RESUMEN
Guidelines for the reduction of cholesterol to prevent atherosclerotic vascular events were recently released by the American Heart Association and the American College of Cardiology. The authors claim to refer entirely to evidence from randomized controlled trials, thereby confining their guidelines to statins as the primary therapeutic option. The guidelines derived from these trials do not specify treatment goals, but refer to the percentage of cholesterol reduction by statin medication with low, moderate, and high intensity. However, these targets are just as little tested in randomized trials as are the cholesterol goals derived from clinical experience. The same applies to the guidelines of the four patient groups which are defined by vascular risk. No major statin trial has included patients on the basis of their global risk; thus the allocation criteria are also arbitrarily chosen. These would actually lead to a significant increase in the number of patients to be treated with high or maximum dosages of statins. Also, adhering to dosage regulations instead of cholesterol goals contradicts the principles of individualized patient care. The option of the new risk score to calculate lifetime risk up to the age of 80 years in addition to the 10-year risk can be appreciated. Unfortunately it is not considered in the therapeutic recommendations provided, despite evidence from population and genetic studies showing that even a moderate lifetime reduction of low-density lipoprotein (LDL) cholesterol or non-HDL cholesterol has a much stronger effect than an aggressive treatment at an advanced age. In respect to secondary prevention, the new American guidelines broadly match the European guidelines. Thus, the involved societies from Germany, Austria and Switzerland recommend continuing according to established standards, such as the EAS/ESC guidelines.
Asunto(s)
Anticolesterolemiantes/administración & dosificación , Aterosclerosis/sangre , Aterosclerosis/prevención & control , Dietoterapia/normas , Hipercolesterolemia/sangre , Hipercolesterolemia/prevención & control , Guías de Práctica Clínica como Asunto , Austria , Cardiología/normas , Humanos , Factores de Riesgo , SuizaRESUMEN
BACKGROUND: Afamin was recently identified as a novel osteoclast-derived coupling factor that can stimulate the in vitro and in vivo migration of preosteoblasts. AIM: In order to understand in more detail the biological roles of afamin in bone metabolism, we investigated its effects on osteoclastic differentiation and bone resorption. METHODS: Osteoclasts were differentiated from mouse bone marrow cells. Tartrate-resistant acid phosphatase (TRAP)-positive multinucleated cells were considered as osteoclasts, and the resorption area was determined by incubating the cells on dentine discs. The intracellular cAMP level was determined using a direct enzyme immunoassay. Signaling pathways were investigated using western blot and RT-PCR. Recombinant afamin was administered exogenously to bone cell cultures. RESULTS: Afamin stimulated both osteoclastogenesis and in vitro bone resorption. Consistently, the expressions of osteoclast differentiation markers were significantly increased by afamin. Although afamin mainly affected the late-differentiation stages of osteoclastogenesis, the expression levels of receptor activator of nuclear factor-κB ligand (RANKL)-dependent signals were not changed. Afamin markedly decreased the levels of intracellular cAMP with reversal by pretreatment with pertussis toxin (PTX), a specific inhibitor of Gi-coupled receptor signaling. In addition, PTX almost completely blocked afamin-stimulated osteoclastogenesis. Furthermore, pretreatment with KN93 and STO609 - Ca2+/cal - mo dulin-dependent protein kinase (CaMK) and CaMK kinase inhibitors, respectively - significantly prevented decreases in the intracellular cAMP level by afamin while attenuating afamin-stimulated osteoclastogenesis. CONCLUSION: Afamin enhances osteoclastogenesis by decreasing intracellular cAMP levels via Gi-coupled receptor and CaMK pathways.
