RESUMEN
BACKGROUND: Five apolipoprotein (apo)-defined apoB-containing lipoprotein (Lp) subclasses designated LpB, LpB:C, LpB:E, LpB:C:E and LpA-II:B:C:D:E are present in human plasma. This study was to determine whether these subclasses functioned equally as acceptors of cholesteryl esters (CE) transferred from high-density lipoproteins (HDL) by CE transfer protein in healthy subjects with normal and mildly increased plasma triglyceride (TG) levels. MATERIALS AND METHODS: After 4 h incubation of plasma from 14 subjects at 37 degrees C, apoB-containing lipoproteins were separated from HDL by heparin-Mn++ precipitation and fractionated by immunochemical methods into these five subclasses. The neutral lipid (NL) composition for each subclass was measured by gas chromatography (GC) and compared between 0 h and 4 h. A subclass was considered to be a CE acceptor if its CE content increased more than 5% at 4 h and a non-acceptor if no change was observed. RESULTS: Employing the above definition, TG-rich LpB:C and LpB:E + LpB:C:E functioned as CE acceptors and TG-poor LpB and LpA-II:B:C:D:E as non-acceptors. Both LpB:C and LpB:E + LpB:C:E could only actively accept CE as long as they retained their TG-rich character and displayed neutral lipid profiles similar to those of very low-density lipoproteins (VLDL) and intermediate density lipoproteins (IDL). When, as a result of lipolysis their TG content dropped below 25%, they ceased to function as CE acceptors. In subjects with elevated plasma TG, LpB:C was the dominant CE acceptor, a condition that may have pro-atherogenic consequences. CONCLUSIONS: Among the apoB-containing particles, LpB:C and LpB:C:E + LpB:E functioned as CE acceptors while LpB and LpA-II:B:C:D:E did not.
Asunto(s)
Apolipoproteínas B/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol/metabolismo , Ésteres del Colesterol/metabolismo , Lipoproteínas/química , Adulto , Anciano , Apolipoproteínas B/análisis , HDL-Colesterol/química , Femenino , Humanos , Inmunohistoquímica , Inmunoprecipitación , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
PURPOSE: There has been substantial recent interest in diabetes disease management interventions, guidelines, and care practices. As the vast majority of diabetes care occurs in primary care settings, it makes sense to evaluate current levels of recommended practices in different primary care settings. METHODS: We report on two separate studies that included a combined total of 389 patients seen by over 30 different providers. Three different sets of recommended practices were assessed: (1) the ADA provider recognition measures, (2) the proposed Diabetes Quality Improvement Project measures, and (3) the state of Oregon Population-Based Guidelines for Diabetes. RESULTS: In general, there was only a moderate level of adherence to recommended practices, and adherence was much lower for behavioral or patient-focused practices as contrasted with laboratory tests. There was considerable variability across providers and across different guidelines activities. CONCLUSIONS: Policy and quality improvement implications and future research issues are discussed, including the need for studying different measurement approaches for evaluating guidelines adherence.
Asunto(s)
Diabetes Mellitus/terapia , Manejo de la Enfermedad , Adhesión a Directriz/estadística & datos numéricos , Guías de Práctica Clínica como Asunto , Pautas de la Práctica en Medicina/normas , Atención Primaria de Salud/métodos , Atención Primaria de Salud/normas , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oregon , Indicadores de Calidad de la Atención de Salud , Encuestas y Cuestionarios , Gestión de la Calidad Total , Estados UnidosRESUMEN
Although the transfer of cholesteryl ester (CE) from high-density lipoprotein (HDL) to the apolipoprotein B-containing lipoproteins (very-low-density lipoproteins + low-density lipoproteins) has been shown to be abnormally increased in a number of conditions associated with increased cardiovascular risk, it has not been studied in patients with essential hypertension (EH). To determine whether subjects with EH have increased CE transport, CE transfer (CET) was estimated isotopically and lipoprotein lipid and phospholipid composition determined in a group of 14 untreated normolipidemic (triglycerides 116+/-46, cholesterol 185+/-30, HDL 38+/-10 mg/dl) otherwise healthy ethnically diverse EH subjects. CET was significantly increased in EH subjects compared to a similar group of normotensive controls (EH: k = 0.27+/- 0.09 vs. control k = 0.11+/-0.02: P < 0.01). Lipoprotein concentration and composition were comparable in the two groups and closely resembled that of an age- and sex-matched reference group. The abnormal increase in CET persisted (k = 0.25+/-0.12) after 3 months of treatment with the angiotensin converting enzyme (ACE) inhibitor ramipril without a change in either plasma or lipoprotein lipids. Thus, CET is increased in normolipidemic subjects with EH and is not affected by the ACE inhibitor ramipril.
