RESUMO
OBJECTIVE: High-density lipoprotein (HDL) lipid composition and function may better reflect cardiovascular risk than HDL cholesterol concentration. This study characterized the relationships between HDL composition, metabolism, and function in metabolic syndrome (MetS) patients and how changes in composition after weight loss (WL) and exercise treatments are related to function. APPROACH AND RESULTS: Plasma samples from MetS patients (n=95) and healthy individuals (n=40) were used in this study. Subsets of the MetS group underwent 12 weeks of no treatment (n=17), WL (n=19), or WL plus exercise (WLEX; n=17). HDL was isolated using density-gradient ultracentrifugation. The HDL lipidome was analyzed by mass spectrometry, and particle size determined by nuclear magnetic resonance. Cholesteryl ester transfer protein activity and ex vivo HDL cholesterol efflux capacity (CEC) were assessed. The HDL lipidome in the MetS patients was substantially different from that in healthy individuals, mean particle size was smaller, and CEC was lower. Several HDL phospholipid and sphingolipid species were associated with HDL diameter and CEC. The HDL lipidome and particle size were modified toward the healthy individuals after WL and WLEX treatments, with greater effects observed in the latter group. Cholesteryl ester transfer protein activity was reduced after WL and WLEX, and CEC was improved after WLEX. CONCLUSIONS: WLEX treatment in MetS patients normalizes the HDL lipidome and particle size profile and enhances CEC. HDL lipids associated with diminished CEC may represent novel biomarkers for early prediction of HDL dysfunction and disease risk and may represent potential therapeutic targets for future HDL therapies. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00163943.
Assuntos
Restrição Calórica , Terapia por Exercício , Lipoproteínas HDL/sangue , Síndrome Metabólica/terapia , Redução de Peso , Biomarcadores/sangue , Proteínas de Transferência de Ésteres de Colesterol/sangue , HDL-Colesterol/sangue , Terapia Combinada , Feminino , Humanos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/diagnóstico , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Tamanho da Partícula , Fosfolipídeos/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Esfingolipídeos/sangue , Células THP-1 , Fatores de Tempo , Resultado do TratamentoRESUMO
OBJECTIVE: Oxidised low density lipoprotein (oxLDL) contributes to atherosclerosis, whereas high density lipoprotein (HDL) is known to be atheroprotective due, at least in part, to its ability to remove oxidised lipids from oxLDL. The molecular details of the lipid transfer process are not fully understood. We aimed to identify major oxidised lipid species of oxLDL and investigate their transfer upon co-incubation with HDL with varying levels of oxidation. APPROACH AND RESULTS: A total of 14 major species of oxidised phosphatidylcholine and oxidised cholesteryl ester from oxLDL were identified using an untargeted mass spectrometry approach. HDL obtained from pooled plasma of normolipidemic subjects (N=5) was oxidised under mild and heavy oxidative conditions. Non-oxidised (native) HDL and oxidised HDL were co-incubated with oxLDL, re-isolated and lipidomic analysis was performed. Lipoprotein surface lipids, oxidised phosphatidylcholines and oxidised cholesterols (7-ketocholesterol and 7ß-hydroxycholesterol), but not internal oxidised cholesteryl esters, were effectively transferred to native HDL. Saturated and monounsaturated lyso-phosphatidylcholines were also transferred from the oxLDL to native HDL. These processes were attenuated when HDL was oxidised under mild and heavy oxidative conditions. The impaired capacities were accompanied by an increase in a ratio of sphingomyelin to phosphatidylcholine and a reduction in phosphatidylserine content in oxidised HDL, both of which are potentially important regulators of the oxidised lipid transfer capacity of HDL. CONCLUSIONS: Our study has revealed the differential transfer efficiency of surface and internal oxidised lipids from oxLDL and their acceptance onto HDL. These capacities were modulated when HDL was itself oxidised.
