RESUMEN
BACKGROUND: The most rapid phase of brain development occurs during the neonatal period. Vitamin A (VA; retinol) is critical for many aspects of this process, including neurogenesis, synaptic plasticity, learning, and memory formation. However, the metabolism of retinol in the neonatal brain has not been extensively explored. OBJECTIVE: We examined the uptake of VA into the brain in neonatal rats raised under VA-marginal conditions (control group) and assessed the effect of VA supplementation on the uptake of VA into the brain. METHODS: Sprague-Dawley neonatal rats (n = 104) nursed by mothers fed a VA-marginal diet were randomly assigned and treated on postnatal day 4 with an oral dose of either VA (6 µg retinyl palmitate/g body weight) or canola oil as the control, both of which contained 1.8 µCi [(3)H]retinol. Pups (n = 4/group at a time) were killed at 13 sampling times from 30 min to 24 d after dosing. The uptake of total retinol, chylomicron-associated retinyl esters (REs), and retinol bound to retinol-binding protein (RBP) was estimated with the use of WinSAAM version 3.0.8. RESULTS: Total retinol mass in the brain was closely dependent on its mass in plasma over time (r = 0.91; P < 0.001). The uptake of retinol into the brain involved both postprandial chylomicrons and RBP, with RBP delivering most of the retinol in the control group [0.27 nmol/d (RBP) compared with 0.01 nmol/d (chylomicrons)]. VA supplementation increased the fractional uptake of chylomicron REs from 0.3% to 1.2% of plasma pool/d, decreased that of RBP retinol from 0.5% to 0.2% of plasma pool/d, and increased the transfer rate of chylomicron REs from nearly zero to 0.7 nmol/d, causing a day-long elevation in the brain mass of total retinol. CONCLUSION: Postprandial chylomicrons may be a primary mechanism for delivering a recently ingested large dose of VA to the brain of neonatal rats raised under VA-marginal conditions.
Asunto(s)
Encéfalo/efectos de los fármacos , Quilomicrones/farmacocinética , Suplementos Dietéticos , Vitamina A/administración & dosificación , Animales , Animales Recién Nacidos , Peso Corporal , Encéfalo/metabolismo , Quilomicrones/sangre , Diterpenos , Relación Dosis-Respuesta a Droga , Femenino , Lipoproteínas/sangre , Masculino , Dinámicas no Lineales , Ratas , Ratas Sprague-Dawley , Proteínas de Unión al Retinol/metabolismo , Ésteres de Retinilo , Vitamina A/análogos & derivados , Vitamina A/sangre , Vitamina A/farmacocinéticaRESUMEN
Disorders of the lipid metabolism may play a role in the genesis of abdominal aorta aneurysm. The present study examined the intravascular catabolism of chylomicrons, the lipoproteins that carry the dietary lipids absorbed by the intestine in the circulation in patients with abdominal aorta aneurysm. Thirteen male patients (72 +/- 5 years) with abdominal aorta aneurysm with normal plasma lipid profile and 13 healthy male control subjects (73 +/- 5 years) participated in the study. The method of chylomicron-like emulsions was used to evaluate this metabolism. The emulsion labeled with 14C-cholesteryl oleate and (3)H-triolein was injected intravenously in both groups. Blood samples were taken at regular intervals over 60 min to determine the decay curves. The fractional clearance rate (FCR) of the radioactive labels was calculated by compartmental analysis. The FCR of the emulsion with (3)H-triolein was smaller in the aortic aneurysm patients than in controls (0.025 +/- 0.017 vs 0.039 +/- 0.019 min-1; P < 0.05), but the FCR of 14C-cholesteryl oleate of both groups did not differ. In conclusion, as indicated by the triglyceride FCR, chylomicron lipolysis is diminished in male patients with aortic aneurysm, whereas the remnant removal which is traced by the cholesteryl oleate FCR is not altered. The results suggest that defects in the chylomicron metabolism may represent a risk factor for development of abdominal aortic aneurysm.