Asunto(s)
Antihipertensivos/uso terapéutico , Proteínas Portadoras/sangre , Ésteres del Colesterol/sangre , Glicoproteínas , Hipertensión/sangre , Ramipril/uso terapéutico , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Proteínas de Transferencia de Ésteres de Colesterol , Femenino , Humanos , Hipertensión/tratamiento farmacológico , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Masculino , Persona de Mediana EdadRESUMEN
METHODS: Apolipoprotein and apoB- and apoA-containing lipoprotein particle concentrations were determined in 10 athyreotic patients 4 weeks after withdrawal of Synthroid replacement therapy [T4, 0.96 +/- 0.66 microgram mL-1; thyroid-stimulating hormone (TSH), 62.7 +/- 22.8 muIU mL-1] and again 4 weeks after reinstitution of treatment. RESULTS: Thyroid hormone replacement was associated with significant decreases in plasma cholesterol (TC), triglyceride (TG), apolipoprotein B and apolipoprotein C-III (P < 0.01). Both the cholesterol ester-rich LP-B particles and triglyceride-rich LP-Bc particles declined significantly in response to thyroid hormone (LP-B withdrawal 81.6 +/- 24.0 vs. replacement 65.1 +/- 22.0; LP-Bc withdrawal 14.3 +/- 6.0 vs. replacement 10.9 +/- 4.8 mg%, P < 0.01). ApoC-III also decreased in high-density lipoprotein (HDL) (apoC-III-HS), and in very low-density lipoprotein (VLDL) + low-density lipoprotein (LDL) (apoC-III-HP), but this reduction was proportionate so that the apo-C-III-HS/apoC-III-HP ratio, an indirect estimate of the efficiency of lipoprotein lipase (LPL), was unchanged. Apolipoprotein A-I concentrations also decreased significantly (withdrawal 140.7 +/- 27.0 vs. replacement 127.1 +/- 30.0 mg%, P < 0.01) in parallel with the changes in LP-A-I and LP-A-I:A-II particles (LP-A-I withdrawal 35.8 +/- 7.7 vs. replacement 31.5 +/- 6.3; LP-A-I:AII withdrawal 104.9 +/- 20.0 vs. replacement 95.5 +/- 26.0; P < 0.05). CONCLUSION: These findings indicate that thyroid hormone influences the transport not only of both TG-rich and cholesterol-rich apoB-containing lipoprotein particles but also of those that contain apoAI.
Asunto(s)
Apolipoproteínas A/sangre , Apolipoproteínas B/sangre , Tiroxina/farmacología , Colesterol/sangre , HDL-Colesterol/sangre , LDL-Colesterol/sangre , VLDL-Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neoplasias de la Tiroides/cirugía , Tiroidectomía , Tirotropina/sangre , Tiroxina/sangre , Tiroxina/uso terapéutico , Triglicéridos/sangreRESUMEN
IDDM patients treated with conventional subcutaneous insulin have an abnormal increase in cholesteryl ester transfer (CET), the proatherogenic step in reverse-cholesterol transport that results in the enrichment of the apolipoprotein (apo) B-containing lipoproteins (VLDL, LDL) with cholesteryl ester (CE). This disturbance is closely linked to iatrogenic hyperinsulinemia and the nonphysiologic stimulation of lipoprotein lipase (LpL), a physiologic activator of CET, because lowering systemic insulin levels by administering insulin through the intraperitoneal insulin route normalizes LpL and CET. Hyperinsulinemia persists in IDDM patients who undergo successful pancreas-kidney transplantation (PKT) when their allografts are placed in the pelvis and drain into the iliac vein. Therefore, to determine whether hyperinsulinemia promotes CET in this setting, we studied CET, LpL, and insulin levels in 14 euglycemic normolipidemic IDDM PKT patients with near-normal kidney function (creatinine 1.5 +/- 0.4 mg/dl). Consistent with our prediction, the net mass of CE transferred from HDL to VLDL + LDL was significantly increased in the PKT group (P < 0.001) compared with nondiabetic renal transplant patients receiving the same immunosuppressive drugs and healthy control subjects. Both basal and arginine-stimulated insulin levels were increased above the kidney transplant group's levels and correlated with the mass of CE transferred at 2 h (r = 0.71, P < 0.05; r = 0.66, P < 0.05, respectively). Total basal LpL activities, LpL and hepatic triacylglycerol lipase activities, and LpL mass all tended to be higher than levels in healthy control subjects. Consistent with these changes in lipase activity, VLDL particle size was significantly reduced (P < 0.025) compared with that of control subjects. These findings indicate that PKT patients with systemically draining allografts have a persisting profile of potentially atherogenic disturbances in insulin levels, LpL, and CET that resemble IDDM patients treated with conventional subcutaneous insulin injections.