Asunto(s)
Albúminas/farmacología , Resorción Ósea/tratamiento farmacológico , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/metabolismo , Glicoproteínas/farmacología , Osteoclastos/efectos de los fármacos , Osteogénesis/efectos de los fármacos , Receptores Acoplados a Proteínas G/metabolismo , Proteínas Recombinantes/farmacología , Fosfatasa Ácida/genética , Fosfatasa Ácida/metabolismo , Animales , Western Blotting , Resorción Ósea/metabolismo , Proteína Quinasa Tipo 1 Dependiente de Calcio Calmodulina/genética , Diferenciación Celular/efectos de los fármacos , Células Cultivadas , AMP Cíclico/metabolismo , Isoenzimas/genética , Isoenzimas/metabolismo , Ratones , Ratones Endogámicos C57BL , FN-kappa B/genética , FN-kappa B/metabolismo , Osteoclastos/citología , Osteoclastos/metabolismo , Ligando RANK/genética , Ligando RANK/metabolismo , ARN Mensajero/genética , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptores Acoplados a Proteínas G/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Transducción de Señal , Fosfatasa Ácida TartratorresistenteRESUMEN
Increased maternal and foetal iron requirements during pregnancy are compensated by an increase of intestinal iron absorption. Animal studies have shown that the expression of the main iron regulator hepcidin is significantly suppressed during pregnancy, but the factors associated with hepcidin suppression remain unknown. To investigate possible suppressors of hepcidin expression during pregnancy we determined serum concentrations of growth-differentiation factor-15 (GDF15), erythropoietin (EPO), soluble hemojuvelin (HJV) and hepcidin in 42 pregnant women at different time points of gestation and correlated them with serum iron and haematological parameters. Serum iron parameters and serum hepcidin concentration significantly decreased during pregnancy, whereas serum concentrations of GDF15, EPO and soluble HJV significantly increased. A negative correlation of hepcidin with EPO and soluble HJV but no correlation between hepcidin and GDF15 was found. Hepcidin and ferritin were positively correlated throughout the pregnancy. Our findings suggest that hepcidin expression is controlled by body iron stores where soluble HJV and EPO may act as suppressors of hepcidin.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/sangre , Proteínas Ligadas a GPI/sangre , Factor 15 de Diferenciación de Crecimiento/sangre , Embarazo/sangre , Adolescente , Adulto , Femenino , Ferritinas/sangre , Proteína de la Hemocromatosis , Hepcidinas , Humanos , Hierro/sangre , Factores de Tiempo , Adulto JovenRESUMEN
Plasma cholesterol metabolism was investigated in normotriglyceridemic patients with end-stage renal disease treated by hemo- or continuous ambulatory peritoneal dialysis (CAPD), and compared with that in a control group with normal renal function. A reversed net transport of free cholesterol from plasma to cultured fibroblasts, as well as greatly reduced levels of plasma cholesterol esterification and cholesterol ester transfer rates to low and very low density lipoproteins (LDL and VLDL), was found in the hemodialysis group compared to the controls. The LDL and VLDL contained increased amounts of free cholesterol and inhibited cholesterol ester transfer when recombined with control plasma. The LDL triglyceride content was doubled in the hemodialysis group, whereas cholesterol esters were decreased. Patients treated by CAPD, in marked contrast, had cholesterol metabolic rates that were within the normal range, as well as normal lipoprotein composition.
Asunto(s)
Colesterol/sangre , Fallo Renal Crónico/sangre , Diálisis Peritoneal Ambulatoria Continua , Diálisis Renal , Apolipoproteína A-I , Apolipoproteína A-II , Apolipoproteínas/sangre , Apolipoproteínas A/sangre , Apolipoproteínas B/sangre , Apolipoproteínas D , Apolipoproteínas E/sangre , Células Cultivadas , Ésteres del Colesterol/sangre , Humanos , Fallo Renal Crónico/terapia , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Triglicéridos/sangreRESUMEN
A 7-yr-old girl with high density lipoprotein (HDL) deficiency and xanthomas has been identified in a Turkish kindred with repetitive consanguinity. She has severely reduced HDL-cholesterol and no apolipoprotein (apo) A-I. ApoA-II is reduced, whereas apoA-IV and apoC-III are normal. ApoB and low density lipoprotein (LDL)-cholesterol are increased. This is reflected in hypercholesterolemia. VLDL and IDL particles are low, and serum triglycerides are normal. The genetic defect could be identified as a base insertion into the third exon of the apoA-I gene. This leads to a nonsense peptide sequence beginning at amino acid 5 of the mature plasma protein and early termination of translation. The patient is homozygous for this mutation. Pedigree analysis indicated an autosomal dominant inheritance with no evidence of another genetic defect of lipoprotein metabolism in the kindred. In HDL deficiency, HDL binding to leukocytes was increased compared to normal. In the postprandial state, binding of labeled HDL3 to leukocytes is unchanged. This is in contrast to results with postprandially isolated leukocytes from controls or Tangier patients, which have a reduced binding capacity for HDL3. These results indicate that postprandial HDL precursors may compete the binding of labeled HDL3. The metabolic consequences of HDL deficiency were analyzed. There is only a small number of HDL-like particles containing apoA-II, apoA-IV, apoE, and lecithin/cholesteryl acyl transferase. The C-apolipoproteins were normal in the proband. Due to the lack of HDL they can only associate with apoB-containing particles, where they may interfere with cellular uptake. Thus, pure apoA-I deficiency leads to a complex metabolic derangement.
