoM might be regulated by these inflammatory factors.
Assuntos
Apolipoproteínas M/sangue , Inflamação/sangue , Inflamação/complicações , Obesidade/sangue , Obesidade/complicações , Adiponectina , Adulto , Glicemia/metabolismo , Pressão Sanguínea , Índice de Massa Corporal , Proteína C-Reativa/metabolismo , Diástole , Feminino , Humanos , Inflamação/fisiopatologia , Insulina/sangue , Resistência à Insulina , Interleucina-6/sangue , Lipídeos/sangue , Masculino , Obesidade/fisiopatologia , Fator de Necrose Tumoral alfa/sangueRESUMO
BACKGROUND: Scavenger receptor BI (SR-BI) is a classic high-density lipoprotein (HDL) receptor, which mediates selective lipid uptake from HDL cholesterol esters (HDL-C). Apolipoprotein M (ApoM), as a component of HDL particles, could influence preß-HDL formation and cholesterol efflux. The aim of this study was to determine whether SR-BI deficiency influenced the expression of ApoM. METHODS: Blood samples and liver tissues were collected from SR-BI gene knockout mice, and serum lipid parameters, including total cholesterol (TC), triglyceride (TG), high and low-density lipoprotein cholesterol (HDL-C and LDL-C) and ApoM were measured. Hepatic ApoM and ApoAI mRNA levels were also determined. In addition, BLT-1, an inhibitor of SR-BI, was added to HepG2 cells cultured with cholesterol and HDL, under serum or serum-free conditions. The mRNA and protein expression levels of ApoM were detected by RT-PCR and western blot. RESULTS: We found that increased serum ApoM protein levels corresponded with high hepatic ApoM mRNA levels in both male and female SR-BI-/- mice. Besides, serum TC and HDL-C were also significantly increased. Treatment of HepG2 hepatoma cells with SR-BI specific inhibitor, BLT-1, could up-regulate ApoM expression in serum-containing medium but not in serum-free medium, even in the presence of HDL-C and cholesterol. CONCLUSIONS: Results suggested that SR-BI deficiency promoted ApoM expression, but the increased ApoM might be independent from HDL-mediated cholesterol uptake in hepatocytes.
Assuntos
Apolipoproteínas M/metabolismo , HDL-Colesterol/metabolismo , Hepatócitos/metabolismo , Receptores Depuradores Classe B/metabolismo , Animais , Apolipoproteínas M/sangue , Apolipoproteínas M/genética , HDL-Colesterol/sangue , Ciclopentanos/farmacologia , Feminino , Genótipo , Células Hep G2 , Hepatócitos/efeitos dos fármacos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Tiossemicarbazonas/farmacologiaRESUMO
BACKGROUND: Apolipoprotein M (apoM) is a 26-kD apolipoprotein that is mainly expressed in specific cell types, such as human liver parenchymal cells and kidney proximal renal tubular epithelial cells. ApoM can regulate the formation of pre-ß-HDL and the reverse cholesterol transport and thus plays an important role in the metabolism of lipids and lipoproteins, meaning that it can affect the development of lipid metabolism disorders. Significantly elevated serum apoM levels are detected in patients with hyperlipidemia. However, few studies have shown how apoM is expressed in primary nephrotic syndrome (PNS), which is often accompanied with hyperlipidemia, and the underlying mechanism is poorly understood. This study was aimed at examining the apoM levels in patients with PNS and at determining the effects of PNS on serum apoM levels in these patients. METHODS: This study included patients with hyperlipidemia (n = 37), the PNS with hyperlipidemia group (n = 62), PNS without hyperlipidemia group (n = 33), and healthy controls (n = 73). The age and body-mass index (BMI) matched among the groups of participants. Their serum apoM concentrations were measured by an enzyme-linked immunosorbent assay. Serum levels of conventional lipids and renal function indices were assessed using an automatic biochemical analyzer. The data were analyzed by means of Pearson's correlation coefficient (continuous variables) or Student's t test (mean differences). RESULTS: The average serum apoM concentrations were higher in the hyperlipidemia group (61.1 ± 23.2 mg/L, P = 0.004) than in the healthy controls (31.6 ± 18.92 mg/L). The serum apoM concentrations were lower in the PNS with hyperlipidemia group (25.1 ± 16.31 mg/L, P = 0.007) and in the PNS without hyperlipidemia group (21.00 ± 17.62 mg/L, P = 0.003) than in the healthy controls. The serum apoM concentrations in the PNS with hyperlipidemia group did not differ significantly from those in the PNS without hyperlipidemia group (P = 0.083). Moreover, serum apoM levels positively correlated with serum high-density lipoprotein cholesterol (HDL-C) and apoA1 levels and negatively correlated with proteinuria in PNS patients (r = 0.458, P = 0.003; r = 0.254, P = 0.022; r = -0.414, P = 0.028). CONCLUSION: Serum apoM concentrations are higher in patients with hyperlipidemia than in healthy controls. Low serum apoM levels in patients with PNS are likely caused by PNS.