Asunto(s)
Proteínas Portadoras/sangre , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/cirugía , Glicoproteínas , Trasplante de Riñón , Lipoproteína Lipasa/sangre , Lipoproteínas/sangre , Trasplante de Páncreas , Adulto , Arginina/farmacología , Proteínas Portadoras/análisis , Proteínas de Transferencia de Ésteres de Colesterol , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Nefropatías Diabéticas/cirugía , Femenino , Humanos , Hiperinsulinismo/sangre , Inyecciones Subcutáneas , Insulina/sangre , Insulina/uso terapéutico , Fallo Renal Crónico/cirugía , Lípidos/análisis , Lípidos/sangre , Lipoproteína Lipasa/análisis , Lipoproteínas/análisis , Masculino , Persona de Mediana Edad , Fósforo/análisis , Trasplante HomólogoRESUMEN
The concentration and activity of cholesteryl ester transfer protein (CETP) is increased in plasma in hypercholesterolemic humans and in experimental animals fed cholesterol. While the concentration of lipo-proteins appears to be the major determinant of CETP activity, we have found previously that dietary measures and pharmacologic agents that alter their lipid composition reduce the activity of CETP in plasma (CET). Since vitamin E is lipophilic and is incorporated into lipoproteins, we have examined the question of whether it too attenuates CET in cholesterol-fed New Zealand White rabbits prior to and 14 weeks after treatment with differing doses (5, 15, 30, 45 mg/kg) of vitamin E. Plasma triglycerides (TG), cholesterol (TC) and phospholipids (Lys, Sph, Lec, PI, PE) all increased significantly to a comparable degree in the rabbits fed cholesterol compared to those fed chow (p < 0.05; p < 0.01); the levels achieved were similar in the vitamin E-treated and untreated groups. As was observed with plasma lipids, cholesteryl ester transfer (CET) was accelerated to the same degree in each of the cholesterol-fed groups independent of whether they received vitamin E compared to chow-fed controls (p < 0.01) and the distribution of cholesterol in apo-B containing lipoproteins (VLDL, IDL, and LDL) was similar in the vitamin E-treated and untreated groups. These findings indicate that vitamin E has no discernible effect on CET when cholesterol levels are markedly elevated.
Asunto(s)
Ésteres del Colesterol/metabolismo , Colesterol/farmacología , Lipoproteínas/química , Lipoproteínas/metabolismo , Vitamina E/farmacología , Animales , Antioxidantes/farmacología , Apolipoproteínas B/metabolismo , Transporte Biológico/efectos de los fármacos , Colesterol/sangre , Hipercolesterolemia/metabolismo , Lipoproteínas/efectos de los fármacos , Fosfolípidos/sangre , Conejos , Triglicéridos/sangre , Vitamina E/sangreRESUMEN
Estrogen replacement therapy reduces the risk of coronary heart disease in women and decreases the extent of atherosclerosis in monkeys. In our previous studies, estrogen treatment decreased arterial LDL degradation and accumulation, thus indicating one mechanism by which estrogen inhibits the progression of atherosclerosis. The influence of progestins on these processes remains nuclear. The objective of this study was to determine the effects of oral estrogen (conjugated equine estrogens) and progestin (medroxyprogesterone acetate) alone or in combination on arterial LDL metabolism after 12 weeks of atherogenic stimulus. This relatively short period of treatment was chosen to determine effects on arterial LDL metabolism before substantial subendothelial macrophage accumulation. In contrast to previous studies (16 to 18 weeks of treatment), when macrophages were present in the intima, neither estrogen nor progestin (nor their combination) had any effect on any index of arterial LDL metabolism. These results suggest that estrogen may preferentially reduce LDL metabolism in macrophages with little effect on cells of the normal artery. In contrast to arterial LDL metabolism, hepatic LDL uptake was significantly increased in animals treated with estrogen or estrogen plus progestin. Despite the increased LDL uptake by the liver, hepatic lipid content was significantly decreased by approximately 50% in both estrogen and estrogen-plus-progestin treatment compared with control and progestin-treated animals. The decrease in hepatic cholesterol content in hypothesized to be due to increased biliary secretion of cholesterol.
Asunto(s)
Terapia de Reemplazo de Estrógeno , Lipoproteínas LDL/metabolismo , Animales , Ésteres del Colesterol/metabolismo , Dieta Aterogénica , Estradiol/sangre , Estrona/sangre , Femenino , Lipasa/metabolismo , Hígado/metabolismo , Macaca fascicularis , Ovariectomía , Factores de Tiempo , Túnica Íntima/anatomía & histologíaRESUMEN
Although the relationship between the actions of cholesteryl ester transfer protein (CETP) and atherosclerosis is complex, a strong body of evidence suggests that its activity (cholesteryl ester transfer [CET]) is proatherogenic. We have previously shown that CET is increased in IDDM patients receiving conventional subcutaneous insulin treatment and normalized when systemic insulin levels are lowered with intraperitoneal insulin delivery (IP). Since CET has been found by many observers to also be accelerated in NIDDM, we sought to determine whether the same salutary effect could be achieved in insulin-requiring NIDDM men before and 7 months after randomization to an intensive treatment regimen (Rx) of either IP (n = 9) or multiple daily insulin injections (MDI; n = 13). HbA1c improved to the same degree in both groups (MDI group: 9.4 +/- 1.1% pre-Rx vs. 7.2 +/- 0.7% post-Rx [P < 0.001]; IP group: 9.2 +/- 1.3% pre-Rx vs. 7.1 +/- 0.5% post-Rx [P < 0.001]). Compared with pre-Rx levels, plasma triglycerides