RESUMO
Postprandial vitamin A and intestinal lipoprotein metabolism was studied in 86 healthy men and women, aged 19-76 yr. Three independent experiments were carried out. In the first experiment, a supplement dose of vitamin A (3,000 retinol equivalents [RE]) was given without a meal to 59 subjects, aged 22-76 yr. In the second experiment, 20 RE/kg body wt was given with a fat-rich meal (1 g fat/kg body wt) to seven younger subjects (aged less than 50 yr) and seven older subjects (aged greater than or equal to 50 yr). In both experiments, postprandial plasma retinyl ester response increased significantly with advancing age (P less than 0.05). In the third experiment, retinyl ester-rich plasma was infused intravenously into nine young adult subjects (aged 18-30 yr) and nine elderly subjects (aged greater than or equal to 60 yr), and the rate of retinyl ester disappearance from plasma during the subsequent 3 h was determined. Mean (+/- SE) plasma retinyl ester residence time was 31 +/- 4 min in the young adult subjects vs. 57 +/- 8 min in the elderly subjects (P less than 0.05). These data are consistent with the concept that increased postprandial plasma retinyl ester concentrations in older subjects are due to delayed plasma clearance of retinyl esters in triglyceride-rich lipoproteins of intestinal origin.
Assuntos
Ingestão de Alimentos , Mucosa Intestinal/metabolismo , Lipoproteínas/metabolismo , Vitamina A/metabolismo , Adulto , Fatores Etários , Idoso , Quilomícrons/metabolismo , Doença das Coronárias/etiologia , Feminino , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-IdadeRESUMO
Six normolipidemic male subjects, after an 8-h overnight fast, were given a bolus injection and then a 15-h constant intravenous infusion of [D3]L-leucine. Subjects were studied in the fasted state and on a second occasion in the fed state (small, physiological meals were given every hour for 15 h). Apolipoproteins were isolated by preparative gradient gel electrophoresis from plasma lipoproteins separated by sequential ultracentrifugation. Incorporation of [D3]L-leucine into apolipoproteins was monitored by negative ionization, gas chromatography-mass spectrometry. Production rates were determined by multiplying plasma apolipoprotein pool sizes by fractional production rates (calculated as the rate of isotopic enrichment [IE] of each protein as a fraction of IE achieved by VLDL (d less than 1.006 g/ml) apo B-100 at plateau. VLDL apo B-100 production was greater, and LDL (1.019 less than d less than 1.063 g/ml) apo B-100 production was less in the fed compared with the fasted state (9.9 +/- 1.7 vs. 6.4 +/- 1.7 mg/kg per d, P less than 0.01, and 8.9 +/- 1.2 vs. 13.1 +/- 1.2 mg/kg per d, P less than 0.05, respectively). No mean change was observed in high density lipoprotein apo A-I production. We conclude that: (a) this stable isotope, endogenous-labeling technique, for the first time allows for the in vivo measurement of apolipoprotein production in the fasted and fed state; and (b) since LDL apo B-100 production was greater than VLDL apo B-100 production in the fasted state, this study provides in vivo evidence that LDL apo B-100 can be produced independently of VLDL apo B-100 in normolipidemic subjects.
Assuntos
Apolipoproteínas A/biossíntese , Apolipoproteínas B/biossíntese , Leucina/metabolismo , Lipoproteínas HDL/biossíntese , Lipoproteínas LDL/biossíntese , Lipoproteínas VLDL/biossíntese , Adulto , Apolipoproteína A-I , Apolipoproteína B-100 , Colesterol/biossíntese , Deutério , Jejum , Alimentos , Humanos , Masculino , Triglicerídeos/biossínteseRESUMO
Triglyceride (TG) enrichment of HDL resulting from cholesteryl ester transfer protein-mediated exchange with TG-rich lipoproteins may enhance the lipolytic transformation and subsequent metabolic clearance of HDL particles in hypertriglyceridemic states. The present study investigates the effect of TG enrichment of HDL on the clearance of HDL-associated apo A-I in humans. HDL was isolated from plasma of six normolipidemic men (mean age: 29.7 +/- 2.7 years) in the fasting state and after a five-hour intravenous infusion with a synthetic TG emulsion, Intralipid. Intralipid infusion resulted in a 2.1-fold increase in the TG content of HDL. Each tracer was then whole-labeled with 125I or 131I and injected intravenously into the subject. Apo A-I in TG-enriched HDL was cleared 26% more rapidly than apo A-I in fasting HDL. A strong correlation between the Intralipid-induced increase in the TG content of HDL and the increase in HDL apo A-I fractional catabolic rate reinforced the importance of TG enrichment of HDL in enhancing its metabolic clearance. HDL was separated further into lipoproteins containing apo A-II (LpAI:AII) and those without apo A-II (LpAI). Results revealed that the enhanced clearance of apo A-I from TG-enriched HDL could be largely attributed to differences in the clearance of LpAI but not LpAI:AII. This is, to our knowledge, the first direct demonstration in humans that TG enrichment of HDL enhances the clearance of HDL apo A-I from the circulation. This phenomenon could provide an important mechanism explaining how HDL apo A-I and HDL cholesterol are lowered in hypertriglyceridemic states.