Assuntos
Lipoproteínas HDL/química , Lipoproteínas LDL/química , Triglicerídeos/química , Adulto , Idoso , Transporte Biológico , Ésteres do Colesterol/química , Cobre/química , Jejum , Feminino , Humanos , Hidroxicolesteróis/química , Cetocolesteróis/química , Lipoproteínas HDL/isolamento & purificação , Lipoproteínas LDL/isolamento & purificação , Lisofosfatidilcolinas/química , Masculino , Pessoa de Meia-Idade , Oxidantes/química , Oxirredução , Fosfatidilcolinas/química , Fosfatidilserinas/química , Esfingomielinas/química , Triglicerídeos/isolamento & purificaçãoRESUMO
OBJECTIVE: Cyclosporin A (CsA) is an immunosuppressant commonly used to prevent organ rejection but is associated with hyperlipidemia and an increased risk of cardiovascular disease. Although studies suggest that CsA-induced hyperlipidemia is mediated by inhibition of low-density lipoprotein receptor (LDLr)-mediated lipoprotein clearance, the data supporting this are inconclusive. We therefore sought to investigate the role of the LDLr in CsA-induced hyperlipidemia by using Ldlr-knockout mice (Ldlr(-/-)). APPROACH AND RESULTS: Ldlr(-/-) and wild-type (wt) C57Bl/6 mice were treated with 20 mg/kg per d CsA for 4 weeks. On a chow diet, CsA caused marked dyslipidemia in Ldlr(-/-) but not in wt mice. Hyperlipidemia was characterized by a prominent increase in plasma very low-density lipoprotein and intermediate-density lipoprotein/LDL with unchanged plasma high-density lipoprotein levels, thus mimicking the dyslipidemic profile observed in humans. Analysis of specific lipid species by liquid chromatography-tandem mass spectrometry suggested a predominant effect of CsA on increased very low-density lipoprotein-IDL/LDL lipoprotein number rather than composition. Mechanistic studies indicated that CsA did not alter hepatic lipoprotein production but did inhibit plasma clearance and hepatic uptake of [(14)C]cholesteryl oleate and glycerol tri[(3)H]oleate-double-labeled very low-density lipoprotein-like particles. Further studies showed that CsA inhibited plasma lipoprotein lipase activity and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. CONCLUSIONS: We demonstrate that CsA does not cause hyperlipidemia via direct effects on the LDLr. Rather, LDLr deficiency plays an important permissive role for CsA-induced hyperlipidemia, which is associated with abnormal lipoprotein clearance, decreased lipoprotein lipase activity, and increased levels of apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9. Enhancing LDLr and lipoprotein lipase activity and decreasing apolipoprotein C-III and proprotein convertase subtilisin/kexin type 9 levels may therefore provide attractive treatment targets for patients with hyperlipidemia receiving CsA.
Assuntos
Ciclosporina , Hiperlipidemias/metabolismo , Metabolismo dos Lipídeos , Receptores de LDL/metabolismo , Animais , Apolipoproteína C-III/sangue , Biomarcadores/sangue , Ésteres do Colesterol/metabolismo , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Hiperlipidemias/sangue , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/genética , Lipase Lipoproteica/sangue , Lipoproteínas HDL/sangue , Lipoproteínas IDL/sangue , Lipoproteínas VLDL/sangue , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Pró-Proteína Convertase 9/sangue , Receptores de LDL/deficiência , Receptores de LDL/genética , Fatores de Tempo , Trioleína/metabolismoRESUMO
PURPOSE OF REVIEW: Dyslipidemia is a powerful risk factor for cardiovascular disease (CVD). Dietary fatty acid composition regulates lipids and lipoprotein metabolism and may confer CVD benefit. This review updates understanding of the effect of dietary fatty acids on lipoprotein metabolism in humans. RECENT FINDINGS: High dietary fish-derived n-3 polyunsaturated fatty acid (PUFA) consumption diminished hepatic triglyceride-rich lipoprotein (TRL) secretion and enhanced TRL to LDL conversion. n-3 PUFA also decreased TRL-apoB-48 concentration by decreasing TRL-apoB-48 secretion. High n-6 PUFA intake decreased liver fat, and plasma proprotein convertase subtilisin/kexin type 9, triglycerides, total-cholesterol and LDL-cholesterol concentrations. Intake of saturated fatty acids with increased palmitic acid at the sn-2 position was associated with decreased postprandial lipemia, which might be due to decreased triglyceride absorption. Replacing carbohydrate with monounsaturated fatty acids increased TRL catabolism. Ruminant trans-fatty acid decreased HDL cholesterol, but the mechanisms are unknown. A new role for APOE genotype in regulating lipid responses was also described. SUMMARY: The major advances in understanding the effect of dietary fatty acids on lipoprotein metabolism have focused on n-3 PUFA. This knowledge provides insights into the importance of regulating lipoprotein metabolism as a mode to improve plasma lipids and potential CVD risk. Further studies are required to better understand the cardiometabolic effects of other dietary fatty acids.
Assuntos
Doenças Cardiovasculares/metabolismo , Dislipidemias/metabolismo , Ácidos Graxos Ômega-3/metabolismo , Ácidos Graxos Ômega-6/metabolismo , Fígado/metabolismo , Animais , Apolipoproteína B-48/sangue , Apolipoproteína B-48/genética , Doenças Cardiovasculares/dietoterapia , Doenças Cardiovasculares/etiologia , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Dislipidemias/complicações , Dislipidemias/dietoterapia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Lipoproteínas/sangue , Lipoproteínas/genética , Fígado/efeitos dos fármacos , Triglicerídeos/sangue , Triglicerídeos/genéticaRESUMO
Ischaemic heart disease accounts for nearly half of the global cardiovascular disease burden. Aetiologies relating to heart disease are complex, but dyslipidaemia, oxidative stress and inflammation are cardinal features. Despite preventative measures and advancements in treatment regimens with lipid-lowering agents, the high prevalence of heart disease and the residual risk of recurrent events continue to be a significant burden to the health sector and to the affected individuals and their families. The development of improved risk models for the early detection and prevention of cardiovascular events in addition to new therapeutic strategies to address this residual risk are required if we are to continue to make inroads into this most prevalent of diseases. Metabolomics and lipidomics are modern disciplines that characterize the metabolite and lipid complement respectively, of a given system. Their application to ischaemic heart disease has demonstrated utilities in population profiling, identification of multivariate biomarkers and in monitoring of therapeutic response, as well as in basic mechanistic studies. Although advances in magnetic resonance and mass spectrometry technologies have given rise to the fields of metabolomics and lipidomics, the plethora of data generated presents challenges requiring specific statistical and bioinformatics applications, together with appropriate study designs. Nonetheless, the predictive and re-classification capacity of individuals with various degrees of risk by the plasma lipidome has recently been demonstrated. In the present review, we summarize evidence derived exclusively by metabolomic and lipidomic studies in the context of ischaemic heart disease. We consider the potential role of plasma lipid profiling in assessing heart disease risk and therapeutic responses, and explore the potential mechanisms. Finally, we highlight where metabolomic studies together with complementary -omic disciplines may make further inroads into the understanding, detection and treatment of ischaemic heart disease.