were not significantly changed by either treatment (MDI group: 136 +/- 80 mg/dl pre-Rx vs. 139 +/- 87 mg/dl post-Rx; IP group: 157 +/- 63 mg/dl pre-Rx vs. 188 +/- 89 mg/dl post-Rx), though an upward trend followed IP. Before randomization, CET estimated with both mass and isotopic assays was greater in the NIDDM subjects than in nondiabetic control subjects (P < 0.001). With improved glycemic control, CE mass transfer declined in both groups, but only reached normal levels in the IP group (MDI group at 2 h: 49.0 +/- 13.7 [mean +/- SD] pg pre-Rx vs. 29.5 +/- 15.3 microg post-Rx [-39.7%, P < 0.01]; IP group at 2 h: 40.8 +/- 23.3 microg pre-Rx vs. 10.9 +/- 6.5 microg post-Rx [-73.2%, P < 0.05]) and remained abnormally increased (P < 0.005) in the subjects receiving MDI. Total lipolytic activity after intensive treatment was unchanged from pretreatment levels, which were similar to those of the reference group. Although directional changes in lipoprotein lipase (LpL) and hepatic triglyceride lipase (HTGL) similar to those found in IDDM after MDI and IP were observed, they were not statistically significant. Thus, while improved glycemic control alone achieved by either MDI or IP reduced the pathological increase in CET in these insulin-treated NIDDM men, normalization was only achieved in those treated with IP. Despite near-normal HbA1c levels, CET remained abnormally increased in NIDDM patients treated rigorously with conventional subcutaneous insulin delivery.
Asunto(s)
Proteínas Portadoras/sangre , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Glicoproteínas , Sistemas de Infusión de Insulina , Insulina/administración & dosificación , Lipoproteína Lipasa/sangre , Adulto , Anciano , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/enzimología , Esquema de Medicación , Hemoglobina Glucada/metabolismo , Humanos , Inyecciones Subcutáneas , Insulina/uso terapéutico , Cinética , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
To determine whether insulin delivered into portal circulation by an implanted pump reversed abnormalities in lipoprotein composition in insulin-dependent diabetes mellitus, 10 well-controlled normolipidaemic patients were studied after conventional intensive sub-cutaneous (ISC) insulin management and then 3 and 6 months after intraperitoneal pump implantation (IP). Glycated haemoglobin (ISC: 6.9 +/- 1.7% vs. IP-3 months 6.3 +/- 0.7; IP-6 months 6.3 +/- 0.8; mean +/- S.D.), plasma triglyceride and cholesterol levels, and the cholesterol content of HDL2 and HDL3 were normal and not significantly changed during these treatments. Fasting free insulin concentrations measured before and after 6 months of IP fell by more than half (ISC 8.22 +/- 6.5 vs IP 2.77 +/- 2.4 mU/ml; p < 0.025). The plasma-free cholesterol/lecithin ratio, a potential new cardiovascular risk factor, was increased during ISC, declined progressively after 3 months of IP, and approached normal by 6 months (ISC 0.96 +/- 0.37 mol/mol vs. IP-3 months 0.91 +/- 0.34; IP 6 months 0.86 +/- 0.10; reference group 0.83 +/- 0.33). In all lipoprotein fractions, sphingomyelin concentrations tended to fall, and lecithin concentrations to rise progressively during IP. As a result, the sphingomyelin/lecithin ratio, an index of the surface rigidity of lipoproteins, declined. The fact that some of the compositional modifications associated with ISC were reversed when insulin was administered intraperitoneally suggests that they may have been iatrogenic and resulted from high systemic insulin levels.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Sistemas de Infusión de Insulina , Lípidos/sangre , Lipoproteínas/sangre , Adulto , Glucemia/metabolismo , Colesterol/sangre , Femenino , Estudios de Seguimiento , Humanos , Inyecciones Subcutáneas , Insulina/administración & dosificación , Insulina/uso terapéutico , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Masculino , Persona de Mediana Edad , Fosfolípidos/sangre , Triglicéridos/sangreRESUMEN
OBJECTIVE: Cholesteryl ester transfer (CET) is accelerated in patients with IDDM treated with conventional (subcutaneous) insulin therapy (CIT) and a number of other disorders associated with premature cardiovascular disease. We have shown that in IDDM this disturbance is closely linked to iatrogenic hyperinsulinemia (HI), because it was reversed when insulin was administered by the intraportal (i.p.) route. In this study, we sought to determine whether HI after successful pancreas-kidney transplantation (PKT) has the same adverse effect on CET. RESEARCH DESIGN AND METHODS: CET was measured by both mass and isotopic assays and compared in two groups of euglycemic non-insulin-requiring IDDM PKT patients with either systemically draining allografts and persistent HI or grafts with portal vein anastomoses that were normoinsulinemic (PK-P). A third group of eight nondiabetic kidney transplant (KT) patients receiving the same immunosuppressive drugs served as control subjects. RESULTS: CET in pancreas-kidney transplantation subjects with systemic venous drainage (PK-S) was increased (P < 0.001) to the same level we have reported previously in IDDM patients receiving CIT and was significantly higher (P < 0.001) than in those subjects with PK-P. CET in the PK-P group did not differ from that of the KT control patients. CONCLUSIONS: CET is affected by variations in systemic insulin levels in pancreas transplant patients with allografts that have differing venous drainage. Because high systemic insulin levels are linked to the activation of (ET, euglycemic HI IDDM pancreas allograft recipients may continue to be at high risk for macrovascular complications.