Assuntos
Apolipoproteína A-I/metabolismo , Lipoproteínas HDL/metabolismo , Triglicerídeos/metabolismo , Adulto , Humanos , Metabolismo dos Lipídeos , Lisofosfatidilcolinas/metabolismo , Masculino , Fosfatidilcolinas/metabolismo , Proteínas/metabolismo , Esfingomielinas/metabolismoRESUMO
BACKGROUND AND PURPOSE: Protective cardiovascular effects of peroxisome proliferator activated receptor (PPAR)alpha and PPARgamma activators have been demonstrated. If used as vasoprotective agents in high risk vascular patients rather than for their metabolic benefits, these agents could be associated with unwanted side effects. As a proof of concept to support the use of combined low doses of PPARalpha and PPARgamma as vascular protective agents in high risk vascular patients, we tested the hypothesis that combined low doses of PPARalpha (fenofibrate) and PPARgamma (rosiglitazone) activators would provide vascular protective benefits similar to full individual doses of these PPAR agonists. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats infused with Ang II (120 ng kg(-1) min(-1)) were treated with rosiglitazone (1 or 2 mg kg(-1) day(-1)) alone or concomitantly with fenofibrate (30 mg kg(-1) day(-1)) for 7 days. Thereafter, vessels was assessed on a pressurized myograph, while NAD(P)H oxidase activity was determined by lucigenin chemiluminescence. Inflammation was evaluated using ELISA for NFkappaB and Western blotting for adhesion molecules. KEY RESULTS: Ang II-induced blood pressure increase, impaired acetylcholine-induced vasorelaxation, altered vascular structure, and enhanced vascular NAD(P)H oxidase activity and inflammation were significantly reduced by low dose rosiglitazone+fenofibrate. CONCLUSIONS AND IMPLICATIONS: Combined low doses of PPARalpha and PPARgamma activators attenuated development of hypertension, corrected vascular structural abnormalities, improved endothelial function, oxidative stress, and vascular inflammation. These agents used in low-dose combination have synergistic vascular protective effects. The clinical effects of combined low-dose PPARalpha and PPARgamma activators as vascular protective therapy, potentially with reduced side-effects and drug interactions, should be assessed.
Assuntos
Angiotensina II/farmacologia , Vasos Sanguíneos/efeitos dos fármacos , Hipertensão/tratamento farmacológico , PPAR alfa/efeitos dos fármacos , PPAR gama/efeitos dos fármacos , Animais , Pressão Sanguínea/efeitos dos fármacos , Vasos Sanguíneos/patologia , Sinergismo Farmacológico , Hipertensão/patologia , Masculino , NADPH Oxidases/sangue , PPAR alfa/fisiologia , PPAR gama/fisiologia , Ratos , Ratos Sprague-DawleyRESUMO
The majority of apolipoprotein (a) [apo(a)] in plasma is characteristically associated with Lipoprotein (a) [Lp(a)], having a buoyant density (1.05-1.08 g/ml) intermediate between low density lipoproteins (LDL) and high density lipoproteins (HDL). In the fed (postprandial) state or in the presence of fasting (endogenous) hypertriglyceridemia, a small proportion of plasma apo(a) is found in the density < 1.006 g/ml fraction of plasma, associated with larger and less dense triglyceride-rich lipoproteins (TRL). In order to further characterize the presence of apo(a) in ultracentrifugally-separated TRL (UTC-TRL), this lipoprotein fraction was isolated from plasma obtained in the fed state (three hours after an oral fat load) from healthy normolipidemic subjects (Lp(a): 38 +/- 8 mg/dl (mean +/- S.E.), n = 4) and also from plasma obtained after an overnight fast from hypertriglyceridemic patients (plasma TG: 8.16 +/- 2.00 mmol/l, Lp(a): 41 +/- 3 mg/dl, n = 18). Apo(a) in 3 h-postprandial UTC-TRL (5 +/- 2% of total plasma apo(a)) and in hypertriglyceridemic UTC-TRL (8 +/- 2% total apo(a)) was separable by electrophoresis and/or gel chromatography (FPLC) from the majority of UTC-TRL lipid. Apo(a) in UTC-TRL fractions had slow pre-beta electrophoretic mobility and was isolated in a lipoprotein size-range smaller than VLDL and larger than LDL, consistent with it being Lp(a). Recentrifugation of UTC-TRL resulted in the majority of apo(a) being recovered in the density > 1.006 g/ml fraction. Addition of proline to plasma samples before ultracentrifugation (final concentration: 0.1 M) substantially reduced the amount of Lp(a) in UTC-TRL. TRL separated from plasma by FPLC contained less apo(a) (2-5% of total plasma apo(a)), but this apo(a) was also readily dissociable from TRL lipid, had slow pre-beta electrophoretic mobility, and was associated with a lipoprotein with the size of Lp(a). Our data suggest that apo(a) in the TRL fraction of subjects with postprandial triglyceridemia or endogenous hypertriglyceridemia is not an integral component of plasma VLDL or chylomicrons, but represents the presence of non-covalently bound Lp(a).