Asunto(s)
Apolipoproteína A-I/genética , Colesterol/metabolismo , Hipolipoproteinemias/genética , Lipoproteínas HDL/deficiencia , Mutación Puntual , Xantogranuloma Juvenil/genética , Secuencia de Aminoácidos , Apolipoproteína A-I/deficiencia , Secuencia de Bases , Transporte Biológico , Niño , HDL-Colesterol/deficiencia , Clonación Molecular , Femenino , Alemania/epidemiología , Haplotipos , Humanos , Hipolipoproteinemias/complicaciones , Intestinos/química , Leucocitos/metabolismo , Lipoproteínas/sangre , Datos de Secuencia Molecular , Linaje , ARN/análisis , Receptores de LDL/análisis , Análisis de Secuencia de ADN , Enfermedad de Tangier , Turquía/etnología , Xantogranuloma Juvenil/complicacionesRESUMEN
The composition of lipoproteins in the plasma of patients with LCAT deficiency (LCAT-D) is grossly altered due to the lack of cholesteryl esters which form the core of normal lipoproteins. When plasma from LCAT-D patients and their relatives was examined we found that nine heterozygotes had plasma Lp(a) levels of 2-13 mg/dl whereas none of 11 affected homozygous individuals from different families contained detectable amounts of Lp(a) in their plasma. Therefore, the binding of apo(a) to LDL density particles was studied in vitro using LDL density fractions prepared from patients, and recombinant apo(a) [r-apo(a)], which was expressed and secreted by transfected COS-7 cells. The LDL from heterozygotes were chemically indistinguishable from normal LDL and homogeneous with regard to morphology, whereas the crude LDL floating fraction from homozygotes consisted of a heterogeneous mixture of large vesicles, and small spheres resembling normal LDL. The LDL density fraction from the LCAT-D patient lacked almost completely cholesteryl esters. Incubation of LCAT-D plasma with active LCAT caused a substantial augmentation of the original subfraction which morphologically resembled normal LDL. Using r-apo(a) and normal LDL or LDL of heterozygous individuals, apoB:r-apo(a) complexes were formed when incubated at 37 degrees C in vitro for 20 h. In contrast, the total LDL floating fraction from a homozygous LCAT-D patient failed to form apoB:r-apo(a) complexes. After treatment with active LCAT, a significant apoB:r-apo(a) association was observed with LCAT-D LDL-density particles. Our data emphasize the importance of the integrity of LDL structure and composition for the formation of Lp(a). In addition, we demonstrate that the absence of LCAT activity has a fundamental impact on the regulation of plasma Lp(a) levels.
Asunto(s)
Apolipoproteínas A/biosíntesis , Deficiencia de la Lecitina Colesterol Aciltransferasa/metabolismo , Lipoproteínas LDL/biosíntesis , Apolipoproteínas A/sangre , Apolipoproteínas A/metabolismo , Apolipoproteínas B/metabolismo , Austria/epidemiología , Femenino , Homocigoto , Humanos , Deficiencia de la Lecitina Colesterol Aciltransferasa/epidemiología , Lipoproteínas LDL/química , Lipoproteínas LDL/ultraestructura , Masculino , Linaje , Unión ProteicaRESUMEN
Patients with terminal renal insufficiency suffer from an increased incidence of atherosclerotic diseases. Elevated plasma concentrations of lipoprotein(a) [Lp(a)] have been established as a genetically controlled risk factor for these diseases. Variable alleles at the apo(a) gene locus determine to a large extent the Lp(a) concentration in the general population. In addition, other genetic and nongenetic factors also contribute to the plasma concentrations of Lp(a). We therefore investigated Apo(a) phenotypes and Lp(a) plasma concentrations in a large group of patients with end-stage renal disease (ESRD) and in a control group. Lp(a) concentrations were significantly elevated in ESRD patients (20.1 +/- 20.3 mg/dl) as compared with the controls (12.1 +/- 15.5 mg/dl, P < 0.001). However, no difference was found in apo(a) isoform frequency between the ESRD group and the controls. Interestingly, only patients with large size apo(a) isoforms exhibited two- to fourfold elevated levels of Lp(a), whereas the small-size isoforms had similar concentrations in ESRD patients and controls. Beside elevated Lp(a) concentrations, ESRD patients had lower levels of plasma cholesterol and apolipoprotein B. These results show that elevated Lp(a) plasma levels might significantly contribute to the risk for atherosclerotic diseases in ESRD. They further indicate that nongenetic factors related to renal insufficiency or other genes beside the apo(a) structural gene locus must be responsible for the high Lp(a) levels.