Asunto(s)
Proteínas Portadoras/sangre , Diabetes Mellitus Tipo 1/cirugía , Nefropatías Diabéticas/cirugía , Glicoproteínas , Fallo Renal Crónico/cirugía , Trasplante de Riñón/métodos , Trasplante de Páncreas/métodos , Adulto , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Nefropatías Diabéticas/sangre , Femenino , Humanos , Terapia de Inmunosupresión/métodos , Fallo Renal Crónico/sangre , Trasplante de Riñón/fisiología , Masculino , Trasplante de Páncreas/fisiología , Vena Porta/cirugía , Triglicéridos/sangreRESUMEN
The net mass transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to the apolipoprotein (apo) B-containing lipoproteins, very low density lipoprotein (VLDL) and low density lipoprotein (LDL) in plasma (cholesteryl ester transfer (CET)) from three patients lacking lipoprotein lipase (LpL) activity was significantly lower (P < 0.001) than in plasma from fasting control subjects with comparable triglyceride levels. Chylomicrons isolated from LpL-deficient fasting plasma showed the same low level of CET activity as observed in the intact plasma when combined with HDL and cholesteryl ester transfer protein (CETP)-containing d 1.063 g/ml bottom fractions from control subjects. Preincubation of chylomicrons and large triglyceride-rich lipoproteins (Sf > 400) from LpL-deficient plasma with milk LpL, however, stimulated the capacity to engage in CET 4- to 5-fold to the same level as chylomicrons and VLDL from control subjects after a fat load. Consistent with these measurements of CET activity in plasma, chylomicrons obtained from the LpL-deficient subjects after a 14-h fast had higher TG/CE ratios than chylomicrons from controls 3 h after ingesting a fat load (LpL-deficient 26.3 +/- 9.0 vs. controls 6.9 +/- 2.1; mean +/- SD). The mass of CETP did not differ in LpL-deficient and control subjects (LpL-deficient 1.03 +/- 0.22 micrograms/ml vs. controls 1.58 +/- 0.58 micrograms/ml). These studies are consistent with earlier in vitro studies showing that the actions of lipoprotein lipase and its lipolytic products are essential, for maximal cholesteryl ester transfer protein activity.
Asunto(s)
Ésteres del Colesterol/metabolismo , HDL-Colesterol/metabolismo , Lipoproteína Lipasa/deficiencia , Quilomicrones/química , Quilomicrones/aislamiento & purificación , Quilomicrones/metabolismo , Ayuno/metabolismo , Femenino , Humanos , Hiperlipidemias/sangre , Hiperlipidemias/enzimología , Hiperlipidemias/metabolismo , Lípidos/sangre , Lipoproteína Lipasa/sangre , Lipoproteínas/sangre , Masculino , Persona de Mediana Edad , Valores de Referencia , Factores de TiempoRESUMEN
Patients with insulin-dependent diabetes mellitus (IDDM) have a pathological increase in cholesteryl ester transfer (CET) that enriches the apolipoprotein B-containing lipoproteins with cholesteryl ester and increases their atherogenicity. Since we have shown earlier that omega-3 (n-3) fatty acids present in marine lipids normalize both CET and lipoprotein composition in non-diabetic patients with hypercholesterolaemia, we sought to determine whether the same beneficial effects could be achieved in nine normolipidaemic (triglycerides 1.10; cholesterol 4.94, high density lipoprotein 1.10 mmol/l) IDDM patients (fructosamine 424 +/- 156; normal 174-286 mumol/l) treated for 2 months with n-3 fatty acids (4.6 g/day). Before treatment, CET measured by both mass and isotopic assays was abnormally accelerated (p < 0.001). While marine lipids modestly decreased triglyceride levels (-14%; p < 0.05 ), CET fell dramatically in all subjects (mass assay: -97% at 1 h; isotopic assay: -58%; p < 0.001) to below control levels with no change in glycaemic control (fructosamine 408 +/- 103 mumol/l). The mass of cholesteryl ester transfer protein paradoxically increased significantly (pre-treatment: 2.04 +/- 0.86 vs post-treatment 2.48 +/- 0.97 micrograms/ml; p < 0.05). Since it is believed that accelerated CET promotes the formation of atherogenic cholesteryl ester-enriched apo B-containing lipoproteins, the capacity of marine lipids to reverse this functional abnormality without altering glycaemic control suggests that these agents may have an adjunctive role to play in the nutritional therapy of IDDM.