Assuntos
Metabolismo dos Lipídeos/fisiologia , Metabolômica/métodos , Isquemia Miocárdica/epidemiologia , Isquemia Miocárdica/metabolismo , Humanos , Fatores de RiscoRESUMO
Dysregulated VLDL-TAG (very-low-density lipoprotein triacylglycerol) metabolism in obesity may account for hypertriacylglycerolaemia and increased cardiovascular disease. ω-3 FAEEs (omega-3 fatty acid ethyl esters) decrease plasma TAG and VLDL concentrations, but the mechanisms are not fully understood. In the present study, we carried out a 6-week randomized, placebo-controlled study to examine the effect of high-dose ω-3 FAEE supplementation (3.2 g/day) on the metabolism of VLDL-TAG in obese men using intravenous administration of d5-glycerol. We also explored the relationship of VLDL-TAG kinetics with the metabolism of VLDL-apo (apolipoprotein) B-100 and HDL (high-density lipoprotein)-apoA-I. VLDL-TAG isotopic enrichment was measured using gas chromatography-mass spectrometry. Kinetic parameters were derived using a multicompartmental model. Compared with placebo, ω-3 FAEE supplementation significantly lowered plasma concentrations of total (-14%, P<0.05) and VLDL-TAG (-32%, P<0.05), as well as hepatic secretion of VLDL-TAG (-32%, P<0.03). The FCR (fractional catabolic rate) of VLDL-TAG was not altered by ω-3 FAEEs. There was a significant association between the change in secretion rates of VLDL-TAG and VLDL-apoB-100 (r=0.706, P<0.05). However, the change in VLDL-TAG secretion rate was not associated with change in HDL-apoA-I FCR (r=0.139, P>0.05). Our results suggest that the TAG-lowering effect of ω-3 FAEEs is associated with the decreased VLDL-TAG secretion rate and hence lower plasma VLDL-TAG concentration in obesity. The changes in VLDL-TAG and apoB-100 kinetics are closely coupled.
Assuntos
Ácidos Graxos Ômega-3/uso terapêutico , Lipoproteínas VLDL/metabolismo , Obesidade Abdominal/dietoterapia , Triglicerídeos/sangue , Apolipoproteínas/metabolismo , Suplementos Nutricionais , Ésteres , Humanos , Lipoproteínas HDL/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade Abdominal/sangue , Triglicerídeos/metabolismoRESUMO
We examined the effects of fenofibrate and atorvastatin on very low density lipoprotein (VLDL) apolipoprotein (apo)E metabolism in the metabolic syndrome (MetS). We studied 11 MetS men in a randomized, double-blind, crossover trial. VLDL-apoE kinetics were examined using stable isotope methods and compartmental modeling. Compared with placebo, fenofibrate (200 mg/day) and atorvastatin (40 mg/day) decreased plasma apoE concentrations (P < 0.05). Fenofibrate decreased VLDL-apoE concentration and production rate (PR) and increased VLDL-apoE fractional catabolic rate (FCR) compared with placebo (P < 0.05). Compared with placebo, atorvastatin decreased VLDL-apoE concentration and increased VLDL-apoE FCR (P < 0.05). Fenofibrate and atorvastatin had comparable effects on VLDL-apoE concentration. The increase in VLDL-apoE FCR with fenofibrate was 22% less than that with atorvastatin (P < 0.01). With fenofibrate, the change in VLDL-apoE concentration was positively correlated with change in VLDL-apoB concentration, and negatively correlated with change in VLDL-apoB FCR. In MetS, fenofibrate and atorvastatin decreased plasma apoE concentrations. Fenofibrate decreased VLDL-apoE concentration by lowering VLDL-apoE production and increasing VLDL-apoE catabolism. By contrast, atorvastatin decreased VLDL-apoE concentration chiefly by increasing VLDL-apoE catabolism. Our study provides new insights into the mechanisms of action of two different lipid-lowering therapies on VLDL-apoE metabolism in MetS.