Assuntos
Apolipoproteínas A/sangue , Lipoproteína(a)/sangue , Lipoproteínas/sangue , Triglicerídeos/sangue , Adulto , Ácido Aminocaproico/farmacologia , Cromatografia em Gel , Cromatografia Líquida , Gorduras na Dieta/administração & dosagem , Eletroforese em Gel de Ágar , Eletroforese em Gel de Poliacrilamida , Feminino , Humanos , Hipertrigliceridemia/sangue , Lipídeos/sangue , Lipoproteínas/química , Masculino , Pessoa de Meia-Idade , Prolina/farmacologia , UltracentrifugaçãoRESUMO
A great number of epidemiological studies have demonstrated that the frequency of the epsilon4 allele of the apolipoprotein E gene (APOE) is markedly higher in sporadic and in familial late onset Alzheimer disease (AD). In the frontal cortex of AD patients, oxidative damage is elevated. We address the hypothesis that the APOE genotype and reactive oxygen-mediated damage are linked in the frontal cortex of AD patients. We have related the APOE genotype to the levels of lipid oxidation (LPO) and to the antioxidant status, in frontal cortex tissues from age-matched control and AD cases with different APOE genotypes. LPO levels were significantly elevated in tissues from Alzheimer's cases which are homozygous for the epsilon4 allele of APOE, compared to AD epsilon3/epsilon3 cases and controls. Activities of enzymatic antioxidants, such as catalase and glutathione peroxidase (GSH-PX), were also higher in AD cases with at least one epsilon4 allele of APOE, while superoxide dismutase (SOD) activity was unchanged. In the frontal cortex, the concentration of apoE protein was not different between controls and AD cases, and was genotype independent. The Ginkgo biloba extract (EGb 761), the neurosteroid dehydroepiandrosterone (DHEA) and human recombinant apoE3 (hapoE3rec) were able to protect control, AD epsilon3/epsilon3 and epsilon3/epsilon4 cases against hydrogen peroxide/iron-induced LPO, while hapoE4rec was completely ineffective. Moreover, EGb 761 and DHEA had no effect in homozygous epsilon4 cases. These results demonstrate that oxidative stress-induced injury and protection by antioxidants in the frontal cortex of AD cases are related to the APOE genotype.
Assuntos
Doença de Alzheimer/metabolismo , Antioxidantes/farmacologia , Apolipoproteínas E/genética , Encéfalo/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais , Idoso , Doença de Alzheimer/genética , Apolipoproteínas E/metabolismo , Desidroepiandrosterona/farmacologia , Desidroepiandrosterona/uso terapêutico , Feminino , Flavonoides/farmacologia , Flavonoides/uso terapêutico , Sequestradores de Radicais Livres/farmacologia , Genótipo , Ginkgo biloba/uso terapêutico , Glutationa/metabolismo , Glutationa Peroxidase/metabolismo , Humanos , Peróxido de Hidrogênio/farmacologia , Ferro/farmacologia , Peroxidação de Lipídeos/genética , Masculino , Fitoterapia , Plantas Medicinais , Proteínas Recombinantes/farmacologiaRESUMO
Multiviriate analysis of epidemiological data has often shown that elevated plasma triglyceride (TG) concentration is not an independent risk factor for coronary heart disease (CHD). However, more recently, subgroup- and meta-analyses have supported an independent association between TG and CHD. The strength of TG to predict the CHD lies in its ability to reflect the presence of atherogenic plasma TG-rich lipoprotein (TRL) remnants. Clinical evidence for the potential atherogenicity of TRL is provided by patients with type III hyperlipoproteinaemia, hepatic lipase deficiency or apolipoprotein E deficiency, who have marked increase in plasma remnant lipoproteins and an increased incidence of CHD. Indirect evidence suggests that the presence of a single epsilon 2 allele may have atherogenic potential by influencing plasma remnant accumulation in the presence of a second environmental or genetic factor. Recent studies have also indicated that the magnitude of postprandial triglyceridaemia is a significant predictor of CHD. Emerging data from angiographic intervention trials have implicated TRL in atherosclerotic disease progression independently of low-density lipoproteins (LDL). Thus, in hypertriglyceridaemic patients, physicians should conduct a thorough clinical evaluation, a family survey, an assessment of associated risk factors and a complete analysis of the plasma lipoprotein profile, in order to assess the atherogenic potential of this hyperlipidaemia.
Assuntos
Doença das Coronárias/etiologia , Triglicerídeos/sangue , Animais , Doença das Coronárias/sangue , Doença das Coronárias/epidemiologia , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Incidência , Análise Multivariada , Fatores de RiscoRESUMO
Pseudo type III (PT-III) dyslipoproteinemia is characterized by a plasma accumulation of triglyceride-rich lipoproteins (TRL) and their remnants. It mimics type III, but its etiology can not be ascribed to a genetic apo E defect. In order to determine whether PT-III is associated with a genetic lipoprotein receptor abnormality, we have measured (in cultured fibroblasts from affected and nonaffected individuals) the in vitro activity of three lipoprotein receptors which are implicated in the catabolism of TRL, namely the low-density lipoprotein receptor (LDL-R), the lipoprotein receptor-related protein (LRP) and the lipolysis-stimulated receptor (LSR). Specific cell association and degradation of 125I-LDL by LDL-R-upregulated PT-III fibroblasts was not significantly different from that of control cells (103 +/- 10% and 98 +/- 17% of controls; 20 microg/ml 125I-LDL). Specific cell association and degradation of rabbit 125I-beta-VLDL was also not significantly different. LRP activity was assessed by measuring the ability of PT-III and control cells to bind three different LRP ligands: activated alpha2-macroglobulin (alpha2M-MA), lactoferrin and apo E-enriched rabbit beta-VLDL. No significant differences were observed (24.0 +/- 2.1 vs. 23.4 +/- 5.7 fmol/mg for 5 nM of 125I-alpha2M-MA; 4.8 +/- 0.3 vs. 5.2 +/- 1.3 microg/mg for 20 microg/ml of 125I-lactoferrin; 319.4 +/- 51.2 vs. 309.5 +/- 23.2 ng/mg for 5 microg/ml of 125I-beta-VLDL, PT-III vs. control, respectively). LSR activity, as assessed by the cell association or degradation of 125I-LDL by fibroblasts in the presence of 0.5 mM oleate and human leptin, was also not different. No evidence was obtained for deficient cellular recognition of PT-III TRL (d < 1.006 g/ml) by normal human fibroblasts or mouse macrophages. These results suggest that PT-III dyslipoproteinemia is not due to an accumulation in plasma of poorly recognized TRL, nor due to a genetic defect in LDL-R, LRP or LSR.