Asunto(s)
Apolipoproteínas B/sangre , Proteínas Portadoras/sangre , Ésteres del Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Ácidos Grasos Omega-3/farmacología , Aceites de Pescado , Glicoproteínas , Lipoproteínas HDL/sangre , Adulto , Biomarcadores/sangre , Glucemia/metabolismo , Cápsulas , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol , HDL-Colesterol/sangre , Dieta para Diabéticos , Ácidos Grasos Omega-3/administración & dosificación , Femenino , Fructosamina , Hexosaminas/sangre , Humanos , Masculino , Valores de ReferenciaRESUMEN
Hyperglycemia associated with diabetes mellitus increases glycation of hemoglobin and serum proteins in human and nonhuman primates. It also has been documented that numerous other circulating proteins may be glycated. In this study we found that most of the major subclasses of lipoproteins (low-density, very low-density, and high-density) from diabetic cynomolgus monkeys were significantly more glycated than were lipoproteins from age- and sex-matched controls. Correlations between levels of glycemic control and glycation of lipoproteins also were significant. Because glycation of lipoproteins has been shown to affect their normal metabolism, this animal model may be useful in determining the interaction between lipoproteins, diabetes mellitus, and the increased risk of atherosclerosis.
Asunto(s)
Proteínas Sanguíneas/metabolismo , Diabetes Mellitus/veterinaria , Lipoproteínas/metabolismo , Macaca fascicularis/metabolismo , Enfermedades de los Monos/metabolismo , Animales , Colesterol/sangre , Diabetes Mellitus/metabolismo , Femenino , Glicosilación , Hemoglobinas , Lípidos/sangre , Lipoproteínas LDL/sangre , Masculino , Triglicéridos/sangreRESUMEN
To characterize further the impact of thyroid dysfunction on the transport of cholesterol in plasma, we studied plasma lipids and cholesteryl ester transfer (CET) in 10 hypothyroid women before and 3 months after thyroid replacement therapy. CET, estimated as the net mass transfer of CE from HDL to the apolipoprotein B-containing lipoproteins (very low density and low density lipoproteins) was significantly decreased at 4 h (P < 0.05) and 6 h (P < 0.001) when the patients were hypothyroid (T4, 2.01 +/- 1.4; TSH, 55.5 +/- 39.9 microIU/mL) and increased to normal levels after hormone replacement and restoration of eumetabolism. Plasma lipid levels in the hypothyroid state closely resembled those in a female reference group, although total plasma cholesterol fell significantly [pretreatment, 218 +/- 36 vs. posttreatment, 192 +/- 49 (P < 0.025); control, 218 +/- 28 mg/dL (mean +/- SD)] after treatment. Concentrations of cholesteryl ester transfer protein (CETP) were unchanged (pretreatment, 2.35 +/- 0.83 vs. posttreatment, 2.30 +/- 1.19 mg/dL). The results of recombination studies using different lipoprotein fractions suggest that decreases in CET during hypothyroidism may be secondary to acceptor lipoprotein (low density and very low density lipoprotein) changes in the hypothyroid state and not to changes in the concentration of CETP itself.
Asunto(s)
Ésteres del Colesterol/sangre , Glicoproteínas , Hipotiroidismo/sangre , Hipotiroidismo/tratamiento farmacológico , Tiroxina/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas B/sangre , Proteínas Portadoras/sangre , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol , Femenino , Humanos , Lipoproteínas HDL/sangre , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
While it is known that the transfer of cholesteryl ester (CE) from high density lipoprotein (HDL) to the apo B-containing lipoproteins is increased in patients with diabetes, the extent to which the various lipoprotein fractions engage in neutral lipid exchange and the magnitude to which triglyceride (TG) is translocated is not known. To examine in greater detail neutral lipid net mass transfer in diabetes, the HDL subfractions and the apo B-containing lipoproteins were separated, and the net mass transfer of CE and TG was compared to that of control subjects. In both groups, bidirectional transfer of CE from HDL3 to very low density lipoprotein (VLDL) + low density lipoprotein (LDL) and of TG from VLDL + LDL to HDL3, took place, but this process was significantly greater (P < .01) in insulin-dependent diabetes mellitus (IDDM). In contrast, CE and TG accumulated in HDL2 to a similar degree in normal and IDDM subjects. In recombination experiments with each of the apo B-containing lipoproteins, IDDM VLDL had a greater capacity to facilitate the exchange of core lipids from both IDDM and control HDL3: on the other hand, LDL from IDDM and control subjects both donated TG and CE to HDL2 and affected little change in HDL3. These findings indicate that all the major plasma fractions normally participate in the trafficking of CE and TG among the lipoproteins during neutral lipid transfer and show that the principal perturbation in cholesteryl ester transfer in IDDM involves altered interaction between VLDL and the HDL3 subfraction.