Assuntos
Apolipoproteínas M/sangue , Síndrome Nefrótica/sangue , Adulto , Apolipoproteína A-I/sangue , Índice de Massa Corporal , Feminino , Humanos , Hiperlipidemias/sangue , Metabolismo dos Lipídeos/fisiologia , Masculino , Pessoa de Meia-IdadeRESUMO
PURPOSE: The purpose of this study was to investigate the correlation between serum levels of serum apolipoprotein M (ApoM), A5 (ApoA5), and high-density lipoprotein (HDL) in patients with obstructive sleep apnea hypopnea syndrome (OSAHS) and study the effects of nasal continuous positive airway pressure treatment on these serum biomarkers. METHODS: Thirty OSAHS patients and 15 non-OSAHS probands as control were selected for the study. Serum HDL, ApoM, and ApoA5 levels in two groups were detected; differences and association among them were analyzed. Patients with moderate and severe OSAHS underwent 3-month auto-continuous positive airway pressure treatment, and a comparative study was conducted to investigate the changes in blood lipids, serum ApoM, and ApoA5. RESULTS: In comparison to the control group, the HDL, ApoM, and ApoA5 serum levels were lower (P < 0.05). HDL was positively correlated to ApoM and ApoA5 (P < 0.001), and ApoM was positively correlated to ApoA5 (r = 0.536, P < 0.001). HDL, ApoM, and ApoA5 were significantly increased in the patients of moderate and severe OSAHS after auto-continuous positive airway pressure treatment for 3 months (P < 0.05). CONCLUSIONS: The HDL level was significantly lower in OSAHS patients. The decrease in serum ApoM and ApoA5 in OSAHS patients was correlated to the severity of OSAHS and HDL levels. Auto-continuous positive airway pressure treatment increased serum levels of ApoM, ApoA5, and HDL in OSAHS patients.
Assuntos
Apolipoproteína A-V/sangue , Apolipoproteínas M/sangue , Lipoproteínas HDL/sangue , Apneia Obstrutiva do Sono/sangue , Adulto , Biomarcadores/sangue , Pressão Positiva Contínua nas Vias Aéreas , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Polissonografia , Estudos Retrospectivos , Fatores de Risco , Processamento de Sinais Assistido por Computador , Apneia Obstrutiva do Sono/terapia , Estatística como AssuntoRESUMO
OBJECTIVE: Apolipoprotein M (apoM) is an essential transporter of plasma Sphingosine-1-Phosphate (S1P), typically attached to all lipoprotein classes, but with a majority bound to high density lipoproteins (HDL). ApoM-deficient mice display an increased activity in brown adipose tissue and a concomitant fast turnover of triglycerides. In what manner apoM/S1P affect the triglyceride metabolism is however still unknown and explored in the present study. METHODS: Triglyceride turnover and potentially associated metabolic pathways were studied in the female human apoM transgenic mouse model (apoM-Tg) with increased plasma apoM and S1P levels. The model was compared with wild type (WT) mice. RESULTS: ApoM-Tg mice had a reduced plasma triglyceride turnover rate and a lower free fatty acid uptake in subcutaneous adipocytes compared to WT mice. Screening for potential molecular mechanisms furthermore revealed a reduction in plasma lipase activity in apoM-Tg animals. Overexpression of apoM also reduced the plasma levels of fibroblast growth factor 21 (FGF21). CONCLUSIONS: The study features the significant role of the apoM/S1P axis in maintaining a balanced triglyceride metabolism. Further, it also highlights the risk of inducing dyslipidaemia in patients receiving S1P-analouges and additionlly emphasizes the apoM/S1P axis as a potential therapeutic target in treatment of hypertriglyceridemia.