Asunto(s)
Apolipoproteínas/química , Fallo Renal Crónico/sangre , Lipoproteína(a)/sangre , Adulto , Anciano , Apolipoproteínas B/sangre , Apoproteína(a) , Arteriosclerosis/etiología , Colesterol/sangre , Femenino , Humanos , Lipoproteína(a)/genética , Masculino , Persona de Mediana Edad , Fenotipo , Polimorfismo GenéticoRESUMEN
In order to study the factors responsible for the formation of high-density lipoprotein subfraction-2 (HDL-2), very-low-density lipoproteins (VLDL) and HDL-3 were mixed and incubated with purified bovine milk lipoprotein lipase, human serum lecithin:cholesterol acyltransferase, cholesteryl ester transfer protein and mixtures thereof. The results can be summarized as follows: Incubation of HDL-3 and VLDL for 24 h at 37 degrees C without enzymes did not cause any significant change in the protein:lipid ratio or in the flotation constant of the HDL. Cholesteryl ester transfer protein treatment caused only an exchange of part of the HDL cholesteryl esters with VLDL triacylglycerols. Lipoprotein lipase caused a slight shift of HDL-hydrated density to lower values; HDL-2b, however, was not formed. Incubation of HDL-3 and VLDL with lecithin:cholesterol acyltransferase or mixtures of lecithin:cholesterol acyltransferase and lipoprotein lipase reduced the HDL-protein:lipid ratio and increased the HDL-flotation rate. The newly formed HDL resembled that of native HDL-2a. The incubation of HDL-3 and VLDL with lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein caused a shift of the HDL-3 into an HDL-2b-like fraction. Particles resembling HDL-2b in the analytical ultracentrifuge were also formed if VLDL + HDL-3 were incubated with lipoprotein lipase or lipoprotein lipase + cholesteryl ester transfer protein in a medium containing low amounts of albumin, insufficient for binding all liberated fatty acids during hydrolysis. The incubation of mixtures of HDL-3 and chylomicrons enriched with apoAI in the presence of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein caused the formation of HDL-2-like particles which resembled those of native HDL-2 also with respect to the apoAI/AII ratio.
Asunto(s)
Proteínas Portadoras/metabolismo , Glicoproteínas , Lipoproteínas HDL/metabolismo , Lipoproteínas VLDL/metabolismo , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Fenómenos Químicos , Química Física , Proteínas de Transferencia de Ésteres de Colesterol , Electroforesis en Gel de Poliacrilamida , Humanos , Lipoproteínas HDL2 , Lipoproteínas HDL3RESUMEN
OBJECTIVES: The objective of this study was to evaluate the relation between apolipoprotein A-IV (apoA-IV) plasma concentrations and coronary artery disease (CAD). BACKGROUND: Experimental in vitro and in vivo studies favor apoA-IV to be protective against the development of atherosclerosis. Mice that overexpress either human or mouse apoA-IV demonstrated a significant reduction of aortic atherosclerotic lesions compared with control mice. Data on apoA-IV plasma concentrations and CAD in humans are lacking. METHODS: We determined in two independent case-control studies of a Caucasian and an Asian Indian population whether apoA-IV plasma concentrations are related to the presence of angiographically assessed CAD. RESULTS: Plasma apoA-IV levels were significantly lower in 114 male Caucasian subjects with angiographically defined CAD when compared with 114 age-adjusted male controls (10.2 +/-3.8 mg/dL vs. 15.1 +/- 4.0 mg/dL, p < 0.001). Logistic regression analysis indicated that the association between apoA-IV levels and CAD was independent of the high-density lipoprotein cholesterol and triglyceride concentrations. The inverse relationship between plasma levels of apoA-IV and the presence of CAD was confirmed in an independent sample of 68 male Asian Indians with angiographically documented CAD and 68 age-matched controls. CONCLUSIONS: The results of this cross-sectional study demonstrate for the first time an association between low apoA-IV concentrations and CAD in humans and suggest that apoA-IV may play an antiatherogenic role in humans.