Asunto(s)
Diabetes Mellitus Tipo 1/sangre , Lípidos/sangre , Lipoproteínas HDL/sangre , Ésteres del Colesterol/sangre , Humanos , Lipoproteínas HDL/clasificación , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Triglicéridos/sangreRESUMEN
OBJECTIVE: Effective antihypertensive agents may differ in their capacity to reduce cardiovascular risk because they induce potentially atherogenic alterations in lipoprotein composition. PATIENTS: To assess this possibility, the effects of five months' treatment with either hydrochlorothiazide (HCTZ) or the converting enzyme inhibitor captopril (CAPT) on lipoprotein lipid composition were compared in thirty normolipidaemic patients with essential hypertension (EH). RESULTS: The sixteen patients treated with HCTZ showed the expected directional alterations in plasma TG (+31%), HDL2-C (-16%), and CHOL (+7.6%); in contrast TG and CHOL were unchanged after captopril in fourteen patients and their HDL2-C declined (-16%). Neither drug altered lipoprotein core lipid composition, but small increases were observed in the HDL2 sphingomyelin/lecithin ratio after both agents. The plasma free (unesterified) cholesterol (FC) lecithin (L) ratio, a new index of cardiovascular risk, was abnormally increased before treatment and was not altered by either drug. CONCLUSION: These findings indicate that HCTZ and CAPT treatment have small, but demonstrable effects on lipoprotein surface lipid composition in patients with EH that are confined to the HDL2 subfraction.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Antihipertensivos/farmacología , Hipertensión/tratamiento farmacológico , Lipoproteínas HDL/sangre , Administración Oral , Adulto , Inhibidores de la Enzima Convertidora de Angiotensina/administración & dosificación , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Antihipertensivos/administración & dosificación , Antihipertensivos/uso terapéutico , Captopril/administración & dosificación , Captopril/farmacología , Captopril/uso terapéutico , Colesterol/sangre , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Hidroclorotiazida/administración & dosificación , Hidroclorotiazida/farmacología , Hidroclorotiazida/uso terapéutico , Hipertensión/metabolismo , Hipertensión/fisiopatología , Lipoproteínas HDL/efectos de los fármacos , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Masculino , Método Simple Ciego , Triglicéridos/sangreRESUMEN
To further characterize the cholesteryl ester transfer protein (CETP)-mediated distribution of neutral lipids that occurs among lipoproteins in plasma, the net mass transfer of core lipids between donor and acceptor lipoproteins in intact plasma was measured in ten healthy normolipidemic subjects. The rate of loss of cholesteryl ester (CE) from high density lipoprotein-3 (HDL3) (19.5 +/- 8.8 nmol/ml per h) was linear and increased significantly (P < 0.01) during the 6-h incubation. Approximately 50% of the CE transferred from HDL3 (118.7 +/- 54.3 nmol/ml) went to very low density lipoprotein (VLDL); the remainder was distributed to low density lipoprotein (LDL) (approximately 30%) and HDL2 (approximately 20%). The rate of loss of triglyceride (TG) from VLDL (14.5 +/- 6.6 nmol/ml per h) to the HDL subfractions and LDL also was linear and increased significantly with time (P < 0.01). About 50% of the TG mass lost from VLDL (85.2 +/- 38.4 nmol/ml) was transferred to LDL and the remainder was recovered in HDL2 (approximately 10%) and HDL3 (approximately 40%). As the number of nmoles of CE lost from HDL3 was almost three times greater than the nmoles of TG it acquired, these findings indicate that the exchange of core lipids in plasma that result from the interaction between CETP-VLDL-HDL3 is not equimolar. Even in the absence of VLDL, HDL3 continued to donate CE to LDL and HDL2 to almost the same degree as in intact plasma (plasma minus VLDL: 17.5 +/- 5.9 nmol/ml per h vs. intact plasma: 20.2 +/- 7.5 nmol/ml per h) without accepting any TG. Our findings demonstrate that independent pathways exist for the transfer of CE and TG among the plasma lipoproteins and, contrary to what is generally believed, a heteroexchange of TG for CE during cholesteryl ester transfer is not obligatory.
Asunto(s)
Lípidos/sangre , Lipoproteínas/sangre , Triglicéridos/sangre , Adulto , Ésteres del Colesterol/sangre , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: Cholesteryl ester transfer (CET) is pathologically increased in insulin-dependent diabetes mellitus (IDDM), and the resulting enrichment of the apolipoprotein B-containing lipoproteins with cholesteryl ester (CE) is believed to increase their atherogenicity. Because we have shown previously that treatment with the lipid-modifying antioxidant probucol normalizes CET in nondiabetic patients with hypercholesterolemia, we sought to determine whether the same beneficial effects could be achieved in IDDM. RESEARCH DESIGN AND METHODS: CET was measured by both mass and isotopic assay in eight normolipidemic (triglyceride, 102; cholesterol, 192; high-density lipoprotein [HDL] cholesterol, 45 mg/dl) IDDM patients (fructosamine 495 +/- 146 mumol/l; normal 174-286) before and after 2 months of treatment with probucol (1.0 g/day). RESULTS: Before treatment, CET was accelerated abnormally (P < 0.001). As expected, probucol decreased plasma (-13%; P < 0.025) and HDL2 cholesterol levels (-52%; P < 0.025) and the concentration of lipoprotein A-I particles (P < 0.025). In conjunction with these changes, CET fell dramatically in all subjects (mass assay: -94%; isotopic assay: -22%, P < 0.001) with no change in the mass of cholesteryl ester transfer protein (CETP) (pretreatment 2.91 +/- 0.97 vs. posttreatment 3.21 +/- 1.03 micrograms/ml). Glycemic control, however, improved significantly (fructosamine 409 +/- 85 mumol/l, P < 0.025). CONCLUSIONS: Because it is believed that accelerated CET promotes the formation of apolipoprotein B-containing lipoproteins enriched with atherogenic CE, the capacity of probucol to reverse this functional abnormality without adversely affecting glycemic control suggests that it has a place in the therapy of IDDM.
