RESUMO
Tangier disease (TD) is an autosomal recessive disorder of lipid metabolism. It is characterized by absence of plasma high-density lipoprotein (HDL) and deposition of cholesteryl esters in the reticulo-endothelial system with splenomegaly and enlargement of tonsils and lymph nodes. Although low HDL cholesterol is associated with an increased risk for coronary artery disease, this condition is not consistently found in TD pedigrees. Metabolic studies in TD patients have revealed a rapid catabolism of HDL and its precursors. In contrast to normal mononuclear phagocytes (MNP), MNP from TD individuals degrade internalized HDL in unusual lysosomes, indicating a defect in cellular lipid metabolism. HDL-mediated cholesterol efflux and intracellular lipid trafficking and turnover are abnormal in TD fibroblasts, which have a reduced in vitro growth rate. The TD locus has been mapped to chromosome 9q31. Here we present evidence that TD is caused by mutations in ABC1, encoding a member of the ATP-binding cassette (ABC) transporter family, located on chromosome 9q22-31. We have analysed five kindreds with TD and identified seven different mutations, including three that are expected to impair the function of the gene product. The identification of ABC1 as the TD locus has implications for the understanding of cellular HDL metabolism and reverse cholesterol transport, and its association with premature cardiovascular disease.
Assuntos
Transportadores de Cassetes de Ligação de ATP/genética , Glicoproteínas/genética , Mutação , Doença de Tangier/genética , Transportador 1 de Cassete de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/metabolismo , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Bases , Pré-Escolar , HDL-Colesterol/deficiência , HDL-Colesterol/metabolismo , Cromossomos Humanos Par 9 , Feminino , Glicoproteínas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Genéticos , Dados de Sequência Molecular , LinhagemRESUMO
In this study we have determined by radioimmunoassay and double immunoelectrophoresis the total quantities and distributions of A apoproteins in three adult patients affected with Tangier disease (hereditary alpha-lipoprotein deficiency). Compared with normal plasma, the total quantities of apoproteins A-I and A-II in Tangier plasma were determined to be less than 1% and 5-7%, respectively. In Tangier patients, approximately 90% of the apoprotein A-I sedimented when ultracentrifugations of plasma were carried out at density 1.21 g/ml KBr. By contrast, more than 95% of the apoprotein A-II floated under those conditions. In normal plasma, approximately 90% of both apoproteins A-I and A-II is found in the 1.063-1.21-g/ml KBr density fraction. These findings suggest that complete dissociation of A apoproteins occurs in Tangier plasma. This dissociation of apoproteins was confirmed by double immunoelectrophoresis with monospecific antisera. Immunochemical and electrophoretic experiments did not provide evidence for a structural abnormality of apoprotein A-I in these patients, The results taken together strongly suggest that normal high-density lipoproteins are absent from Tangier plasma.
Assuntos
Apoproteínas/sangue , Transtornos das Proteínas Sanguíneas/genética , Lipoproteínas HDL/deficiência , Adulto , Apolipoproteínas/sangue , Transtornos das Proteínas Sanguíneas/sangue , Feminino , Humanos , Imunoeletroforese , Masculino , Pessoa de Meia-Idade , RadioimunoensaioRESUMO
Small unilamellar liposomes prepared from sphingomyelins with defined 14C-labeled fatty acids were studied after injection into rats. The liposomes contained trace amounts of [3H]cholesteryl linoleyl ether (CLE), which served as a nonexchangeable and nonhydrolyzable marker. The liposomes were cleared from the circulation with an initial t1/2 of about 90 min. [14C]18:0- and [14C]18:1-containing sphingomyelins were cleared at a similar rate, but [14C]18:2-sphingomyelin disappeared much faster. The liver accounted for up to 70% of [3H]cholesteryl ether injected with 18:0-sphingomyelin liposomes, and for up to 50% with liposomes prepared from 18:1 or 18:2-sphingomyelin. The initial uptake of the liver appeared to be of the entire particle, and the loss of 14C label with time indicated metabolism of the sphingomyelins. With [14C]18:0-sphingomyelin liposomes, up to 8% of liver radioactivity was recovered in neutral lipids 6 h after injection, and this value was 17 and 22% with [14C]18:2- and [14C]18:1-sphingomyelins, respectively. The recovery in 'carcass' of [3H]cholesteryl ether 3 h after injection of [14C]18:2-sphingomyelin liposomes was 33% and of 14C label, 21%. Injection of 18:1- or 18:2-sphingomyelin liposomes (5.4 mumol/100 g body weight) resulted in a 2-fold increase of plasma unesterified cholesterol; a 30% increase was seen with 18:0 liposomes (2.63 mumol/100 g body weight). In experiments with cultured cells, the unsaturated sphingomyelin liposomes alone enhanced cholesterol efflux more extensively than the saturated ones, but their efficacies became similar when mixed with apoprotein (apo) A-I. At equimolar concentration, apo C-III1 or C-III2 had a smaller effect than apo A-I. It is concluded that 18:1- or 18:2-sphingomyelin tends to form small unilamellar liposomes which may reach also extrahepatic tissues. The liposomes able to enhance cholesterol release in vitro and in vivo. Since they are not a substrate for lecithin-cholesterol acyltransferase, they should be able to deliver the free cholesterol to the liver, where they are also rapidly metabolized.