Asunto(s)
Apolipoproteínas A/sangre , Enfermedad Coronaria/sangre , Austria , Estudios de Casos y Controles , HDL-Colesterol/sangre , Enfermedad Coronaria/etnología , Estudios Transversales , Etnicidad , Humanos , India , Masculino , Persona de Mediana Edad , Concentración Osmolar , Valores de Referencia , Análisis de Regresión , Triglicéridos/sangre , Población BlancaRESUMEN
Concentrations of HDL cholesterol, apolipoprotein (apo) A-I and apo A-II were found to be significantly decreased in patients with insulin-dependent diabetes (IDD) and non-insulin-dependent diabetes (NIDD) compared with carefully selected controls matched for sex, age and body weight. LDL cholesterol and apo B levels did not differ significantly between diabetics and controls. Concentrations of lipoprotein Lp(a), an independent risk factor for coronary artery disease in non-diabetics, were above 20 mg/dl in only 14% of diabetics and in 5% of controls. LCAT activity was normal in diabetics, irrespective of type of diabetes, sex and age of patients. No correlation between HbA1 and either HDL cholesterol or A-I and A-II was found in IDD and NIDD. A positive correlation between HbA1 and either triglyceride or VLDL triglyceride was noted in IDD and NIDD. There was also a positive correlation between insulin dosage in IDD and HDL cholesterol, apolipoprotein A-I and A-II.
Asunto(s)
Diabetes Mellitus/sangre , Lipoproteínas/sangre , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Adolescente , Adulto , Anciano , Apolipoproteína A-I , Apolipoproteína A-II , Apolipoproteínas/sangre , Apolipoproteínas B , Colesterol/sangre , HDL-Colesterol , LDL-Colesterol , VLDL-Colesterol , Diabetes Mellitus/enzimología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 2/sangre , Femenino , Humanos , Lipoproteína(a) , Lipoproteínas HDL/sangre , Lipoproteínas LDL/sangre , Lipoproteínas VLDL/sangre , Masculino , Persona de Mediana Edad , Triglicéridos/sangreRESUMEN
The highly atherogenic lipoprotein(a) [Lp(a)] is significantly elevated in patients with renal disease. It is discussed controversially whether Lp(a) concentrations decrease after renal transplantation and whether the mode of immunosuppressive therapy influences the Lp(a) concentrations. In a prospective study the Lp(a) concentrations before and on average 48 months after renal transplantation were measured in 145 patients. The determinants of the relative changes of Lp(a) concentrations were investigated in a multivariate analysis. Patients treated by CAPD showed a larger decrease of Lp(a) than hemodialysis patients, reflecting their markedly higher Lp(a) levels before transplantation. The relative decrease of Lp(a) was higher with increasing Lp(a) concentrations before transplantation in combination with an increasing molecular weight of apolipoprotein(a) [apo(a)]. That means that the relative decrease of Lp(a) is related to the Lp(a) concentration and the apo(a) size polymorphism. With increasing proteinuria and decreasing glomerular filtration rate, the relative decrease of Lp(a) became less pronounced. Neither prednisolone nor cyclosporine (CsA) had a significant impact on the Lp(a) concentration changes. Azathioprine (Aza) was the only immunosuppressive drug which had a dose-dependent influence on the relative decrease of Lp(a) levels. These data clearly demonstrate a decrease of Lp(a) following renal transplantation which is caused by the restoration of kidney function. The relative decrease is influenced by Aza but not by CsA or prednisolone.