Asunto(s)
Anticolesterolemiantes/uso terapéutico , Proteínas Portadoras/sangre , Ésteres del Colesterol/sangre , Diabetes Mellitus Tipo 1/sangre , Glicoproteínas , Probucol/uso terapéutico , Adulto , Anticolesterolemiantes/farmacología , Apolipoproteínas/sangre , Proteínas Portadoras/efectos de los fármacos , Colesterol/sangre , Proteínas de Transferencia de Ésteres de Colesterol , HDL-Colesterol/sangre , LDL-Colesterol/sangre , Diabetes Mellitus Tipo 1/tratamiento farmacológico , Femenino , Fructosamina , Hexosaminas/sangre , Humanos , Cinética , Lipoproteínas/sangre , Masculino , Probucol/farmacología , Valores de Referencia , Factores de Tiempo , Triglicéridos/sangreRESUMEN
Vascular cell membranes from patients with essential hypertension (EH) and animals with genetic forms of hypertension have been found to have alterations in the content of free cholesterol and negatively charged phospholipids that may modify their function. Since membrane and lipoprotein lipids exchange freely, the lipid composition of lipoproteins may be an indirect measure of the content of vascular and other cells. To determine whether abnormalities are present in the lipid and phospholipid composition of lipoproteins from patients with EH, 30 EH (11 women; 19 men) and 20 normotensive control subjects were studied. Since significant gender differences were present in a number of parameters of lipoprotein composition, male and female data were examined separately. The EH group of both sexes tended to have higher plasma TG and VLDL + LDL and HDL2 lipid levels than their respective controls. Not only were the calcium-binding phospholipids phosphatidylinositol (PI) + phosphatidylserine (PS), and the membrane fluidizer phosphatidylethanolamine (PE) were significantly reduced in their VLDL + LDL, but all phospholipids (L, sphingomyelin (SPH), PI + PS, and PE) were significantly reduced in their neutral lipid content in both the HDL2 and HDL3 subfractions. These directional changes in lipoprotein FC and phospholipid in the EH women significantly increased the EH FC/PC (mol/mol) ratio in their plasma, a new cardiovascular risk factor, (EH 1.08 +/- 0.22 vs. control 0.86 +/0 0.08; P < 0.01) and lowered the SPH/PC ratio HDL2 and HDL3 in EH patients of both sexes. These findings showed that lipoproteins in normolipidemic EH women are relatively enriched in FC and in EH patients of both sexes depleted in certain phospholipids lacking in lipoproteins, their functional properties could be altered and vascular tone increased.
Asunto(s)
Hipertensión/sangre , Lipoproteínas/química , Fosfolípidos/análisis , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Fosfatidilcolinas/análisis , Fosfatidiletanolaminas/análisis , Fosfatidilinositoles/análisis , Fosfatidilserinas/análisis , Esfingomielinas/análisis , Triglicéridos/sangreRESUMEN
To determine whether the specificity of lecithin: cholesterol acyltransferase (LCAT) influences the susceptibility to atherosclerosis, we compared the composition and in vitro synthesis of cholesteryl ester (CE) in the plasmas of 14 vertebrate species with varying predisposition to atherosclerosis. The susceptible species (Group I) had significantly higher ratios of 16:0 CE/20:4 CE in their plasma than the resistant species (Group II). The in vitro formation of labeled CE species in native plasma from labeled cholesterol correlated highly with the mass composition, showing that the LCAT reaction is the predominant source of plasma CE in all the animal species examined. Isolated LCATs from Group I species also synthesized CE with higher ratios of 16:0/20:4 than LCATs from Group II when egg phosphatidylcholine (PC) was used as the acyl donor. In addition, the Group I LCATs exhibited lower specificity towards sn-2-20:4 and sn-2-22:6 PCs, and higher specificity towards sn-2-18:2 PC species than Group II LCATs. With 16:0-20:4 PC as the substrate, all Group I LCATs synthesized more 16:0 CE than 20:4 CE, whereas all Group II LCATs, with the exception of dog enzyme, synthesized predominantly 20:4 CE, showing that the two types of LCAT have different positional specificities towards this PC. These results suggest that there are two classes of LCAT in nature that differ from each other in their substrate and positional specificities, possibly because of differences in their active-site architectures. We propose that the presence of one type of LCAT, which cannot efficiently transfer certain long chain polyunsaturated acyl groups and which consequently synthesizes more saturated CE, may increase the risk of atherosclerosis.