Assuntos
Colesterol/metabolismo , Ácidos Graxos/metabolismo , Lipossomos , Esfingomielinas/metabolismo , Glândulas Suprarrenais/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Relação Dose-Resposta a Droga , Eritrócitos/metabolismo , Ácidos Graxos/farmacologia , Fígado/metabolismo , Pulmão/metabolismo , Masculino , Ratos , Esfingomielinas/farmacologia , Baço/metabolismoRESUMO
Syrian hamsters were rendered hypercholesterolemic by supplementation of their diet with 1% cholesterol and 15% butter. The hamsters were injected intraperitoneally (i.p.) with about 20 mg of phospholipid liposomes containing trace amounts of [3H]cholesteryl linoleyl ether ([ 3H]CLE) alone or combined with 10 mg delipidated high-density lipoprotein (apoHDL). After 2 h the peritoneal cavity was washed repeatedly with up to 15 ml phosphate-buffered saline. 60%-70% of [3H]CLE were retained after i.p. injection without apoHDL, 30-50% in the presence of apoHDL. The amount of free cholesterol recovered in the peritoneal lavage was significantly higher when apoHDL was combined with 18:2 sphingomyelin or dilinoleyl phosphatidylcholine liposomes, when compared to either liposomes or apoHDL alone. It is suggested that supplementation of dialysate with HDL apolipoproteins and phospholipids in patients undergoing continuous peritoneal dialysis could be of use in a cholesterol depletion regimen.
Assuntos
Colesterol/metabolismo , Hipercolesterolemia/metabolismo , Lipoproteínas HDL/metabolismo , Lavagem Peritoneal , Fosfolipídeos/metabolismo , Animais , Cricetinae , Masculino , MesocricetusRESUMO
The metabolism of sphingomyelin labeled with 3-[3H]sphingosine and [14C]16:0 or [14C]18:2 fatty acid was studied in cultured Hep G2 cells or macrophages and after injection into rats. In pulse-chase experiments, the loss of 3H and 14C-label was more rapid when the cells had been pulsed with 18:2 than with 16:0 sphingomyelin. At the end of 24 h chase, the labeled ceramide contained more [14C]18:2 fatty acid than [14C]16:0. In addition, the 3H-label derived from 3-[3H]sphingomyelin was recovered also as free sphingosine. After injection in vivo, more [3H]sphingosine-labeled sphingomyelin was present in the liver 3 and 24 h after injection of 16:0 than after injection of 18:2 sphingomyelin. The ratio of [3H]ceramide derived from 16:0 sphingomyelin to that derived from 18:2 sphingomyelin as percent of injected dose was 1.84 3 h after injection and 1.31 after 24 h. The ratio of 3H/14C in liver ceramide was 6.4 3 h after injection of 18:2 sphingomyelin and 3.4 after 16:0 sphingomyelin. The present results show that 3-[3H]sphingomyelin is metabolized quite extensively and that the fate of the sphingosine moiety is related to the type of fatty acid present in the phospholipid. These findings indicate that there is little or no reutilization of 18:2 ceramide for sphingomyelin formation and suggest that sphingosine derived from 18:2 sphingomyelin is channeled primarily for catabolism.