Asunto(s)
Arteriosclerosis/sangre , Trasplante de Riñón/fisiología , Lipoproteína(a)/sangre , Adulto , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Inmunosupresores/administración & dosificación , Pruebas de Función Renal , Masculino , Persona de Mediana Edad , Diálisis Peritoneal Ambulatoria Continua , Estudios Prospectivos , Diálisis RenalRESUMEN
Molecular biology and genetics were the hallmarks of the conference. Attendees from 20 European countries participated in lively discussions with international speakers. The opening round table session entitled 'Genetic approach to complex diseases' was chaired by Harald Funke. Steve Humphries (London) presented association studies and Harald Funke (Munster) presented multiparameter analyses, as models of genetic epidemiological approaches to atherosclerosis. Gerd Utermann (Innsbruck) showed, through sib pair linkage analysis, how apo (a) gene polymorphism determines plasma levels of Lp(a). Klaus Lindpainter (Basel) described novel genetic strategies heading for a more targeted medicine, through the identification of genetic mechanisms of disease and therapeutic responses. Session I, chaired by Richard James (Geneva) and Guido Franceschini (Milano), on 'Basic mechanisms of action of drugs' highlighted molecular and cellular actions by which present (fibrates, statins) or future (ACAT or MTP inhibitors) drugs or hormones may modulate lipoprotein metabolism. Marten Hofker (Leiden) and Philippa Talmud (London) chaired Session II on 'Regulation of gene expression', which reported cellular regulations by nuclear receptors (PPARs), or the regulation of lipid trafficking by membrane receptors (SR-BI, Megalin, Apo-E receptor, scavenger receptors) or by intracellular (IFN gamma signalling pathways) or extracellular proteins (lipases). Beyond gene expression, Session III, 1st part, entitled 'Lipoprotein modifying enzymes' was chaired by Katriina Aalto-Setälä (Tampere). Roles of lipases (HL, LPL) and transfer proteins (CETP, PLTP), as well as structures of lipid binding molecules (LCAT, apolipoproteins), were further explored. The 'Gene interactions' session chaired by Rudolph Poledne (Prague), and 'Novelties' chaired by Hans Dieplinger (Innsbruck), reported elegant models of cross-bred, tissue specific knock-out or YAC-transgenic mice for lipoprotein metabolism, and descriptions of gene interactions in polygenic disorders or new loci for familial lipid disorders (familial combined hyperlipidemia, metabolic syndrome and Tangier disease) in humans.
Asunto(s)
Arteriosclerosis/genética , Lipoproteínas , Sociedades Médicas , Animales , Europa (Continente) , Regulación de la Expresión Génica/fisiología , Humanos , RatonesRESUMEN
Recent studies have indicated controversial effects of low molecular weight heparin (LMWH) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin (UFH). We therefore conducted a cross-sectional multicentre study comparing 153 patients treated with LMWH and 153 patients with UFH, matched for sex, age and diabetes mellitus. Both groups have been treated with LMWH or UFH for six months or longer (14.9 vs. 23.4 months). We observed no differences between the UFH and LMWH treatment groups for total cholesterol, LDL cholesterol, triglycerides, apoB, apoA-IV or Lp(a). The only significant differences were seen for HDL cholesterol and the corresponding apolipoprotein apoA-I, which were significantly higher in the UFH group (HDL cholesterol: 0.97 +/- 0.35 mM/l vs. 0.87 +/- 0.37 mM/l, p < 0.05; apoA-I 1.23 +/- 0.27 g/l vs. 1.15 +/- 0.27 g/l, p < 0.05). We conclude that the results of studies investigating the influence of LMWH on lipid metabolism are as heterogeneous as the substances themselves. This challenges the beneficial influence supposedly had by LMWH preparations on lipid metabolism.
Asunto(s)
Anticoagulantes/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Heparina/uso terapéutico , Lipoproteínas/sangre , Diálisis Renal , Adulto , Anciano , Estudios Transversales , Diabetes Mellitus/sangre , Diabetes Mellitus/terapia , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The sites and mechanisms of the catabolism of atherogenic lipoprotein(a) (Lp(a)) are not well understood. Lp(a) is increased in patients with end-stage renal disease, suggesting a renal catabolism of Lp(a). To gain a better insight into renal handling of Lp(a), we established a heterologous rat model to study the renal catabolism of human Lp(a). Pure human Lp(a) was injected into Wistar rats, and animals were sacrificed at different time points (30 minutes to 24 hours). Intact Lp(a) was cleared from the circulation of injected rats with a half-life time of 14.5 hours. Strong intracellular immunostaining for apolipoprotein(a) (apo(a)) was observed in the cytoplasm of proximal tubular cells after 4, 8, and 24 hours. Apolipoprotein B (apoB) was colocalized with glomerular apo(a) 1 to 8 hours after Lp(a) injection, but renal capillaries and tubules remained negative. No relevant amounts of apo(a) fragments were found in the plasma of rats after injection of Lp(a). During all urine collection periods, apo(a) fragments with molecular weights of 50 to 160 kd were detected in the urine, however. Our results show that human Lp(a) injected into rats accumulates intracellularly in the rat kidney, and apo(a) fragments are excreted in the urine. The kidney apparently plays a major role in fragmentation of Lp(a). Despite the fact that rodents lack endogenous Lp(a), rats injected with human Lp(a) may provide a useful heterologous animal model to study the renal metabolism of Lp(a) further.