Assuntos
Apolipoproteínas E/metabolismo , Fenofibrato/uso terapêutico , Ácidos Heptanoicos/uso terapêutico , Lipoproteínas VLDL/metabolismo , Síndrome Metabólica/tratamento farmacológico , Síndrome Metabólica/metabolismo , Pirróis/uso terapêutico , Adulto , Apolipoproteínas B/sangue , Apolipoproteínas B/metabolismo , Apolipoproteínas E/sangue , Atorvastatina , Método Duplo-Cego , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lipoproteínas VLDL/sangue , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-IdadeRESUMO
Moderate chronic kidney disease (CKD) (defined by an estimated glomerular filtration rate of 30-60 ml/min) is associated with mild hypertriglyceridemia related to delayed catabolism of triglyceride-rich lipoprotein particles. Altered apolipoprotein C-III (apoC-III) metabolism may contribute to dyslipidemia in CKD. To further characterize the dyslipidemia of CKD, we investigated the kinetics of plasma apoC-III in 7 nonobese, nondiabetic, non-nephrotic CKD subjects and 7 age- and sex-matched healthy controls, using deuterated leucine ([5, 5, 5, ²H3]leucine), gas chromatography-mass spectrometry, and multicompartmental modeling. Compared with controls, CKD subjects had higher concentrations of plasma and VLDL triglycerides and plasma and VLDL apoC-III (P < 0.05). The increased plasma apoC-III concentration was associated with a decreased apoC-III fractional catabolic rate (FCR) (1.21 ± 0.15 vs. 0.74 ± 0.12 pools/day, P = 0.03). There were no differences between apoC-III production rates of controls and those of CKD subjects. In CKD subjects, plasma apoC-III concentration was significantly and negatively correlated with apoC-III FCR (r = -0.749, P = 0.05) but not with apoC-III production rate. Plasma apoC-III concentration was positively correlated with plasma and VLDL triglycerides and VLDL apoB concentrations and negatively correlated with VLDL apoB FCR (P < 0.05 for all). ApoC-III FCR was negatively correlated with plasma and VLDL triglycerides and VLDL apoB concentration and positively correlated with VLDL apoB FCR (P < 0.05 for all). Altered plasma apoC-III metabolism is a feature of dyslipidemia in moderate CKD. Modification of apoC-III catabolism may be an important therapeutic target for reducing cardiovascular disease risk in moderate CKD.
Assuntos
Apolipoproteína C-III/sangue , Nefropatias/sangue , Apolipoproteína C-III/metabolismo , Apolipoproteínas B/sangue , Estudos de Casos e Controles , VLDL-Colesterol/sangue , Doença Crônica , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Humanos , Leucina/sangue , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
PURPOSE OF REVIEW: We review stable isotope tracer studies of apolipoprotein B-100 (apoB) kinetics concerning genetic polymorphisms and mutations that affect human lipoprotein metabolism. RECENT FINDINGS: In obese men, the allelic combination of the apoB signal peptide, SP24, and cholesteryl ester transfer protein, CETP B1B1, is independently associated with lower VLDL apoB secretion. Microsomal triglyceride transfer protein -493G/T carriers have reduced IDL apoB and LDL apoB production as compared with controls. Mutations in cholesterol transporters (ATP-binding cassette transporter G8 and Niemann-Pick C1 Like 1) are associated with reduced VLDL apoB secretion and increased LDL apoB production and catabolism. The ATP-binding cassette transporter G8 400K variant is a significant, independent predictor of VLDL apoB secretion. Mutations in lipases (lipoprotein lipase and hepatic lipase) and transfer proteins (lecithin-cholesterol acyltransferase and cholesteryl ester transfer protein) alter their functional activity, which impact on VLDL and LDL kinetics. SUMMARY: Mutations in genes that regulate intrahepatic apoB assembly and lipid substrate availability to the liver impact on VLDL apoB secretion. Lipoprotein tracer studies can provide functional insight into the potential impact of genetic polymorphisms in regulating apoB metabolism in humans.
Assuntos
Apolipoproteína B-100/genética , Apolipoproteína B-100/metabolismo , Animais , Apolipoproteína B-100/química , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Humanos , Cinética , Lipase/metabolismo , Mutação , Sinais Direcionadores de ProteínasRESUMO
Reduced HDL (high-density lipoprotein) concentration in the MetS (metabolic syndrome) is associated with increased risk of cardiovascular disease and is related to defects in HDL-apoA-II (apolipoprotein A-II) kinetics. Dietary restriction is the most commonly used weight loss strategy. In the present study, we examined the effect of weight loss on HDL-apoA-II kinetics in men with the MetS at the start and end of a 16-week intervention trial of a hypocaloric low-fat diet (n=20) compared with a weight maintenance diet (n=15), using a stable isotope technique and compartmental modelling. The low-fat diet achieved a significant reduction (P<0.01) in BMI (body mass index), abdominal fat compartments and HOMA (homoeostasis model assessment) score compared with weight maintenance. Weight loss also significantly (P<0.05) decreased both the production rate (-23%) and FCR (fractional catabolic rate) (-12%) of HDL-apoA-II, accounting for a net decrease in apoA-II concentration (-9%). Reductions in the HDL-apoA-II production rate were significantly associated with changes in body weight (r=0.683, P<0.01), plasma triacylglycerols (triglycerides) (r=0.607, P<0.01) and, to a lesser extent, plasma insulin (r=0.440, P=0.059) and HOMA-IR (HOMA of insulin resistance) (r=0.425, P=0.069). Changes in the apoA-II FCR were also significantly associated with reductions in visceral adipose tissue mass (r=0.561, P=0.010). In conclusion, in obese men with the MetS, short-term weight loss with a low-fat low-caloric diet lowers plasma apoA-II concentrations by decreasing both the production and catabolism of HDL-apoA-II. The cardiometabolic significance of this effect on HDL metabolism remains to be investigated further.