Asunto(s)
Aneurisma de la Aorta Abdominal/metabolismo , Ésteres del Colesterol/farmacocinética , Quilomicrones/farmacocinética , Lipólisis , Trioleína/farmacocinética , Anciano , Aneurisma de la Aorta Abdominal/sangre , Aneurisma de la Aorta Abdominal/etiología , Índice de Masa Corporal , Radioisótopos de Carbono , Estudios de Casos y Controles , Ésteres del Colesterol/administración & dosificación , Quilomicrones/administración & dosificación , Emulsiones , Humanos , Inyecciones Intravenosas , Masculino , Tasa de Depuración Metabólica , Trioleína/administración & dosificaciónRESUMEN
OBJECTIVE: To investigate whether increasing body mass index (BMI) produces increasingly intense disturbances in the metabolism of chylomicrons, the lipoproteins that carry the dietary lipids absorbed by the intestine in the circulation. SUBJECTS: Four groups of 10 normolipidemic nondiabetic women at the normal (BMI<25 kg/m(2)), preobese (BMI 25-30), obese (BMI 30-40) and morbid obese (BMI>40). METHODS: Chylomicron metabolism was studied using the method of triglyceride-rich emulsions that mimic chylomicrons. The chylomicron-like emulsion doubly labeled with (3)H-triolein (TO) and (14)C-cholesteryl-oleate (CO) was intravenously injected to calculate the plasma fractional clearance rates (FCR, in min(-1)) by a compartmental analysis model. FCR-TO mirrors both the lipolysis from lipoprotein lipase that the emulsion suffers while still in the circulation, and the triglycerides portion that is not broken down and is removed from the plasma together with the remnant particles. Lipolysis index is calculated subtracting CO from TO areas under the curve. RESULTS: FCR-TO did not differ among the four groups. The lipolysis index was positively correlated with BMI (r=0.310; P=0.05). On the other hand, FCR-CO progressively diminished from the normal to the morbid obese group (0.069+/-0.01; 0.064+/-0.01; 0.031+/-0.003; 0.029+/-0.005 min(-1), respectively, P=0.003) and there was a negative correlation between FCR-CO and BMI (r=-0.388; P=0.01). CONCLUSION: In obesity, the capacity to break down chylomicron triglycerides by lipoprotein lipase in vivo increases, but the ability of the organism to remove the resulting chylomicron remnants particles progressively diminishes as the BMI rises. Remnant accumulation most likely predisposes to coronary artery disease development.
Asunto(s)
Índice de Masa Corporal , Quilomicrones/farmacocinética , Obesidad/sangre , Adulto , Análisis de Varianza , Apolipoproteínas/análisis , Glucemia/análisis , Radioisótopos de Carbono , Femenino , Humanos , Marcaje Isotópico , Lípidos/sangre , Obesidad/fisiopatología , Curva ROCRESUMEN
BACKGROUND: Lipoatrophic diabetes is characterized by the near absence of adipose tissue and the presence of insulin-resistant diabetes. Fasting hypertriglyceridaemia and increased postprandial lipidaemia are also present, but the metabolism of chylomicrons, the triglyceride-rich lipoproteins in the circulation that carry the dietary fats absorbed by the intestine, was not specifically investigated. Because both the activity of insulin-dependent lipoprotein lipase that catalyses the chylomicron lipolysis and the storage of the lipolysis products are affected in the disease, it is important to evaluate how those changes may ultimately affect the chylomicron lipolysis and removal of chylomicron remnants from the circulation. OBJECTIVE: The aim of the study was to evaluate the chylomicron intravascular metabolism in patients with lipoatrophic diabetes. PATIENTS: Six patients with lipoatrophic diabetes (four females, two males) aged 22.2 +/- 4.4 years, with body mass index (BMI) 21.6 +/- 3.6 kg/m(2), were compared with 12 healthy control subjects (seven females, five males) aged 24.3 +/- 2.1 years with BMI 22.5 +/- 2.7 kg/m(2). MEASUREMENTS: The plasma kinetics of intravenously injected chylomicron-like emulsions labelled with (3)H-triglycerides ((3)H-TG) and with (14)C-cholesteryl esters ((14)C-CE) were determined, the former tracing the chylomicron lipolysis by lipoprotein lipase and the latter the removal of chylomicron remnants from the plasma. RESULTS: Triglyceride values (8.3 +/- 9.2 mmol/l) in the patients were higher (P < 0.005) and high density lipoprotein (HDL) cholesterol values (0.8 +/- 0.2 mmol/l) lower (P < 0.0005) than in controls (0.7 +/- 0.2 and 1.3 +/- 0.4 mmol/l, respectively) whereas total cholesterol, apoprotein B (apo B) and apo A1 were similar. The fractional clearance rate (FCR, in min(-1)) of (3)H-TG was 0.014 +/- 0.016 and the FCR of (14)C-CE was 0.008 +/- 0.012 in the patients and 0.046 +/- 0.024 and 0.024 +/- 0.012 in the controls, respectively (P < 0.05). Thus FCRs of both emulsion labels were markedly reduced in the patients, indicating that lipolysis and remnant removal were diminished. Diminished remnant removal may be due to either deficient lipolysis or deficient removal mechanisms. CONCLUSION: The metabolism of chylomicrons tested by the emulsion method is impaired in lipoatrophic diabetes.