Assuntos
Ácidos Linoleicos/metabolismo , Fígado/metabolismo , Ácidos Palmíticos/metabolismo , Esfingomielinas/metabolismo , Esfingosina/metabolismo , Animais , Linhagem Celular/metabolismo , Humanos , Ácido Linoleico , Lipossomos , Macrófagos/metabolismo , Masculino , Ácido Palmítico , Ratos , Esfingomielinas/administração & dosagemRESUMO
The metabolism of sphingomyelins and ceramides with defined labeled fatty acids was compared after injection in vivo or incubation with cultured cells. The liver was the major site of uptake of sphingomyelins and ceramides with 18:2 or 16:0 fatty acids, but with both sphingolipids a higher recovery of radioactivity was found with 16:0 species. The distribution of radioactivity among liver lipids showed that 1.5 h after injection of 18:2 sphingomyelin, only 21% of the label was found as sphingomyelin, and this value was 37% in the case of 16:0 sphingomyelin. There was a very marked difference in the metabolism of 18:2 and 16:0 ceramides. After injection of 18:2 ceramide only 14% of the radioactivity was recovered as sphingomyelin, and this value was more than 50% with 16:0 ceramide. [14C]18:2 ceramide was converted also to glucoceramide and hydrolyzed more extensively than 16:0 ceramide. These observations were extended to sphingomyelins and ceramides with other fatty acids, using Hep-G2 cells in culture. Significantly more radioactivity was recovered as labeled sphingomyelin after incubation with 16:0, 18:0, 20:0 and 24:0 sphingomyelins than with 18:1 and 18:2 sphingomyelins, while more labeled phosphatidylcholine and phosphatidylethanolamine were found with the unsaturated sphingomyelins. In analogy to the findings in vivo, in the Hep-G2 cells more 16:0, 18:0 and 24:0 ceramides were converted to sphingomyelin than 18:1 or 18:2 ceramides. These differences were also seen with cultured macrophages, in which a more marked reutilization for sphingomyelin formation was found with the saturated ceramide series. The sphingomyelin liposomes were tested also for their capacity to mobilize cholesterol, and a rise in plasma unesterified cholesterol occurred after injection of 18:2 sphingomyelin. Marked enhancement of cholesterol efflux from cholesterol ester-loaded macrophages was also seen with 18:1 and 18:2, 20:0 sphingomyelin in the presence of delipidated high-density lipoprotein. The present results demonstrate that the metabolic fate of sphingolipids is related to their fatty acid composition. While ceramides with saturated fatty acids are predominantly reutilized for sphingomyelin formation, those with unsaturated fatty acids undergo probably more rapid hydrolysis with liberation of fatty acids and channeling into glycerolipids.
Assuntos
Ceramidas/metabolismo , Fígado/metabolismo , Esfingomielinas/metabolismo , Animais , Ácidos Graxos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Masculino , Ratos , Células Tumorais CultivadasRESUMO
Human skin fibroblasts (HSF) were exposed to sphingomyelinase 50 or 5 mU/ml for 60 min, washed with 5 mM EDTA or 20% serum and with phosphate-buffered saline, and postincubated for 24 h in the presence of [14C]16:0 sphingomyelin (SP) liposomes. The recovery of up to 48% of label in the medium in ceramide provided evidence of persistence of sphingomyelinase activity. The rate of hydrolysis of [14C]16:0 SP remained the same irrespective of whether the liposomes were added immediately after the wash, or 3 or 6 h thereafter. In HSF labeled with [3H]cholesterol exposure to 50 mU/ml of sphingomyelinase for 60 min resulted in an increase in labeled cholesteryl ester (CE) at 6 and 24 h of postincubation. Addition of sphingomyelin liposomes reduced markedly the fraction of cellular labeled cholesteryl ester recovered after 24 h, while phosphatidylcholine liposomes were not effective. When the enzyme concentration had been reduced 5-20 fold the effect of sphingomyelin liposomes on cellular 3H-CE was evident already after 6 h of postincubation and some effect was seen also with phosphatidylcholine liposomes. Increase in the concentrations of SP liposomes to 150 micrograms/ml restored labeled cholesteryl ester to control values at 24 h. A significant reduction occurred also with 18:1 phosphatidylcholine liposomes but labeled cholesteryl ester remained 50-100% higher when compared with 18:1 or 18:2 SP. No correlation was seen between the rates of cholesteryl ester decrease and free cholesterol efflux into the medium. The inability to remove residual sphingomyelinase by regular washing procedures exaggerates and prolongs the recovery period of sphingomyelin during postincubation and delays the return of the cholesteryl ester pool to control levels. This can be counteracted by addition of phospholipid liposomes that can compete for the enzyme with the plasma membrane sphingomyelin and also substitute the hydrolyzed molecule in the plasma membrane to impede cholesterol flow to cell interior.