Assuntos
Apolipoproteína A-II/sangue , Dieta com Restrição de Gorduras , Lipoproteínas HDL/sangue , Síndrome Metabólica/sangue , Redução de Peso/fisiologia , Antropometria/métodos , Composição Corporal/fisiologia , Índice de Massa Corporal , Dieta Redutora , Humanos , Resistência à Insulina/fisiologia , Lipídeos/sangue , Lipoproteínas/sangue , Masculino , Síndrome Metabólica/dietoterapia , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-IdadeRESUMO
We investigated the relationship of plasma adipocytokine concentrations with VLDL apolipoprotein B (apoB)-100 kinetics in men. Plasma adiponectin, leptin, resistin, interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) concentrations were measured using enzyme immunoassays and insulin resistance by homeostasis model assessment (HOMA) score in 41 men with BMI of 22-35 kg/m(2). VLDL apoB kinetics were determined using an intravenous infusion of 1-[(13)C]leucine, gas chromatography-mass spectrometry, and compartmental modeling. Visceral and subcutaneous adipose tissue mass (ATM) were determined using magnetic resonance imaging, and total ATM was measured by bioelectrical impedance. In univariate regression, plasma adiponectin and leptin concentrations were inversely and directly associated, respectively, with plasma triglyceride; HOMA score; and visceral, subcutaneous, and total ATMs. Conversely, adiponectin and leptin were directly and inversely correlated, respectively, with VLDL apoB catabolism and HDL cholesterol concentration (P < 0.05). Resistin, IL-6, and TNF-alpha were not significantly associated with any of these variables. In multivariate regression, adiponectin was the most significant predictor of plasma VLDL apoB concentration (P = 0.001) and, together with total or subcutaneous ATM, was an independent predictor of VLDL apoB catabolism (P < 0.001); HOMA score was the most significant predictor of VLDL apoB hepatic secretion (P < 0.05). Leptin was not an independent predictor of VLDL apoB kinetics. In conclusion, plasma VLDL apoB kinetics may be differentially controlled by adiponectin and insulin resistance, with adiponectin regulating catabolism and insulin resistance regulating hepatic secretion in men. Total body fat may also independently determine the rate of VLDL catabolism, but leptin, resistin, IL-6, and TNF-alpha do not have a significant effect in regulating apoB kinetics.
Assuntos
Tecido Adiposo/fisiologia , Apolipoproteínas B/sangue , Resistência à Insulina/fisiologia , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Lipoproteínas VLDL/sangue , Adiponectina , Adulto , Apolipoproteína B-100 , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/sangue , Cinética , Modelos Logísticos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: We examined the association of plasma apolipoprotein (apoB) B-48, remnant-like particle (RLP)-cholesterol and non-HDL cholesterol concentrations with apoB-100 kinetics in overweight-obese men. METHODS AND RESULTS: Very-low density lipoprotein (VLDL), intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) apoB-100 kinetics were measured in 53 men (BMI 33 +/- 4 kg/m(2)) using stable isotopes and multicompartmental modeling to estimate production rate (PR) and fractional catabolic rate (FCR). Fasting apoB-48 and RLP-cholesterol concentrations were measured using immunoassays. In univariate regression, apoB-48 and RLP-cholesterol were inversely associated with VLDL-apoB-100 FCR and IDL-apoB-100 FCR (P < 0.01 for all), but not with VLDL-, IDL- and LDL-apoB-100 PRs. Plasma non-HDL-cholesterol concentration was significantly and positively associated with the secretion rate of VLDL-apoB-100 (P < 0.05), and inversely correlated with the FCR of LDL-apoB-100 (P < 0.01). CONCLUSIONS: Our findings suggest that in overweight-obese men plasma concentrations of apoB-48, RLP-cholesterol and non-HDL-cholesterol are partly dependent on catabolism of apoB-100 containing lipoproteins.