Asunto(s)
Ésteres del Colesterol/farmacocinética , Quilomicrones/farmacocinética , Diabetes Mellitus Lipoatrófica/metabolismo , Triglicéridos/farmacocinética , Adulto , Radioisótopos de Carbono/farmacocinética , Estudios de Casos y Controles , Emulsiones , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Estadísticas no Paramétricas , Tritio/farmacocinéticaRESUMEN
Slow chylomicron intravascular catabolism has been associated with coronary artery disease and screening for drugs that can speed-up this process can be important. In this study, the effects of etofibrate upon chylomicron metabolism was tested by determination of the plasma kinetics of a chylomicron-like emulsion model in 12 patients with coronary artery disease, aged 59+/-11 years, (total cholesterol: 240+/-41 mg/dl; triglycerides: 188+/-42 mg/dl) submitted to a randomized, crossover, double-blind, placebo-controlled study with administration of 1 g per day etofibrate or placebo for 1-month. A 1-month washout period was inserted between the treatment periods. Patients were intravenously injected a chylomicron-like emulsion doubly labeled with 14C-cholesteryl oleate and 3H-triolein at baseline and after treatments. After etofibrate treatment, there was decrease of total cholesterol and triglyceride plasma levels and a trend to increase high-density lipoprotein cholesterol plasma levels. Etofibrate elicited 62% enhancement of post-heparin lipolytic activity and 100% increase of 3H-triglyceride fractional clearance rate compared with placebo treatment. 14C-cholesterol ester fractional clearance rate was 260% greater after etofibrate than after placebo. Therefore, a potent effect of etofibrate on both chylomicron lipolysis and remnant removal was achieved, indicating that this drug can be used to improve this metabolism in future prospective studies.
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Quilomicrones/farmacocinética , Ácido Clofíbrico/administración & dosificación , Enfermedad Coronaria/sangre , Lipólisis/efectos de los fármacos , Biomarcadores/sangre , Colesterol/sangre , HDL-Colesterol/sangre , Quilomicrones/administración & dosificación , Quilomicrones/efectos de los fármacos , Ácido Clofíbrico/análogos & derivados , Enfermedad Coronaria/tratamiento farmacológico , Estudios Cruzados , Método Doble Ciego , Interacciones Farmacológicas , Emulsiones , Femenino , Humanos , Inyecciones Intravenosas , Masculino , Persona de Mediana Edad , Pronóstico , Triglicéridos/sangreRESUMEN
OBJECTIVE: To evaluate the effects of gemfibrozil upon the intravascular metabolism of chylomicron-like emulsions in endogenous hypertriglyceridemia. METHODS: We evaluated the plasma kinetics of a chylomicron-like emulsion in 39 subjects: 27 hypertriglyceridemics, total cholesterol (TC) expressed as median (%25; %75) 7.47 (6.1; 8.19) mmol/l and plasma triglycerides (TG) 4.28 (3.6; 18.5) mmol/l and in 12 normolipidemics, TC 4.7 (3.85; 5.37) mmol/l and TG 0.91 (0.64; 1.75) mmol/l. Hypertriglyceridemics were evaluated at baseline and after a 30-day 1200-mg/day gemfibrozil (n=8) or placebo treatment (n=7). The emulsion labelled with 14C-cholesteryl oleate (14C-CO) and 3H-triolein (3H-TO) was injected intravenously after a 12-h fast. The plasma kinetics of 3H-TO and 14C-CO were determined to assess, respectively, lipolysis and clearance of chylomicron and remnants by compartmental analysis. RESULTS: The residence times (in minutes) of 3H-TO and 14C-CO of hypertriglyceridemics were roughly twice the values of normolipidemics, i.e. 8.0 (5.5; 12.0) versus 15.0 (11.0; 24.0) and 21.5 (14.0; 33.0) versus 44.0 (32.0; 72.0), P=0.001. Gemfibrozil treatment of hypertriglyceridemic patients reduced the residence times of 3H-TO and 14C-CO, respectively, by 46% (P=0.003) and 53% (P=0.008). Effects were noted on the slow phase of emulsion plasma removal, which was reduced in hypertriglyceridemics. After treatment, the emulsion residence times determined in hypertriglyceridemics attained the values of the normolipidemic group. CONCLUSIONS: Gemfibrozil treatment normalised the defects in chylomicron-like emulsion catabolism observed in endogenous hypertriglyceridemia patients.