Assuntos
Ésteres do Colesterol/metabolismo , Fibroblastos/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Humanos , Hidrólise , Lipossomos , Fosfatidilcolinas/metabolismo , Pele/citologia , Esfingomielinas/metabolismoRESUMO
Conflicting evidence has accumulated with years regarding the putative negative effect of apolipoprotein A-II on apo A-I mediated cholesterol efflux. In this study, this question was reexamined and in addition to the interaction of apo A-II with apo A-I, its possible effect on apo E and apo A-IV was investigated as well. Free cholesterol (FC) donors were the main components of atheroma, namely, mouse peritoneal macrophages (MP), bovine aortic smooth muscle (SMC) and fibroblasts labeled with [3H]FC. Acceptors of FC were dioleoylphosphatidylcholine (DOPC) liposomes containing apo A-I, rh-apo A-IV or rh-apo E alone or together with apo A-II. When [3H]FC labeled MP were incubated for 2 or 4 h with equimolar concentrations of apo A-I, A-II, A-IV or E, the lowest [3H]cholesterol efflux occurred with apo A-II. Exposure of [3H]FC MP to liposomes containing apo A-I/A-II at 1:2 M/M (keeping the total protein concentration at 50 micrograms/ml), resulted in a lower [3H]FC efflux as compared to apo A-I alone. However, when apo A-I or apo A-IV protein concentration was kept constant and supplemented with apo A-II, a lower [3H]FC efflux was found only at 1:3 M/M of apo A-I/A-II. Apo A-II added to apo E had no effect on FC efflux. With aortic SMC and fibroblasts, no inhibitory effect of addition of apo A-II to apo A-I or apo A-IV on cholesterol efflux was seen at apo A-I/A-II of 1:1 or 1:2 M/M. The uptake of macrophage derived [3H]FC by SMC or HepG2 cells was studied using the serum-free efflux media, containing PC liposomes + apolipoproteins, from 3H-labeled macrophages. The cellular uptake of [3H]FC was higher when apo A-II had been added to apo A-I or apo A-IV than when the apolipoproteins were added alone. In conclusion, apo A-II was found to be less effective in cholesterol efflux and to interfere with the action of A-I only when the cholesterol donors were macrophages and when the relative amount of apo A-I to apo A-II was low. This was not the case when SMC or fibroblasts served as cholesterol donors. In the presence of apo A-II, enhanced [3H]cholesterol delivery to cells was seen which could contribute to the proatherogenic activity of apo A-II.
Assuntos
Apolipoproteína A-II/farmacologia , Apolipoproteína A-I/metabolismo , Colesterol/metabolismo , Animais , Apolipoproteína A-II/metabolismo , Arteriosclerose/metabolismo , Transporte Biológico , Bovinos , Células Cultivadas , Lipossomos , Fígado/metabolismo , Macrófagos/metabolismo , Camundongos , TrítioRESUMO
A group of 252 chronic hemodialysis patients was examined for various risk factors. Special emphasis was placed upon the comparison of patients who had marked cardiovascular alterations with the remainder of the group. The seriousness of the risk factors was determine by hypertension and hyperlipoproteinemia, 78% of the patients received antihypertensive medication or had changes in the fundus of the eye or both. In 74% of the patients there were pathological changes in the plasma lipids or lipoproteins or both. Hypertriglyceridemia (49%) and a HDL cholesterol decrease (61%) were the most striking findings. The average VLDL cholesterol value was significantly higher and the HDL cholesterol significantly lower in the coronary heart disease group than in the remaining group. These results show that hyperlipoproteinemia and a decrease in HDL, together with other risk factors such as hypertension and anemia, play an important role in the accelerated development of atherosclerosis in a hemodialysis group.