Assuntos
Fibroblastos/metabolismo , Hiperlipoproteinemias/metabolismo , Receptores Imunológicos/metabolismo , Receptores de LDL/metabolismo , Animais , Arteriosclerose/etiologia , Arteriosclerose/metabolismo , Células Cultivadas , Quilomícrons/metabolismo , Humanos , Hipercolesterolemia/etiologia , Hipercolesterolemia/metabolismo , Hiperlipoproteinemias/classificação , Hiperlipoproteinemias/complicações , Hiperlipoproteinemias/genética , Hipertrigliceridemia/etiologia , Hipertrigliceridemia/metabolismo , Fígado/metabolismo , Proteína-1 Relacionada a Receptor de Lipoproteína de Baixa Densidade , Macrófagos/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , Coelhos , Receptores Imunológicos/genética , Receptores de LDL/genéticaRESUMO
Rats fed a high-cholesterol semipurified diet containing casein developed higher levels of serum cholesterol than soy-fed animals. The hypercholesterolaemia of casein-fed rats was due to accumulation of very low density lipoproteins (VLDL), as measured by increased concentrations of serum VLDL cholesterol, protein and apoprotein B. High density lipoprotein (HDL) cholesterol was similar for the two dietary groups. Cholesterol absorption, as measured by the dual isotope ratio method and by direct measurement of cholesterol secretion into thoracic duct lymph, did not differ between the two groups. Cholesterol kinetics were derived from plasma cholesterol specific radioactivity curves and the casein-fed rats had a similar rate of plasma cholesterol production, but a significantly lower plasma cholesterol fractional catabolic rate (FCR) compared with the soy-fed rats. Kinetics of plasma VLDL apoprotein B, derived from analysis of reinjected 125I-labelled VLDL protein, also showed a lower fractional catabolic rate with casein feeding. This suggests that the accumulation of VLDL in the plasma of rats fed dietary casein is not due to excess VLDL production but to deficient VLDL removal. The hypercholesterolaemia appears to be a consequence of diminished VLDL catabolism.
Assuntos
Caseínas/administração & dosagem , Colesterol/sangue , Proteínas Alimentares/administração & dosagem , Glycine max , Hipercolesterolemia/sangue , Lipoproteínas VLDL/sangue , Proteínas de Plantas/administração & dosagem , Animais , Colesterol na Dieta/administração & dosagem , Cinética , Lipoproteínas/sangue , Lipoproteínas HDL/sangue , Lipoproteínas IDL , Lipoproteínas LDL/sangue , Linfa/metabolismo , Masculino , Ratos , Ratos EndogâmicosRESUMO
The effect of fenofibrate (FEN), compared with placebo (PL), on total plasma homocysteine (tHcy) levels in the fasted and fed states has been examined. Twenty men with established coronary artery disease (CAD) or with at least two cardiovascular risk factors, who had elevated plasma triglyceride levels (> 2.3 mmol/l) and reduced HDL-C levels (< 0.91 mmol/l), and in whom a fibric acid derivative was clinically indicated were studied. The study was a randomized, PL controlled, double-blind study designed to test the effect of micronized FEN on postprandial lipemia. Plasma tHcy levels were investigated as a post-hoc analysis. After a 4-week dietary stabilization period, patients were randomized to PL or FEN (200 mg/day) for 8 weeks, followed by an 8-h postprandial study, consisting of 1 g fat/kg body weight (35% cream). The methionine content of cream was approximately 0.53 mg/ml. A 5-week washout period was then followed by a second 8-week treatment period (FEN or PL), at the end of which a second postprandial study was undertaken. Blood was sampled in the fasted state (0 h) and postprandially at 2, 4, 6 and 8 h. Plasma was stored at -80 degrees C for homocysteine, vitamins B(6), B(12) and folate measurements. FEN caused a marked decrease in all triglyceride-rich lipoprotein parameters, no change in LDL-C, and an increase in HDL-C levels. Fen treatment was associated with an increase in fasting tHcy (PL: 10.3+/-3.3 micromol/l to FEN: 14.1+/-3.8 micromol/l, 40.4+/-20.5%, P < 0.001) and fed tHcy levels 6 h post-fat load (PL: 11.6+/-3.3 micromol/l vs. FEN: 17.1+/-5.4 micromol/l, P < 0.001). Homocysteine levels were increased by the fat load; PL: 14% (P < 0.001) and FEN: 21%, P < 0.001 at the 2, 4, 6 and 8 h time points. Change in tHcy level on FEN was not associated with changes in plasma levels of folate, vitamins B(6) or B(12) or creatinine. Amino acid analysis revealed that methionine and cysteine were significantly increased on FEN (P < 0.005). The incidence of hyperhomocysteinemia (defined as tHcy level >14 micromol/l) was PL: 2/20 (10%) and FEN: 9/20 (45%) (chi(2) = 4.51, P = 0.034). There was no correlation between changes in plasma triglyceride levels and tHcy levels. Since tHcy is considered an emerging cardiovascular risk factor, the ability of FEN to increase plasma tHcy levels could potentially mitigate the potential of this drug to protect against cardiovascular disease.