Assuntos
Apolipoproteínas B/sangue , Apolipoproteínas B/metabolismo , Lipoproteínas/sangue , Lipoproteínas/metabolismo , Obesidade/sangue , Obesidade/metabolismo , Sobrepeso/fisiologia , Triglicerídeos/sangue , Triglicerídeos/metabolismo , Apolipoproteína B-100 , Apolipoproteína B-48 , Colesterol , Humanos , MasculinoRESUMO
Dyslipidemia is a major risk factor for cardiovascular disease (CVD). Dietary fatty-acid composition regulates lipids and lipoprotein metabolism and may confer CVD benefit. This review updates understanding of the effect of dietary fatty-acids on human lipoprotein metabolism. In elderly participants with hyperlipidemia, high n-3 polyunsaturated fatty-acids (PUFA) consumption diminished hepatic triglyceride-rich lipoprotein (TRL) secretion and enhanced TRL to low-density lipoprotein (LDL) conversion. n-3 PUFA also decreased TRL-apoB-48 concentration by decreasing TRL-apoB-48 secretion. High n-6 PUFA intake decreased very low-density lipoprotein (VLDL) cholesterol and triglyceride concentrations by up-regulating VLDL lipolysis and uptake. In a study of healthy subjects, the intake of saturated fatty-acids with increased palmitic acid at the sn-2 position was associated with decreased postprandial lipemia. Low medium-chain triglyceride may not appreciably alter TRL metabolism. Replacing carbohydrate with monounsaturated fatty-acids increased TRL catabolism. Trans-fatty-acid decreased LDL and enhanced high-density lipoprotein catabolism. Interactions between APOE genotype and n-3 PUFA in regulating lipid responses were also described. The major advances in understanding the effect of dietary fatty-acids on lipoprotein metabolism has centered on n-3 PUFA. This knowledge emphasizes the importance of regulating lipoprotein metabolism as a mode to improve plasma lipids and potentially CVD risk. Additional studies are required to better characterize the cardiometabolic effects of other dietary fatty-acids.
Assuntos
Ácidos Graxos Monoinsaturados/farmacologia , Ácidos Graxos Ômega-3/farmacologia , Ácidos Graxos Ômega-6/farmacologia , Ácidos Graxos/farmacologia , Metabolismo dos Lipídeos/efeitos dos fármacos , Apolipoproteínas E/sangue , Doenças Cardiovasculares/sangue , HDL-Colesterol/sangue , VLDL-Colesterol/sangue , Dislipidemias/sangue , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores de Risco , Triglicerídeos/sangueRESUMO
INTRODUCTION: The objective of the study was to examine post hoc associations between plasma sphingolipids and lipoprotein kinetics in men with the metabolic syndrome after rosuvastatin treatment. MATERIALS AND METHODS: Plasma sphingolipid profiling, determined by tandem mass spectrometry, was performed in a randomized, double-blind, triple-crossover trial (n = 12) of 5-week treatment periods with placebo or rosuvastatin (10 or 40 mg/d) with 2-week washouts between treatments. RESULTS AND DISCUSSION: Baseline plasma ceramides were associated with very low-density lipoprotein (VLDL) apolipoprotein (apo)-B-100 concentration (r = 0.58, P < .05) and inversely with VLDL apoB-100 fractional catabolic rate (FCR; r = -0.67, P = .02). Posttreatment changes with rosuvastatin (40 mg/d) in plasma ceramides were inversely associated with VLDL apoB-100 FCR (r = -0.62, P = .03) independent of changes in plasma triglycerides, cholesterol, and low-density lipoprotein-cholesterol. By contrast, baseline and postrosuvastatin treatment plasma sphingomyelin levels were not associated with apoB-100 kinetics. Plasma ceramides and sphingomyelin were not associated with the kinetics or concentrations of high-density lipoprotein apoA-I, and low-density lipoprotein apoB. In the metabolic syndrome, the ability of rosuvastatin to increase VLDL apoB-100 FCR may reflect ceramide-specific mechanistic actions and/or sphingolipid exchange.