Assuntos
Doença das Coronárias/etiologia , Hiperlipoproteinemias/complicações , Hipertensão/complicações , Diálise Renal/efeitos adversos , Fatores Etários , Arteriosclerose/etiologia , Colesterol/sangue , HDL-Colesterol , VLDL-Colesterol , Feminino , Glomerulonefrite/terapia , Humanos , Lipoproteínas HDL/sangue , Lipoproteínas VLDL/sangue , Masculino , Pessoa de Meia-Idade , Pielonefrite/terapia , Risco , Fatores de Tempo , Triglicerídeos/sangueRESUMO
According to our hypothesis, organ-specific lectins (e.g., the D-galactose-specific hepatic binding protein) play an important role in the organ location of metastatic malignant cells. The rapid clearance and uptake by the liver of tritiated alpha 1-acid-(asialo)glycoprotein from the circulation of Balb/c mice was markedly delayed after preinjection of D-galactose or arabinogalactan. The preinjection (1 h) and regular application (for 3 days after tumor cell inoculation in Balb/c mice) of the receptor blocking agents D-galactose and arabinogalactan prevented the settling of sarcoma L-1 tumor in the liver completely, but did not influence the settling in the lung. Other galactans, dextrans, and phosphate-buffered saline showed no effect. Therefore, when lectins were blocked with competitive-specific glycoconjugates, colonization was prevented.
Assuntos
Receptor de Asialoglicoproteína , Proteínas de Transporte/antagonistas & inibidores , Neoplasias Hepáticas/secundário , Metástase Neoplásica , Sarcoma Experimental/patologia , Animais , Assialoglicoproteínas/metabolismo , Galactanos/farmacologia , Galactose/farmacologia , Lectinas/antagonistas & inibidores , Neoplasias Hepáticas/prevenção & controle , Camundongos , Camundongos Endogâmicos BALB CRESUMO
An in vivo comparison of three dosages (3 g, 6 g, 12 g) of two different fish oil preparations in terms of plasma concentrations of their major active components eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) was performed. The plasma accumulation was measured during 28 days of ingestion and an equally long wash out period. Data were scrutinized for bioavailability in order to distinguish between the efficiency of the two preparations. Rapid increases in EPA and DHA plasma concentrations can be demonstrated at all dosages during a 28-day ingestion period. EPA accumulated more during ingestion of high than of low dosages of fish oil. DHA revealed almost identical increases and peak values in plasma concentrations in all subgroups. The present data demonstrate dose dependent increases of EPA concentrations whereas DHA plasma concentrations are comparable in all dosages investigated. Measurable EPA and DHA plasma concentration levels are inappropriate means to explain clinical effectiveness. These results were found in both commercially available fish oil preparations. Direct comparison of both preparations revealed no differences in bioavailability.
Assuntos
Gorduras Insaturadas na Dieta/metabolismo , Ácidos Docosa-Hexaenoicos/sangue , Ácido Eicosapentaenoico/sangue , Ácidos Graxos Ômega-3/farmacocinética , Óleos de Peixe/farmacocinética , Adulto , Disponibilidade Biológica , Gorduras Insaturadas na Dieta/administração & dosagem , Combinação de Medicamentos , Eritrócitos , Feminino , Hematócrito , Hemoglobinas/análise , Humanos , MasculinoRESUMO
In patients undergoing high-dose ifosfamide treatment tubular nephrotoxicity with hypophosphatemia has been described. Long-lasting hypophosphatemia may be associated with bone disease including rickets. Serum osteocalcin is considered a sensitive marker for reduced osteoblast activity and bone formation. In our study we determined osteocalcin serum levels in 11 children with cancer and chemotherapy, comparing them with fractional reabsorption of phosphate, aminoaciduria and a1-microglobulin excretion. A decrease of serum levels of osteocalcin and serum phosphate during chemotherapy was found. Progressive hyperaminoaciduria, a1-microglobulin loss and a low fractional reabsorption of phosphate were also detected during chemotherapy. All parameters tended to become normal after treatment. We conclude that serum osteocalcin levels may decrease soon after the initiation of chemotherapy, indicating low osteoblast activity, probably as a result of phosphate loss. Patients with decreased osteocalcin levels may therefore be at risk for osteoporosis.