Assuntos
Apolipoproteínas M/sangue , Triglicerídeos/metabolismo , Animais , Feminino , Humanos , Cinética , Camundongos , Camundongos Transgênicos , Triglicerídeos/sangueRESUMO
BACKGROUND: Apolipoprotein M (ApoM) may have a role in the susceptibility of type 2 diabetes mellitus (T2DM). Polymorphisms in the promoter region of the ApoM gene were found to be significantly associated with diabetes. The aim of this study was to investigate the association of ApoM SNP rs805297 (C-1065A) with the susceptibility of T2DM and related microvascular complications in South Egypt. METHODS: We conducted a case-control study of 60 T2DM patients and 60 healthy control subjects. Lipid profile, fasting, and 2 hours postprandial glucose and creatinine levels were estimated. Patients were subjected to general and Fundus examinations, and screening for nephropathy by urinary albumin levels. ApoM level was assayed by ELISA. Genotyping of the human ApoM gene polymorphism SNP rs805297 (C-1065A) was done by PCR-restriction fragment length polymorphism followed by sequencing to confirm the polymorphism results. RESULTS: ApoM was not different between T2DM and the control group (p=0.075) and was negatively correlated with LDL-c (p=0.029). There were significant differences in ApoM genotypes (p=0.001) and allele frequencies (p=0.019) between T2DM and the control group. A significant reduction in FBG, 2hPPG, and HbA1c levels in the heterozygous than the wild genotype in the group with diabetes with no difference in other lab parameters and microvascular complications. The C-allele is associated with lower blood glucose levels and retinopathy. The wild (CC) genotype is considered as a risk factor for developing T2DM in South Egyptians but not CA+AA genotypes. CONCLUSIONS: In South Egyptians the ApoM polymorphism rs805297 (C-1065A) wild type (CC) was associated with T2DM susceptibility and may have a role in controlling hyperglycemia in these patients. The A-allele is associated with hyperglycemia and diabetic retinopathy.
Assuntos
Apolipoproteínas M/genética , Diabetes Mellitus Tipo 2/epidemiologia , Diabetes Mellitus Tipo 2/genética , Estudos de Associação Genética/métodos , Microvasos , Polimorfismo de Nucleotídeo Único/genética , Adulto , Apolipoproteínas M/sangue , Estudos de Casos e Controles , Diabetes Mellitus Tipo 2/sangue , Egito/epidemiologia , Feminino , Humanos , Masculino , Microvasos/metabolismo , Microvasos/patologia , Pessoa de Meia-IdadeRESUMO
CONTEXT: Recent studies have discovered a role of apolipoprotein M (apoM) in energy metabolism, and observational analyses in humans suggest an association with type 2 diabetes. The causal relationship remains however elusive. OBJECTIVE: To investigate whether reduced plasma apoM concentrations are causally linked to increased risk of type 2 diabetes. DESIGN: Prospective study design analyzed by Mendelian randomization. SETTING AND PARTICIPANTS: Two cohorts reflecting the Danish general population: the Copenhagen City Heart Study (CCHS, n = 8589) and the Copenhagen General Population Study (CGPS; n = 93 857). Observational analyses included a subset of participants from the CCHS with available plasma apoM (n = 725). Genetic analyses included the complete cohorts (n = 102 446). During a median follow-up of 16 years (CCHS) and 8 years (CGPS), 563 and 2132 participants developed type 2 diabetes. MAIN OUTCOME MEASURES: Plasma apoM concentration, genetic variants in APOM, and type 2 diabetes. RESULTS: First, we identified an inverse correlation between plasma apoM and risk of type 2 diabetes in a subset of participants from the CCHS (hazard ratio between highest vs lowest quartile (reference) = 0.32; 95% confidence interval = 0.1-1.01; P for trend = .02). Second, genotyping of specific single nucleotide polymorphisms in APOM further revealed a 10.8% (P = 6.2 × 10-5) reduced plasma apoM concentration in participants with variant rs1266078. Third, a meta-analysis including data from 599 451 individuals showed no association between rs1266078 and risk of type 2 diabetes. CONCLUSIONS: The present study does not appear to support a causal association between plasma apoM and risk of type 2 diabetes.