Assuntos
Anticolesterolemiantes/uso terapêutico , Apolipoproteína B-100/sangue , Ceramidas/sangue , Fluorbenzenos/uso terapêutico , Lipoproteínas VLDL/sangue , Síndrome Metabólica/tratamento farmacológico , Pirimidinas/uso terapêutico , Esfingomielinas/sangue , Sulfonamidas/uso terapêutico , Adulto , Apolipoproteína B-100/química , Humanos , Cinética , Metabolismo dos Lipídeos/efeitos dos fármacos , Masculino , Síndrome Metabólica/sangue , Síndrome Metabólica/complicações , Metabolismo/efeitos dos fármacos , Pessoa de Meia-Idade , Obesidade Abdominal/sangue , Obesidade Abdominal/complicações , Obesidade Abdominal/tratamento farmacológico , Rosuvastatina CálcicaRESUMO
CONTEXT: Statins are effective cholesterol-lowering agents that reduce cardiovascular disease risk but also have pleiotropic effects that may extend to other lipid classes. OBJECTIVE: The purpose of this article was to investigate, in a post hoc analysis, the dose-dependent effects of rosuvastatin on plasma sphingolipids and phospholipids in men with the metabolic syndrome. METHODS: Subjects (n = 12) were studied in a randomized, double-blind, triple-crossover trial of a 5-week treatment period with placebo or rosuvastatin (10 or 40 mg/day) with 2-week washouts between treatments. Plasma sphingolipid profiling was determined by liquid chromatography electrospray ionization-tandem mass spectrometry. RESULTS: Rosuvastatin at 10 mg/d (R10) and 40 mg/d (R40) significantly (all P < .001 unless stated otherwise) lowered plasma cholesterol (-34% and -42% [% change with R10 and with R40, respectively]), low-density lipoprotein cholesterol (-49% and -57%) and triglyceride (-24%, P =.03 and -42%) concentrations. Compared with placebo, R10 and R40 significantly decreased the plasma levels of total sphingolipids including those of ceramide (-33% and -37%), sphingomyelin (-27% and -31%), monohexosylceramide (-40% and -47%), dihexosylceramide (-31% and -34%), and trihexosylceramide (-29% and -31%), and GM3 gangliosides (-29% and -26%), lysophosphatidylcholine (-32% and -37%), alkylphosphatidylcholine (-19% and -19%), phosphatidylcholine (-17% and -19%), alkenylphosphatidylcholine (plasmalogen) (-20% and -22%), alkylphosphatidylethanolamine (-20%, P =.008 and -24%, P =.02), alkenylphosphatidylethanolamine (plasmalogen) (-24%, P =.003 and -23%, P =.007), phosphatidylglycerol (-24%, P =.07, -31%, P =.046), and phosphatidylinositol (-34% and -40%). No significant changes were found with phosphatidylethanolamine and phosphatidylserine. Significant dose effects were found with the majority of the plasma sphingolipids, whereas only phosphatidylcholine, lysophosphatidylcholine, alkylphosphatidylcholine, alkenylphosphatidylcholine (plasmalogen), and phosphatidylinositol had significant dose effects. Similar changes were found with plasma sphingolipids when results were normalized to the total phosphatidylcholine concentration. CONCLUSIONS: Rosuvastatin dose-dependently lowers plasma sphingolipids and phospholipids, independent of low-density lipoprotein lowering, in men with the metabolic syndrome.
Assuntos
Fluorbenzenos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Síndrome Metabólica/sangue , Fosfolipídeos/sangue , Pirimidinas/farmacologia , Esfingolipídeos/sangue , Sulfonamidas/farmacologia , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Fluorbenzenos/administração & dosagem , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Masculino , Pessoa de Meia-Idade , Pirimidinas/administração & dosagem , Rosuvastatina Cálcica , Sulfonamidas/administração & dosagemRESUMO
Reduced HDL cholesterol, commonly found in subjects with obesity and type 2 diabetes, is associated with increased risk of cardiovascular disease (CVD). ApoA-II, a constituent apolipoprotein of certain HDL particles, plays an important role in the regulation of cholesterol efflux, HDL remodelling, and cholesteryl ester uptake via its interactions with lipid transfer proteins, lipases, and cellular HDL receptors. Recent studies have linked apoA-II directly with triglyceride and glucose metabolism. Most of the data are, however, derived from cellular systems and transgenic animal models. Direct evidence from human studies is scarce. Clinical studies demonstrate that apoA-II is a strong predictor of risk for CVD. There is no evidence, however, that selective therapeutic modification of apoA-II impacts on atherosclerosis and clinical outcomes. More research is required to investigate further the significance of apoA-II in clinical medicine.
Assuntos
Apolipoproteína A-II/metabolismo , Aterosclerose/metabolismo , Doenças Cardiovasculares/metabolismo , HDL-Colesterol/metabolismo , Dislipidemias/metabolismo , Humanos , Resistência à Insulina/fisiologia , Metabolismo dos Lipídeos , Síndrome Metabólica/metabolismo , Triglicerídeos/metabolismoRESUMO
AIMS: We investigated the associations between indices of cholesterol metabolism and features of the metabolic syndrome (MS) in the presence and absence of type-2 diabetes (T2DM). METHODS: Men with the MS (N=140) and 10 age- and sex-matched controls were recruited. Plasma lathosterol and campesterol were measured by gas chromatography-mass spectrometry, and their ratios to total cholesterol were used to estimate cholesterol metabolism. RESULTS: Compared with healthy controls, MS subjects had significantly higher lathosterol:cholesterol and lower campesterol:cholesterol ratios (p<0.05). In the MS subjects without T2DM (N=82), campesterol:cholesterol ratio was positively associated with age and negatively associated with plasma triglyceride and insulin concentrations, while in MS subjects with T2DM (N=58), the ratio was positively associated with age and adiponectin concentration, and negatively associated with BMI and insulin. Age and fasting insulin were independent predictors of campesterol:cholesterol ratio in MS subjects with T2DM. There was a significant negative association between plasma lathosterol:cholesterol with campesterol:cholesterol ratio (r=-0.436, p=0.014) in MS subjects without T2DM but not in MS subjects with T2DM. CONCLUSIONS: Cholesterol absorption efficiency was lower and cholesterol synthesis higher in MS subjects with or without T2DM compared with healthy individuals. Moreover, the reciprocal relationship between cholesterol synthesis and cholesterol absorption is lost in the presence of diabetes.