Assuntos
Fenofibrato/efeitos adversos , Hiper-Homocisteinemia/induzido quimicamente , Hipolipemiantes/efeitos adversos , Adulto , Doença da Artéria Coronariana/complicações , Doença da Artéria Coronariana/epidemiologia , Laticínios , Gorduras na Dieta/farmacologia , Método Duplo-Cego , Ingestão de Alimentos , Jejum/sangue , Humanos , Hipertrigliceridemia/sangue , Hipertrigliceridemia/complicações , Hipertrigliceridemia/tratamento farmacológico , Lipídeos/sangue , Masculino , Metionina/farmacocinética , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
In order to quantitate the contribution of triglyceride-rich lipoprotein (TRL) apolipoprotein(a) to total plasma apo(a) concentration in the fed and fasted states, we have studied a group of 20 male subjects (age 49 +/- 3 years) with fasting apo(a) concentrations varying from 39 to 1385 U/l. After a 12-h overnight fast, each subject was given a fat-rich meal (1 g fat/kg body weight) and venous blood samples were obtained at hourly intervals for 10 h. TRL were isolated from bihourly plasma samples by ultracentrifugation (d less than 1.006 g/ml) and apo(a) was measured by radioimmunoassay. Total plasma apo(a) concentration did not change after the meal. However, TRL apo(a) increased significantly (0 h: 3 +/- 1, 4 h: 30 +/- 7 U/l; p less than 0.001) and 'd greater than 1.006' apo(a) decreased (0 h: 267 +/- 56, 4 h: 231 +/- 50 U/l; P less than 0.05). Similar postprandial changes were observed in apoB concentration (TRL apo B at 0 h: 10.3 +/- 1.5, 4 h: 13.6 +/- 1.7 g/l, P less than 0.001, 'd greater than 1.006' apoB at 0 h: 118 +/- 7, 4 h: 110 +/- 7 g/l, P less than 0.001). In the fasted state 2.0 +/- 1.0% and in the fed state (4 h postprandially) 16.0 +/- 4.6% of total plasma apo(a) was found in the TRL fraction. Eleven subjects had less than 10% of total apo(a) in TRL, 5 had 25% or more apo(a) in TRL in the fed state. Postprandial increase in TRL apo(a) was significantly correlated (r = 0.75, P less than 0.001) with increase in plasma triglycerides. TRL apo(a) concentration in the fed state was not correlated with total fasting cholesterol, triglyceride, apo(a) or HDL cholesterol concentration. We conclude that in some individuals, TRL apo(a) makes a significant contribution to total plasma apo(a) concentration in the fed state.
Assuntos
Apolipoproteínas A/análise , Gorduras na Dieta/administração & dosagem , Lipoproteínas/sangue , Adulto , Idoso , Apolipoproteínas B/sangue , Colesterol/sangue , Jejum/sangue , Humanos , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
Remnant-like particle (RLP) lipid and apolipoprotein (apo) levels were determined in the plasma of normolipidemic and hyperlipidemic subjects, in order to investigate the relationship between RLP levels and the concentration of other plasma lipoprotein parameters. Plasma RLP fractions were isolated with the use of an immunoaffinity gel (RLP-Cholesterol Jimro II, Japan Immunoresearch Lab.), containing specific anti-apoB-100 and anti-apoA-I antibodies. Four groups of human subjects were selected, who had either matching or significantly different levels of plasma triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C): (1) normolipidemic control (NC) subjects (n = 10), (2) patients with elevated levels of LDL-C (type IIa, LDL-C (mean +/- S.E.), 4.65 +/- 0.09 mmol/l, n = 10), (3) hypertriglyceridemic (HTG) patients with elevated LDL-C (type IIb, TG: 3.86 +/- 0.36; LDL-C: 4.67 +/- 0.21 mmol/l, n = 10), and (4) HTG patients with normal LDL-C (type IV, TG: 3.71 +/- 0.39 mmol/l, n = 10). NC subjects (RLP-C: 0.22 +/- 0.01; RLP-TG: 0.24 +/- 0.03 mmol/l) had RLP apoB, apoC-III and apoE levels of 3.2 +/- 0.3, 1.8 +/- 0.3, and 1.4 +/- 0.1 mg/dl, representing 3.2 +/- 0.4, 14.5 +/- 1.4 and 32.1 +/- 2.1% of total plasma levels, respectively. RLP lipid and apolipoprotein concentrations were significantly higher in HTG groups (type IIb and IV) compared to NTG groups (NC and type IIa) (e.g. RLP-C: 0.50 +/- 0.07 and 0.58 +/- 0.11 vs. 0.22 +/- 0.01 and 0.21 +/- 0.01 mmol/l, respectively (P < 0.01); RLP apoB: 8.4 +/- 1.6 and 8.2 +/- 0.9 vs. 3.2 +/- 0.3 and 3.4 +/- 0.2 mg/dl, respectively (P < 0.01)). No significant difference in RLP levels was observed between groups having different LDL levels, and thus no correlation existed between RLP-C and LDL-C levels (r = 0.24, n.s.). RLP-C and RLP apoB levels were, however, correlated with VLDL-C and VLDL apoB (r = 0.86, P < 0.001 and r = 0.70, P < 0.001, respectively). These results demonstrate that elevated levels of both RLP lipids and apolipoproteins are characteristic of patients with increased levels of plasma triglyceride, and not patients with increased levels of LDL.