Asunto(s)
Riñón/metabolismo , Lipoproteína(a)/metabolismo , Fragmentos de Péptidos/metabolismo , Animales , Apolipoproteínas/administración & dosificación , Apolipoproteínas/metabolismo , Apolipoproteínas B/metabolismo , Apoproteína(a) , Semivida , Humanos , Lipoproteína(a)/administración & dosificación , Masculino , Modelos Animales , Ratas , Ratas WistarRESUMEN
A very simple and fast method for the determination of lecithin:cholesterol acyltransferase is described. The method is based on the enzymatic determination of free cholesterol in a serum or plasma sample before and after 40 min incubation at 37 degrees C. The proposed procedure is particularly useful for routine application in a clinical laboratory. It works with a coefficient of variation of less than 5%.
Asunto(s)
Pruebas Enzimáticas Clínicas/métodos , Fosfatidilcolina-Esterol O-Aciltransferasa/sangre , Colesterol/sangre , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: The association between lipoprotein(a) levels, apolipoprotein(a) size and the (TTTTA)(n) polymorphism which is located in the 5' non-coding region of the apo(a) gene was studied in 263 patients with severe coronary heart disease and 97 healthy subjects. METHODS: Lp(a) levels were measured by ELISA, apo(a) isoform size was determined by SDS-agarose gel electrophoresis, and analysis of the (TTTTA)(n) was carried out by PCR. For statistical calculation, both groups were divided into low (at least one apo(a) isoform with < or = 22 Kringle IV) and high (both isoforms with >22 KIV) apo(a) isoform sizes, and into low number (<10 in both alleles) and high number of (> or =10 at least one allele) TTTTA repeats. RESULTS: Lp(a) levels were higher (P=0.007), apo(a) isoforms size < or =22 KIV and TTTTA repeats > or = 10 were more frequent (P=0.007 and 0.01) in cases than in controls. Lp(a) levels were found to be increased with low apo(a) weight in both groups (both P<0.0001). In multivariate logistic regression analysis, only the Lp(a) levels (P=0.005) and (TTTTA)(n) polymorphism (P=0.002) were found to be significantly associated with CHD. CONCLUSION: Nevertheless, these results indicate that in CHD patients the (TTTTA)(n) polymorphism has an effect on Lp(a) levels which is independent of the apo(a) size.
Asunto(s)
Apolipoproteínas/sangre , Apolipoproteínas/genética , Enfermedad Coronaria/sangre , Enfermedad Coronaria/genética , Lipoproteína(a)/sangre , Lipoproteína(a)/genética , Polimorfismo Genético/genética , Adulto , Anciano , Anciano de 80 o más Años , Apolipoproteínas/química , Apoproteína(a) , Femenino , Humanos , Lipoproteína(a)/química , Masculino , Repeticiones de Microsatélite/genética , Persona de Mediana Edad , Análisis Multivariante , Isoformas de Proteínas/química , Valores de ReferenciaRESUMEN
Afamin, an 87 kDa human plasma glycoprotein with specific binding properties for vitamin E (alpha-tocopherol) was recently characterized (Jerkovic, 1997; Vögele, 1999). In the present study the in vitro effects on neuronal cells of native human Afamin, of Afamin pre-loaded with vitamin E (Afamin+), and of vitamin E were investigated. Isolated cortical chicken neurons were maintained either under apoptosis-inducing low serum conditions or exposed to oxidative stress by the addition of H2O2 or beta-amyloid peptide(25-35). Afamin and vitamin E synergistically enhance the survival of cortical neurons under apoptotic conditions. Furthermore, Afamin alone protects cortical neurons from cell death in both experimental settings. Therefore, the plasma glycoprotein Afamin apparently displays a neuroprotective activity not only by virtue of binding and transporting vitamin E but also on its own.
Asunto(s)
Antioxidantes/metabolismo , Proteínas Portadoras , Glicoproteínas , Neuronas/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Albúmina Sérica/farmacología , Vitamina E/metabolismo , Animales , Antioxidantes/farmacología , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Humanos , Técnicas In Vitro , Neuronas/citología , Fármacos Neuroprotectores/metabolismo , Albúmina Sérica/metabolismo , Albúmina Sérica Humana , Vitamina E/farmacologíaRESUMEN
The effects of enzymatic action on human low density lipoproteins (LDL) occurring during in vitro incubation of plasma have been studied by chemical analysis, analytical ultracentrifugation, negative stain electron microscopy and X-ray small angle scattering. Chemically, the action of cholesteryl ester exchange and transfer proteins(s) (CEPT) leads to a relative increase in trigylcerides at the expense of cholesteryl esters. Morphologically, the particles maintain their characteristic features detectable by X-ray small angel scattering. Additional action of lecithin/cholesterol acyl transferase (LCAT) causes mainly a decrease in polar lipid contents and a reduction in particle size. The associated changes in the thermotropic transition were found to be strongly correlated to the triglyceride/cholesteryl ester ratio.