Assuntos
Biomarcadores/sangue , Colesterol/sangue , Colesterol/metabolismo , Diabetes Mellitus Tipo 2/sangue , Síndrome Metabólica/sangue , Adiponectina/sangue , Apolipoproteína A-I/sangue , Apolipoproteínas/sangue , Glicemia/metabolismo , Pressão Sanguínea , Colesterol/análogos & derivados , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Homeostase , Humanos , Masculino , Pessoa de Meia-Idade , Obesidade/sangue , Obesidade/metabolismo , Fitosteróis/sangue , Valores de Referência , Triglicerídeos/sangueRESUMO
OBJECTIVE: The purpose of this study was to examine the effect of weight loss on LDL and HDL kinetics and plasma retinol-binding protein-4 (RBP-4) and adiponectin levels in men with the metabolic syndrome. RESEARCH DESIGN AND METHODS: LDL apolipoprotein (apo)B-100 and HDL apoA-I kinetics were studied in 35 obese men with the metabolic syndrome at the start and end of a 16-week intervention trial of a hypocaloric, low-fat diet (n = 20) versus a weight maintenance diet (n = 15) using a stable isotope technique and multicompartmental modeling. RESULTS: Consumption of the low-fat diet produced significant reductions (P < 0.01) in BMI, abdominal fat compartments, and homeostasis model assessment score compared with weight maintenance. These were associated with a significant increase in adiponectin and a fall in plasma RBP-4, triglycerides, LDL cholesterol, and LDL apoB-100 concentration (P < 0.05). Weight loss significantly increased the catabolism of LDL apoB-100 (+27%, P < 0.05) but did not affect production; it also decreased both the catabolic (-13%) and production (-13%) rates of HDL apoA-I (P < 0.05), thereby not altering plasma HDL apoA-I or HDL cholesterol concentrations. VLDL apoB-100 production fell significantly with weight loss (P < 0.05). The increase in LDL catabolism was inversely correlated with the fall in RBP-4 (r = -0.54, P < 0.05) and the decrease in HDL catabolism with the rise in adiponectin (r = -0.56, P < 0.01). CONCLUSIONS: In obese men with metabolic syndrome, weight loss with a low-fat diet decreases the plasma LDL apoB-100 concentration by increasing the catabolism of LDL apoB-100; weight loss also delays the catabolism of HDL apoA-I with a concomitant reduction in the secretion of HDL apoA-I. These effects of weight loss could partly involve changes in RBP-4 and adiponectin levels.
Assuntos
Adiponectina/sangue , Dieta com Restrição de Gorduras , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Síndrome Metabólica/sangue , Proteínas Plasmáticas de Ligação ao Retinol/metabolismo , Redução de Peso , Apolipoproteína B-100/sangue , Humanos , Cinética , Masculino , Obesidade/sangue , População BrancaRESUMO
BACKGROUND: Adipocytokines are bioactive peptides that may play an important role in the regulation of glucose and lipid metabolism. In this study, we investigated the association of plasma adipocytokine concentrations with markers of triglyceride-rich lipoprotein (TRL) metabolism in men. METHODS: Fasting adiponectin, leptin, resistin, interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), apolipoprotein (apo) B-48, apo C-III, and remnant-like particle (RLP)-cholesterol concentrations were measured by immunoassays and insulin resistance by homeostasis assessment (HOMA) score in 41 nondiabetic men with a body mass index of 22-35 kg/m2. Visceral and subcutaneous adipose tissue masses (ATMs) were determined by magnetic resonance imaging and total ATM by bioelectrical impedance. RESULTS: In univariate regression, plasma adiponectin and leptin concentrations were inversely and directly associated with plasma apoB-48, apoC-III, RLP-cholesterol, triglycerides, VLDL-apoB, and VLDL-triglycerides (P <0.05). Resistin, IL-6, and TNF-alpha were not significantly associated with any of these variables, except for a direct correction between apoC-III and IL-6 (P <0.05). In multivariate regression including HOMA, age, nonesterified fatty acids, and adipose tissue compartment, adiponectin was an independent predictor of plasma apoB-48 (beta coefficient = -0.354; P = 0.048), apoC-III (beta coefficient = -0.406; P = 0.012), RLP-cholesterol (beta coefficient = -0.377; P = 0.016), and triglycerides (beta coefficient = -0.374; P = 0.013). By contrast, leptin was not an independent predictor of these TRL markers. Plasma apoB-48, apoC-III, RLP-cholesterol, and triglycerides were all significantly and positively associated with plasma insulin, HOMA, and visceral, subcutaneous, and total ATMs (P <0.05). CONCLUSIONS: These data suggest that the plasma adiponectin concentration may not only link abdominal fat, insulin resistance, and dyslipidemia, but may also exert an independent role in regulating TRL metabolism.