Assuntos
Apolipoproteínas/sangue , Colesterol , Hiperlipidemias/sangue , Lipoproteínas/sangue , Triglicerídeos/sangue , Adulto , Índice de Massa Corporal , Humanos , Lipoproteínas LDL/sangue , Masculino , Valores de ReferênciaRESUMO
Tangier disease (TD), caused by mutations in the gene encoding ATP-binding cassette 1 (ABCA1), is a rare genetic disorder in which homozygotes have a marked deficiency of high density lipoproteins (HDL), as well as concentrations of low density lipoproteins (LDL) that are typically 40% of normal. Although it is well known that the reduced levels of HDL in TD are due to hypercatabolism, the mechanism responsible for the low LDL levels has not been defined. Recently, it has been reported that intestinal cholesterol absorption is altered in ABCA1 deficient mice, suggesting that aberrant cholesterol metabolism may contribute to the LDL reductions in TD. In order to explore this possibility, as well as to define the role that ABCA1 plays in the metabolism of apolipoprotein (apoB)-containing lipoproteins, we determined the kinetics of apoB-100 within lipoproteins, and cholesterol absorption, biosynthesis, and turnover, in a compound heterozygote for TD. The levels of HDL cholesterol, LDL cholesterol and LDL apoB-100 in this subject were 7, 27 and 69% of normal, respectively, the latter of which was due to a two-fold increase in LDL catabolism (0.54 vs. 0.26+/-0.07 poolsday(-1)) relative to controls (n=11). NMR analysis of plasma lipoproteins revealed that 91% of the LDL cholesterol in the TD subject was contained within small, dense LDL, as compared with only 20% for controls (n=70). Cholesterol absorption was 97% of the value for controls (n=15) in the TD subject, at 45%, with cholesterol synthesis and turnover increased modestly by 17 and 25%, respectively. Our data are consistent with the concept that the reductions of LDL observed in TD are due to enhanced catabolism, secondary to changes in LDL composition and size, with neither cholesterol absorption nor metabolism significantly influenced by mutations in ABCA1.
Assuntos
Apolipoproteínas B/metabolismo , Colesterol/metabolismo , Doença de Tangier/metabolismo , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/genética , Idoso , Apolipoproteína B-100 , LDL-Colesterol/metabolismo , Heterozigoto , Homozigoto , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Doença de Tangier/genéticaRESUMO
Cardiovascular risk factors have traditionally been divided into 2 categories: modifiable risk factors (smoking, hypertension, elevated cholesterol, reduced high density lipoprotein cholesterol, and diabetes), and nonmodifiable risk factors (age, gender, and hereditary factors). However, more recent data indicate clustering of several metabolic and familial factors that are often related to each other. A pattern of lipoprotein abnormalities characterized by increased hepatic production of apolipoprotein B-containing lipoprotein particles, high blood pressure, visceral obesity, and peripheral insulin resistance are identified with increasing frequency in subjects with premature coronary artery disease (CAD). The metabolic substrates for many such disorders are being uncovered, and genetic analysis of affected kindred have, often with conflicting results, suggested associations with candidate genes. In the context of a multifactorial approach, aggressive treatment of lipoprotein disorders in high-risk individuals, or in the secondary prevention of cardiovascular diseases, has resulted in a decreased rate of progression of CAD and a marked reduction in clinical events. Further work in the field of hemostatic factors has shown that fibrinogen, activated coagulation factor VII, spontaneous platelet aggregation, and elevated levels of plasminogen activator inhibitor-1 (PAI-1), are all associated with CAD. There is a strong association between lipids (especially triglyceride-rich lipoproteins) and fibrinogen, PAI-1, and activation of factor VII. In addition, vascular function, especially endothelial cell physiology, has been shown to be compromised in the presence of multiple risk factors and to be improved with intensive therapy aimed at reducing risk factors, especially plasma lipoprotein levels. The implications for clinical practice are important. In the primary prevention of cardiovascular disease, proper risk stratification must be carried out with specific attention given to lifestyle changes. Cessation of smoking and changes in diet (both qualitative and quantitative), exercise, and serenity are often required. In the prevention of cardiovascular disease in subjects at high risk, or in the secondary prevention of CAD, a clear justification exists for aggressive lifestyle changes, often coupled with lipid-lowering therapy and adequate blood pressure control. Basic research is providing us with a better understanding of the molecular interactions between lipoproteins and hemostatic factors. It is becoming increasingly necessary to develop novel pharmaceutical agents with the combined ability to reduce atherogenic lipoprotein levels while also reducing susceptibility to thrombosis.