Assuntos
Ifosfamida/farmacologia , Neoplasias/sangue , Osteocalcina/sangue , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores/sangue , Criança , Humanos , Ifosfamida/administração & dosagem , Ifosfamida/efeitos adversos , Nefropatias/induzido quimicamente , Neoplasias/tratamento farmacológico , Osteoblastos/fisiologia , Fosfatos/sangueRESUMO
INTRODUCTION: The elimination of high molecular weight proteins may have a positive influence on disorders of the microcirculation due to an improvement in rheological parameters. We therefore attempted to evaluate the rheological efficacy of membrane differential filtration (MDF). PATIENTS AND METHODS: Ten patients suffering from macular disease underwent MDF. Rheological and biochemical parameters as well as visual acuity were determined one day before and after therapy: The study aimed at a reduction in plasma viscosity, standardized whole blood viscosity at hematocrit 0.45 and erythrocyte aggregation at hematocrit 0.3. RESULTS: Severe side-effects were not observed. The rheological parameters were significantly reduced. In detail the posttreatment values were reduced as compared to the pretreatment values as follows: plasma viscosity 85%, standardised whole blood viscosity 86% (hematocrit 0.45), erythrocyte aggregation 59% (hematocrit 0.3), total protein 81%, IgG 66%, IgA 59%, IgM 33%, alpha-2-macroglobulin 30%, triglycerides 102%, total cholesterol 47%, VLDL cholesterol 94%, LDL cholesterol 33%, HDL cholesterol 62%. Visual acuity was improved in 7/10 patients. CONCLUSIONS: MDF is a safe and highly effective method for lowering biochemical and improving rheological parameters which led to improvement in visual acuity. We have already replaced plasma exchange with MDF in our clinical practice of hemorrheological therapy.
Assuntos
Remoção de Componentes Sanguíneos , Filtração/métodos , Degeneração Macular/terapia , Idoso , Contagem de Células Sanguíneas , Análise Química do Sangue , Coagulação Sanguínea , Proteínas Sanguíneas/metabolismo , Eletrólitos/sangue , Agregação Eritrocítica , Feminino , Hematócrito , Humanos , Lipídeos/sangue , Masculino , Membranas Artificiais , Pessoa de Meia-Idade , Peso Molecular , Reologia , Resultado do TratamentoRESUMO
In a prospective and double-blind study, the long-term effects of low dose fish oil on serum lipids and lipoproteins was tested in patients with normal or moderately elevated serum lipids and compared to the effects of olive oil. The compliance to the study medication was evaluated by analysis of serum fatty acids and proved to be very good. Dietary supplementation with 9 g fish oil, respective 3.15 g n-3 fatty acids per day over one year resulted in a decrease of serum-triglycerides by 26% and increase of HDL-cholesterol by 26%. Treatment with 9 g olive oil resulted in an 18% increase of HDL-cholesterol. There was no effect on serum-triglyceride levels.
Assuntos
Arteriopatias Oclusivas/sangue , Doença das Coronárias/sangue , Óleos de Peixe/administração & dosagem , Lipídeos/sangue , Lipoproteínas/sangue , Adulto , Idoso , Colesterol/sangue , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos ProspectivosRESUMO
In accordance with metabolic properties in the mucosal and liver cells, the exogenous fatty acids may be classified as short chain (C4 and C6), medium chain (C8 and C10), transitional (C12 and C14) and long chain (C16 upward) fatty acids. The postprandial fatty acid metabolism takes place in two phases. In the first, approximately 8 hour phase, the clearance of chylomicrons and most of the chylomicron remnants as well as the uptake of short and medium chain fatty acids by the liver are completed. Most of the exogenous long chain fatty acids (chylomicron fatty acids) are cleared extrahepatically. However, about 10% of the long chain fatty acids are taken up by the liver, and during the second postprandial phase, lasting about 24 hours, the liver secretes most of these exogenous fatty acids with very low density lipoproteins. The exogenous fatty acids may circulate between the liver and adipose tissue until they are finally metabolized mainly in extrahepatic tissues.