Asunto(s)
Glicoproteínas , Lipoproteínas LDL/sangre , Proteínas Portadoras/metabolismo , Proteínas de Transferencia de Ésteres de Colesterol , Humanos , Técnicas In Vitro , Microscopía Electrónica , Fosfatidilcolina-Esterol O-Aciltransferasa/metabolismo , Dispersión de Radiación , Triglicéridos/sangre , UltracentrifugaciónRESUMEN
Recent studies have indicated a beneficial effect of one particular low molecular weight heparin preparation (Fragmin) on lipid metabolism in patients on chronic hemodialysis as compared to unfractionated heparin. We conducted a prospective crossover study with paired comparison of two different anticoagulant agents to examine the effects of a recently released new low molecular weight heparin (Sandoparin) on lipid and lipoprotein parameters in 24 patients starting hemodialysis. During the first six months of observation patients received Sandoparin. Then patients were switched to unfractionated heparin and observed for further six months. After switching from Sandoparin to unfractionated heparin we observed significant decreases in total cholesterol (from 168.6 +/- 42.2 to 154.4 +/- 41.9 mg/dl, p < 0.02), LDL cholesterol (from 106.4 +/- 35.2 to 89.9 +/- 32.3 mg/dl, p < 0.005), triglycerides (from 148.7 +/- 85.0 to 121.4 +/- 88.8 mg/dl, p < 0.05) and apolipoprotein B (from 100.0 +/- 35.3 to 89.9 +/- 30.4 mg/dl, p < 0.05) and a significant increase in HDL cholesterol (from 32.8 +/- 12.5 to 37.7 +/- 17.5 mg/dl, p < 0.02). This is in contrast to earlier results and can possibly be explained by a higher percentage of fractions with high M(r) in the investigated Sandoparin, which results in a more pronounced depletion of lipoprotein lipase. Together with the enhanced hepatic clearance of lipoprotein lipase induced by low molecular weight heparins, this may decrease lipoprotein lipase activity with a subsequent increase in plasma triglycerides, total and LDL cholesterol. We conclude from our data that a general recommendation for clinical use of low molecular weight heparin in hemodialysis patients cannot be given.
Asunto(s)
Fibrinolíticos/uso terapéutico , Heparina de Bajo-Peso-Molecular/uso terapéutico , Lipoproteínas/sangre , Diálisis Renal , Insuficiencia Renal/terapia , Adulto , Colesterol/sangre , Terapia Combinada , Estudios Cruzados , Femenino , Humanos , Lipoproteínas/efectos de los fármacos , Masculino , Estudios Prospectivos , Insuficiencia Renal/sangre , Triglicéridos/sangreRESUMEN
Since the early detection of LCAT by Glomset, a great deal of research has been conducted for establishing the role of this enzyme in the Lp metabolism. It became apparent that LCAT produces more than 3/4 of the CE found in plasma. LCAT acts primarily on Lp with high PC/FC contents and high PC/FC ratios. For expression of the full activity, apo-Lp cofactors such as apo-AI, -CI, -AIV and -E are necessary. Although it was believed for a long time that HDL are the only substrate for LCAT we could demonstrate that LDL and even apoA/C/E free LpB is utilized by LCAT. The CE formed in PC/FC rich Lp are transferred to VLDL and LDL by specific proteins, which also promote the exchange of CE against TG. TG in these particles are hydrolyzed by liver lipase providing new space in the core for further cholesterol esterification. Thus LCAT exerts its physiological role in concert with other enzymes e.g. LPL, hepatic lipase and possibly phospho-lipases as well as with exchange and transfer processes partly catalyzed by specific exchange/transfer proteins. The main function of LCAT without doubt is the reverse cholesterol transport from periphery to liver counteracting the accumulation of CE in reticulo endothelial cells by the scavenger pathway. Metabolic studies revealed that the cholesterol clearance from the circulation proceeds in the same order of magnitude as the esterification by LCAT takes place. This possibly implies that LCAT might be the rate limiting enzyme for cholesterol catabolism from blood.