Assuntos
Doença das Coronárias/epidemiologia , Hiperlipoproteinemias/epidemiologia , Adulto , Fatores de Coagulação Sanguínea/fisiologia , Análise por Conglomerados , Doença das Coronárias/genética , Doença das Coronárias/metabolismo , Doença das Coronárias/prevenção & controle , Progressão da Doença , Feminino , Humanos , Hipercolesterolemia/epidemiologia , Hipercolesterolemia/genética , Hipercolesterolemia/metabolismo , Hipercolesterolemia/prevenção & controle , Hiperlipoproteinemias/genética , Hiperlipoproteinemias/metabolismo , Hiperlipoproteinemias/prevenção & controle , Estilo de Vida , Lipoproteínas/sangue , Masculino , Pessoa de Meia-Idade , Prevenção Primária , Fatores de RiscoRESUMO
The SHR/N-corpulent rat is a new genetically obese strain that is both hyperlipidemic and diabetic. The high density lipoprotein (HDL) fraction from 12-week-old obese males contained significantly greater amounts of protein (+83%), free (+72%) and esterified (+76%) cholesterol, phospholipid (+94%), and triglyceride (+78%). HDL from obese rats were also enriched in C apolipoproteins (apo C-III0 and apo C-III3) but had similar relative amounts of both apo A-I and apo E compared to HDL from their lean littermates. HDL protein turnover, measured with 125I-labeled HDL, showed that obese rats had a smaller fractional catabolic rate (FCR) than lean rats, but due to their much larger HDL pool size, they had a significantly higher rate of HDL protein catabolism (obese, 1.98 +/- 0.07 mg/whole animal/h v lean, 1.32 +/- 0.05 mg/whole animal/h). Therefore, under steady-state conditions, HDL protein production must also have been increased in the obese animals. To determine whether the increased catabolism of HDL protein was associated with increased catabolism of cholesteryl ester (CE), tissue uptake of HDL CE was measured using the nonhydrolyzable ether analogue [3H]cholesteryl linoleyl ether. After four hours 41.6 +/- 1.6% of the injected dose was cleared from the plasma of lean rats compared with 37.0 +/- 1.1% from the plasma of obese rats.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Diabetes Mellitus/metabolismo , Hiperlipidemias/metabolismo , Lipoproteínas HDL/metabolismo , Obesidade , Animais , Apolipoproteínas/sangue , HDL-Colesterol/metabolismo , Complicações do Diabetes , Modelos Animais de Doenças , Eletroforese em Gel de Poliacrilamida , Hiperlipidemias/complicações , Fígado/metabolismo , Taxa de Depuração Metabólica , RatosRESUMO
The distribution of apolipoprotein C-III (apoC-III) between high-density lipoprotein (HDL) and apoB-containing lipoproteins has been used in lipid-lowering angiographic trials to establish a link between impaired triglyceride (TG)-rich lipoprotein (TRL) metabolism and the progression of coronary artery disease. To investigate the extent to which plasma lipoprotein apoC-III levels reflect the presence in plasma of potentially atherogenic remnant lipoproteins, we studied 4 groups of subjects: (1) normolipidemic (NL, n = 10), (2) hypercholesterolemic (HC, type IIa, low-density lipoprotein cholesterol [LDL-C] > 3.4 mmol/L, n = 10), (3) hypertriglyceridemic (HTG, type IV, TG > 2.3 mmol/L, n = 10), and (4) combined hyperlipidemic (CHL, type IIb, TG > 2.3 mmol/L, LDL-C > 3.4 mmol/L, n = 10). The apoC-III level was measured in plasma lipoproteins separated either by density (ultracentrifugation) or by size (fast protein liquid chromatography [FPLC]), and was compared with 4 parameters reflecting remnant lipoprotein levels (ie, very-low-density lipoprotein cholesterol [VLDL-C], intermediate-density lipoprotein cholesterol [IDL-C], remnant-like particle cholesterol [RLP-C], and intermediate-sized lipoprotein [ISL] apoE). Our results demonstrate that (1) increased amounts of apoC-III associated with plasma VLDL, TRL, or apoB-containing lipoproteins (LpB), as well as increased levels of TRL remnant lipoproteins, are a characteristic of HTG patients rather than patients with increased LDL, and (2) plasma levels of apoC-III in VLDL, TRL, or LpB, as well as the HDL apoC-III to LpB apoC-III ratios, are strongly correlated with circulating levels of TRL, although these apoC-II parameters more closely reflect the balance between TRL TG production and lipolysis than the extent of plasma TRL remnant accumulation.