Assuntos
Apolipoproteínas M/sangue , Apolipoproteínas M/genética , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/genética , Idoso , Estudos de Coortes , Dinamarca/epidemiologia , Diabetes Mellitus Tipo 2/epidemiologia , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Fatores de RiscoRESUMO
PURPOSE: Risk stratification in chronic systolic heart failure (HF) is critical to identify the patients who may benefit from advanced therapies. It is aimed at identifying new biomarkers to improve prognosis evaluation and help to better understand HF physiopathology. EXPERIMENTAL DESIGN: Prognostic evaluation is performed in 198 patients with chronic systolic HF: 99 patients who died from cardiovascular cause within three years are individually matched for age, sex, and HF etiology (ischemic vs not) with 99 patients who are alive after three years of HF evaluation. A proteomic profiling of 15 apolipoproteins (Apo) is performed: Apo-A1, -A2, -A4, -B100, -C1, -C2, -C3, -C4, -D, -E, -F, -H, -J, -L1, and -M using LC-MRM-MS. RESULTS: In univariate analysis, the levels of Apo-B100 and -L1 are significantly lower and the levels of Apo-C1, -J, and -M are significantly higher in patients who died from cardiovascular cause as compared with patients alive. In the final statistical model, Apo-C1, Apo-J, and Apo-M improve individually the prediction of cardiovascular death. Ingenuity pathway analysis indicates these three Apo in a network associated with lipid metabolism, atherosclerosis signaling, and retinoid X receptor activation. CONCLUSIONS: Proteomic profiling of apolipoproteins using LC-MRM-MS might be useful in clinical practice for risk stratification of HF patients.
Assuntos
Apolipoproteína C-I/sangue , Apolipoproteínas M/sangue , Clusterina/sangue , Insuficiência Cardíaca/sangue , Proteoma/metabolismo , Biomarcadores/sangue , Feminino , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Estatísticos , Valor Preditivo dos Testes , Prognóstico , Fatores de RiscoRESUMO
OBJECTIVE: In sepsis, the protection of the vascular endothelium is essential and the maintenance of its function is critical to prevent further deterioration. High-density lipoprotein (HDL)-associated sphingosine-1-phosphate (S1P) is a bioactive lipid in plasma and its role in sepsis has not been extensively studied. This study aimed to investigate the effects of HDL-S1P on sepsis in cellular and animal models, as well as human plasma samples. MEASUREMENTS: We established an animal model of sepsis with different severities achieved by caecal ligation and puncture (CLP) and lipopolysaccharide (LPS) injection, and then explored the relationship between HDL-S1P and lung endothelial dysfunction in vivo. To determine the effects of HDL-S1P in the pulmonary endothelium of septic rats, we then injected HDL-S1P into septic rats to find out if it can reduce the lung injury caused by sepsis. Further, we explored the mechanism in vitro by studying the role of S1P-specific receptor agonists and inhibitors in LPS-stimulated human umbilical vein endothelial cells. We also explored the relationship between plasma HDL-S1P content and sepsis severity in septic patients by analysing their plasma samples. RESULTS: HDL-S1P concentrations in plasma were negatively correlated with endothelial functional damage in sepsis, both in the animal model and in the septic patients in our study. In vivo, HDL-S1P injection significantly reduced pulmonary oedema and endothelial leakage in septic rats. In vitro, cell experiments showed that HDL-S1P effectively protected the proliferation and migration abilities of endothelial cells, which could be partly explained by its biased activation of the S1P receptor 1. CONCLUSION: Our study preliminary explored the function of HDL-S1P in sepsis in cellular and animal models, as well as human subjects. The results indicate HDL-S1P protected endothelial functions in septic patients. Thus, it has therapeutic potential and can be used for the clinical treatment of sepsis.