Asunto(s)
Quilomicrones/farmacocinética , Gemfibrozilo/uso terapéutico , Hipertrigliceridemia/tratamiento farmacológico , Hipertrigliceridemia/metabolismo , Hipolipemiantes/uso terapéutico , Adulto , Anciano , Apolipoproteínas/sangre , Estudios de Casos y Controles , Colesterol/sangre , Simulación por Computador , Emulsiones Grasas Intravenosas/farmacocinética , Femenino , Humanos , Modelos Lineales , Masculino , Persona de Mediana Edad , Modelos Biológicos , Estadísticas no Paramétricas , Triglicéridos/sangreRESUMEN
The speed of the plasma removal of chylomicrons, the lipoproteins that carry dietary lipids absorbed in the intestine, may influence atherogenesis. Thus, the effects of a 30-day pravastatin or placebo treatment on the plasma kinetics of chylomicron-like emulsions were evaluated in 25 patients with coronary artery disease who were not hypertriglyceridemic in a randomized, single-blinded study. Eleven patients (53 +/- 4 years, 10 men) received pravastatin 40 mg/day and 14 received placebo (52 +/- 3 years, 13 men). Emulsions labeled with triolein ((3)H-TO) and cholesteryl oleate ((14)C-CO) to assess lipolysis and clearance of chylomicron and remnants, respectively, were injected intravenously in a bolus after a 12-hour fast. Blood samples were collected during 60 minutes to determine radio isotope decaying curves and fractional catabolic rates. Subjects were studied at baseline and after the treatment period. Compared with placebo (data expressed as mean +/- SEM), pravastatin treatment increased the (14)C-CO fractional catabolic rates (70 +/- 45% vs 18 +/- 10%, p = 0.01), reduced total cholesterol (-21 +/- 3% vs -3 +/- 2% p = 0.0001), low-density lipoprotein (LDL) cholesterol (-25 +/- 5% vs 4 +/- 6%, p = 0.0001), and apolipoprotein B levels (-22 +/- 3% vs -7 +/- 3% p = 0.01). (3)H-TO fractional catabolic rates, plasma triglycerides, very-low-density lipoprotein (VLDL) cholesterol and high-density lipoprotein (HDL) cholesterol variations did not differ between the groups. The fractional catabolic rate of (14)C-CO was inversely correlated with plasma apolipoprotein B levels (r = -0.7, p = 0.04). This suggests that besides reducing LDL cholesterol, pravastatin also increases chylomicron remnant clearance, with possible antiatherogenic implications.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Quilomicrones/efectos de los fármacos , Enfermedad Coronaria/tratamiento farmacológico , Pravastatina/uso terapéutico , Anticolesterolemiantes/farmacología , Apolipoproteínas B/sangre , Quilomicrones/sangre , Quilomicrones/farmacocinética , Enfermedad Coronaria/sangre , Enfermedad Coronaria/metabolismo , Emulsiones Grasas Intravenosas , Femenino , Humanos , Lípidos/sangre , Lipólisis/efectos de los fármacos , Masculino , Tasa de Depuración Metabólica , Persona de Mediana Edad , Pravastatina/farmacología , Método Simple CiegoRESUMEN
Plasma lipoprotein composition, plasma kinetics of autologous [125I]HDL and the metabolism of iv administered radioactively labelled artificial chylomicrons were studied in postmenopausal women during a control period and after 4 months of oral estradiol-17 beta treatment (1 mg/m2 body surface per day). Drug treatment significantly raised plasma HDL-cholesterol levels (19%) in the fasting state and total apolipoprotein A-I (16%), but did not interfere with triglyceride, VLDL, LDL or apolipoprotein-B values. As compared with the control period, estradiol-17 beta administration significantly slowed down plasma [125I]HDL clearance by about 82% and reduced the delipidation index of the injected artificial chylomicrons by 47% as a consequence of impaired plasma lipolytic activity.