Assuntos
Apolipoproteínas C/sangue , Hiperlipidemias/sangue , Lipoproteínas/sangue , Adulto , Apolipoproteína C-III , Apolipoproteínas C/metabolismo , Humanos , Hiperlipidemias/metabolismo , Lipoproteínas/metabolismo , Lipoproteínas HDL/sangue , Lipoproteínas LDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Triglicerídeos/sangueRESUMO
We investigated postprandial vitamin A metabolism by measuring retinyl ester, triglyceride, and apolipoprotein (apo)B-48 in the plasma lipoproteins of human subjects before and after fat-feeding. Following a 14-hour fast, eight healthy subjects (two men, six women, 28 to 79 years) were given a fat-rich meal (1 g fat/kg body weight) containing vitamin A (40 retinol equivalents per kilogram body weight). Blood was collected every 3 hours for 12 hours and lipoproteins were isolated by sequential ultracentrifugation. Mean plasma retinyl ester concentration peaked 6 hours after the fat-rich meal, whereas mean plasma triglyceride peaked at 3 hours. Data obtained from hourly samples in 3 subjects showed that changes in the postprandial plasma concentration of retinyl ester occurred 1 to 2 hours after changes in the plasma triglyceride concentration. In triglyceride-rich lipoproteins (TRL) of d less than 1.006 g/mL, retinyl ester similarly peaked at 6 hours, whereas triglyceride as well as apoB-48 peaked at 3 hours. Although retinyl esters were found mainly in TRL in the initial postprandial period (84%, 3 hours; 83%, 6 hours), in fasting and postprandial plasma, particularly 9 or more hours after fat-feeding, a large percentage of plasma retinyl esters were in low-density lipoproteins (LDL) (44%, fasting; 9%, 3 hours; 9%, 6 hours; 19%, 9 hours; 32%, 12 hours). A small percentage of retinyl esters were also found in postprandial high-density lipoproteins (HDL) (2% to 7%). ApoB-48 was not detected in LDL of fasting or postprandial plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Biomarcadores/sangue , Quilomícrons/sangue , Ingestão de Alimentos , Absorção Intestinal , Lipoproteínas/sangue , Vitamina A/sangue , Adulto , Idoso , Apolipoproteínas E/sangue , Colesterol/sangue , Feminino , Humanos , Cinética , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Triglicerídeos/sangue , Vitamina A/análogos & derivadosRESUMO
Plasma triglyceride concentration in human subjects peaks once, twice or three times in the twelve-hour period following the ingestion of a fat-rich meal. Triglyceride-rich lipoproteins (TRL) containing apolipoprotein (apo)B-48 (of intestinal origin), and TRL containing apoB-100 (predominantly of hepatic origin) both contribute to postprandial changes in plasma triglyceride concentration. To test the hypothesis that earlier peaks in postprandial triglyceridemia are due predominantly to the secretion of TRL from the intestine, while later peaks are due to the secretion of TRL from the liver, TRL apoB-48, TRL apoB-100 and retinyl ester (a marker of intestinal lipoproteins) were measured in plasma samples from subjects fed a fat-rich meal (1 g fat/kg body wt). Data from seven subjects (four fed 40 retinol equivalents vitamin A/kg body wt, three fed 20 retinol equivalents vitamin A/kg body wt, with the fat meal), showed that postprandial peaks in plasma triglyceride were always associated with increases in plasma retinyl ester concentration. In four subjects, who were selected because they had two clearly defined postprandial triglyceride peaks, the plasma concentration of TRL triglyceride, apoB-48, apoE and apoC increased in conjunction with both the earlier (three hour) and later (nine hour) peaks in plasma triglyceride. Increase in TRL apoB-100 was associated with both peaks in two of the four subjects. Our data suggest that 1) TRL from the liver and intestine contribute to both earlier and later peaks in postprandial triglyceridemia; and 2) the rate of appearance of TRL from the intestine is not constant after dietary fat absorption.
Assuntos
Ingestão de Alimentos , Mucosa Intestinal/metabolismo , Lipoproteínas/fisiologia , Fígado/metabolismo , Triglicerídeos/metabolismo , Adulto , Idoso , Apolipoproteína B-48 , Apolipoproteínas B/sangue , Diterpenos , Feminino , Humanos , Lipoproteínas/metabolismo , Masculino , Pessoa de Meia-Idade , Concentração Osmolar , Ésteres de Retinil , Triglicerídeos/sangue , Vitamina A/análogos & derivados , Vitamina A/sangueRESUMO
The epsilon4 allele of apolipoprotein E (apoE) is associated with increased risk for the development of Alzheimer's disease (AD), possibly due to interactions with the beta-amyloid (Abeta) protein. The mechanism by which these two proteins are linked to AD is still unclear. To further assess their potential relationship with the disease, we have determined levels of apoE and Abeta isoforms from three brain regions of neuropathologically confirmed AD and non-AD tissue. In two brain regions affected by AD neuropathology, the hippocampus and frontal cortex, apoE levels were found to be decreased while Abeta(1-40) levels were increased. Levels of apoE were unchanged in AD cerebellum. Furthermore, levels of apoE and Abeta(1-40) were found to be apoE genotype dependent, with lowest levels of apoE and highest levels of Abeta(1-40) occurring in epsilon4 allele carriers. These results suggest that reduction in apoE levels may give rise to increased deposition of amyloid peptides in AD brain.
Assuntos
Doença de Alzheimer/genética , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Lobo Frontal/metabolismo , Hipocampo/metabolismo , Idoso , Doença de Alzheimer/patologia , Cerebelo/metabolismo , Cerebelo/patologia , Feminino , Lobo Frontal/patologia , Genótipo , Hipocampo/patologia , Humanos , Masculino , Valores de ReferênciaRESUMO
Major advances have been made in our understanding of the role of apolipoprotein E (apoE) in the onset and development of atherosclerosis. Increasing evidence from both animal and human studies suggests that apoE is able to protect against atherosclerosis by: a) promoting efficient uptake of triglyceride-rich lipoproteins from the circulation; b) maintaining normal macrophage lipid homeostasis; c) playing a role in cellular cholesterol efflux and reverse cholesterol transport; d) acting as an antioxidant; e) inhibiting platelet aggregation; and f) modulating immune function. In humans, apoE is polymorphic, and this genetic variation has a strong effect on its antiatherogenic characteristics. Thus, compared to the epsilon3 allele, the epsilon4 allele promotes atherosclerosis, whereas the epsilon2 allele is either pro- or anti-atherogenic, depending on the influence of both environmental and genetic factors. ApoE and its gene are prime targets for therapeutic intervention aimed at preventing or treating atherosclerotic vascular disease.