Assuntos
Endotélio/metabolismo , Lipoproteínas HDL/sangue , Lesão Pulmonar/complicações , Lisofosfolipídeos/sangue , Sepse/sangue , Sepse/complicações , Esfingosina/análogos & derivados , Idoso de 80 Anos ou mais , Animais , Apolipoproteínas M/sangue , Movimento Celular , Proliferação de Células , Células Epiteliais/patologia , Feminino , Regulação da Expressão Gênica , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Masculino , Ratos , Sepse/metabolismo , Sepse/patologia , Esfingosina/sangueRESUMO
Perinatal and long-term offspring morbidities are strongly dependent on the preservation of placental vascular homeostasis during pregnancy. In adults, the HDL-apoM-S1P complex protects the endothelium and maintains vascular integrity. However, the metabolism and biology of cord blood-derived HDLs (referred to as neonatal HDL, nHDL) strikingly differ from those in adults. Here, we investigate the role of neonatal HDLs in the regulation of placental vascular function. We show that nHDL is a major carrier of sphingosine-1-phosphate (S1P), which is anchored to the particle through apoM (rs = 0.90, p < 0.0001) in the fetal circulation. Furthermore, this complex interacts with S1P receptors on the feto-placental endothelium and activates specifically extracellular signal-regulated protein kinases 1 and 2 (ERK) and phospholipase C (PLC) downstream signaling, promotes endothelial cell proliferation and calcium flux. Notably, the nHDL-S1P complex triggers actin filaments reorganization, leading to an enhancement of placental endothelial barrier function. Additionally, nHDL induces vasorelaxation of isolated placental chorionic arteries. Taken together, these results suggest that circulating nHDL exerts vasoprotective effects on the feto-placental endothelial barrier mainly via S1P signaling.
Assuntos
Sangue Fetal/metabolismo , Lipoproteínas HDL/metabolismo , Lisofosfolipídeos/metabolismo , Placenta/irrigação sanguínea , Esfingosina/análogos & derivados , Apolipoproteínas M/sangue , Apolipoproteínas M/metabolismo , Células Cultivadas , Endotélio Vascular/metabolismo , Feminino , Humanos , Lipoproteínas HDL/sangue , Lisofosfolipídeos/sangue , Sistema de Sinalização das MAP Quinases , Gravidez , Esfingosina/sangue , Esfingosina/metabolismo , Fosfolipases Tipo C/metabolismoRESUMO
Here, we show that the liver-derived apolipoprotein M (ApoM) protects the lung and kidney from pro-fibrotic insults and that this circulating factor is attenuated in aged mice. Aged mouse hepatocytes exhibit transcriptional suppression of ApoM. This leads to reduced sphingosine-1-phosphate (S1P) signaling via the S1P receptor 1 (S1PR1) in the vascular endothelial cells of lung and kidney. Suboptimal S1PR1 angiocrine signaling causes reduced resistance to injury-induced vascular leak and leads to organ fibrosis. Plasma transfusion from Apom transgenic mice but not Apom knockout mice blocked fibrosis in the lung. Similarly, infusion of recombinant therapeutics, ApoM-Fc fusion protein enhanced kidney and lung regeneration and attenuated fibrosis in aged mouse after injury. Furthermore, we identified that aging alters Sirtuin-1-hepatic nuclear factor 4α circuit in hepatocytes to downregulate ApoM. These data reveal an integrative organ adaptation that involves circulating S1P chaperone ApoM+ high density lipoprotein (HDL), which signals via endothelial niche S1PR1 to spur regeneration over fibrosis.
Assuntos
Envelhecimento/metabolismo , Apolipoproteínas M/metabolismo , Rim/metabolismo , Pulmão/metabolismo , Lisofosfolipídeos/metabolismo , Regeneração , Esfingosina/análogos & derivados , Envelhecimento/sangue , Envelhecimento/patologia , Animais , Apolipoproteínas M/sangue , Apolipoproteínas M/genética , Comunicação Celular , Células Cultivadas , Endotélio Vascular/metabolismo , Feminino , Fibrose , Hepatócitos/metabolismo , Rim/crescimento & desenvolvimento , Rim/patologia , Pulmão/crescimento & desenvolvimento , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato/metabolismoRESUMO
The axis of apolipoprotein M (apoM) and sphingosine-1-phosphate (S1P) is of importance to plasma lipid levels, endothelial function, and development of atherosclerosis. Menopause is accompanied by dyslipidemia and an increased risk of atherosclerosis, which can be lowered by exercise training. The aim of this study was to explore if effects of menopause and training are paralleled by changes in the apoM/S1P axis. Healthy, late premenopausal [ n = 38, age 49.2 (SD 2)] and recent postmenopausal [ n = 37, age 53.3 (SD 3)] women from the Copenhagen Women Study participated in a 3-mo, aerobic high-intensity exercise intervention. Before training, plasma apoM was higher in postmenopausal [1.08 µmol/l (SD 0.2)] compared with premenopausal [0.82 µmol/l (SD 0.2)] women ( P < 0.0001). Plasma S1P was similar in the two groups [0.44 µmol/l (SD 0.1) and 0.46 µmol/l (SD 0.1), respectively]. Thus, the pretraining S1P/apoM ratio was 26% lower in postmenopausal than premenopausal women ( P < 0.0001). After the training program, plasma apoM increased from 0.82 µmol/l (SD 0.2) to 0.90 µmol/l (SD 0.3) in premenopausal women and from 1.08 µmol/l (SD 0.2) to 1.16 µmol/l (SD 0.3) in postmenopausal women ( P < 0.05). Plasma S1P increased from 0.44 µmol/l (SD 0.1) to 0.47 µmol/l (SD 0.1) in premenopausal women and from 0.46 µmol/l (SD 0.1) to 0.48 µmol/l (SD 0.1) in postmenopausal women ( P < 0.05). The results suggest that menopause is accompanied by higher plasma apoM but not S1P concentrations and that exercise training increases plasma apoM and S1P in healthy middle-aged women irrespective of menopausal status. NEW & NOTEWORTHY The apolipoprotein M/sphingosine-1-phosphate (apoM/S1P) complex is involved in maintaining a healthy endothelial barrier function. Our study is the first, to our knowledge, to show how menopause affects the apoM/S1P axis. The results suggest that menopause is accompanied by higher plasma apoM but not S1P concentrations. Second, to our knowledge the study is also the first to show that exercise training increases both apoM/S1P in women irrespective of menopausal status.
Assuntos
Apolipoproteínas M/sangue , Exercício Físico/fisiologia , Lisofosfolipídeos/sangue , Pós-Menopausa/sangue , Pré-Menopausa/sangue , Esfingosina/análogos & derivados , Feminino , Humanos , Pessoa de Meia-Idade , Esfingosina/sangueRESUMO
BACKGROUND: Apolipoprotein M (apoM) is a 25-kDa apolipoprotein present in 5% of high-density lipoprotein (HDL) particles. It is suggested to be anti-atherogenic and to play a key role in sustaining endothelial barrier integrity. SLE patients have increased cardiovascular disease risk, and we aimed to investigate if apoM levels reflect endothelial function in SLE. Since apoM plasma levels decrease during inflammatory conditions, our aim was also to determine the impact of SLE disease activity on apoM plasma levels. METHODS: Plasma concentrations of apoM were measured by ELISA in two patient groups with systemic lupus erythematosus (SLE) and in 79 healthy control individuals. In patient group I (n = 84), evaluation time points were selected with the objective to include a wide range of clinical and laboratory variables reflecting disease activity which was measured as SLEDAI. In patient group II consisting of 140 consecutive patients, endothelial function was measured by a finger plethysmograph. A low Reactive Hyperemia Index (RHI) value indicates endothelial dysfunction. RESULTS: SLE patients had decreased levels of apoM compared to healthy controls (p < 0.01), with apoM levels correlating inversely with SLEDAI (r = - 0.31, p < 0.01) as well as with levels of CRP (r = - 0.26, p = 0.02) and positively with levels of C3 (r = 0.29, p < 0.01). ApoM levels were particularly low in patients with active disease from the kidney and skin and in patients with leukopenia or positive anti-dsDNA antibody test (p < 0.05). ApoM levels correlated with RHI values in young SLE patients (r = 0.32, p = 0.01), consistent with the important role of apoM in regulating endothelial integrity. CONCLUSIONS: ApoM levels may be regulated by SLE-related inflammatory processes and could be a marker of disease activity and endothelial dysfunction, in particular in young SLE patients. Further studies are needed to investigate the predictive value of apoM in the development of a cardiovascular disease.