Assuntos
Gorduras na Dieta/metabolismo , Ácidos Graxos/metabolismo , Colesterol/metabolismo , Ésteres do Colesterol/metabolismo , Quilomícrons/metabolismo , Humanos , Metabolismo dos Lipídeos , Fígado/metabolismo , Triglicerídeos/metabolismoRESUMO
A group of 218 patients with severe hypercholesterolemia (LDL cholesterol > 260 mg/dl) living in the Cologne area were screened for mutations in the 3 half of exon 4 of the low density lipoprotein (LDL) receptor gene by the single-strand conformation polymorphism (SSCP) method. The analysed fragment was 242 bp in length and comprised approximately 6% of the coding region. In 11 patients an abnormal SSCP pattern was observed. Two of the abnormal fragment patterns were identical. The results of the SSCP screening could be confirmed by direct DNA sequencing. Three of the ten different mutations were previously described (3 bp deletion: codon 197; Asp200-->Gly; Glu207-->stop). Of the newly identified mutations there were two deletions, two insertions, one combined insertion and deletion mutation and two single base pair substitutions [1 bp deletion: G in codon 197; 37 bp deletion: T in codon 196-208 or AT in 196-207 and GA in codon 208; 18 bp insertion: codon 201-206; 8 bp insertion: codon 155-156 and GA in codon 157; 6 bp insertion (codon 196-197) and 5 bp deletion (codon 199, C in codon 198 and G in codon 198 or 200); Asp200-->Tyr; Asp203-->Val]. The 8-bp insertion was detected in a second unrelated individual. The analysis of the functional consequences of the mutations indicates that all mutations were causative of the LDL cholesterol elevation.
Assuntos
Éxons , Testes Genéticos , Hipercolesterolemia/genética , Receptores de LDL/genética , Sequência de Bases , Colesterol/sangue , Primers do DNA , Alemanha , Humanos , Dados de Sequência Molecular , Mutação Puntual/genética , Polimorfismo Conformacional de Fita Simples , Deleção de Sequência/genéticaRESUMO
The effects of 20 and 40 g postoperative intravenous human albumin (HA) infusion on the serum protein fractions and on the colloid osmotic pressure (COP) were analyzed in 72 septic and aseptic patients. Only aseptic patients showed an increase in the COP as well as the serum albumin concentration during at least a 24-h-period. In septic patients, however, the increased serum albumin concentration dropped rapidly to the initial values. This can be only explained by a disturbance of the membrane permeability. In contrast, the behavior of the serum globulin concentration was not essentially influenced by septic or non septic conditions.
Assuntos
Proteínas Sanguíneas/metabolismo , Albumina Sérica/administração & dosagem , Infecção da Ferida Cirúrgica/sangue , Adulto , Idoso , Testes de Coagulação Sanguínea , Cuidados Críticos , Feminino , Fibrinogênio/metabolismo , Hematócrito , Humanos , Lipídeos/sangue , Masculino , Pessoa de Meia-Idade , Soroglobulinas/metabolismo , Infecção da Ferida Cirúrgica/terapia , Equilíbrio HidroeletrolíticoRESUMO
We have studied the effect of simvastatin, an inhibitor of the rate-limiting enzyme in cholesterol biosynthesis, alone and in combination with cholestyramine in 48 patients. Simvastatin 40 mg decreased total serum cholesterol, LDL cholesterol and apolipoprotein B by 35%, 40% and 35%, respectively, while HDL cholesterol and apolipoprotein A-I increased by 10% (p less than 0.01) and 7% (p less than 0.05), respectively. The addition of 8 g cholestyramine caused a further decrease in total cholesterol and LDL cholesterol to a total of 42% and 49%, respectively. Eighteen of the 48 patients have now been under combined treatment for 2 years. The initial high decreases in total cholesterol and LDL cholesterol were stabilized for the whole period. Some patients developed gastrointestinal complaints, which made necessary a reduction of simvastatin in two cases. Biochemical side effects (e.g. increases in CK and transaminases) were not observed.
Assuntos
Anticolesterolemiantes/uso terapêutico , Resina de Colestiramina/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases , Hiperlipoproteinemia Tipo II/tratamento farmacológico , Lovastatina/análogos & derivados , Adulto , Quimioterapia Combinada , Feminino , Humanos , Lovastatina/uso terapêutico , Masculino , Pessoa de Meia-Idade , SinvastatinaRESUMO
In the study of the relatively slow amylase-catalysed hydrolysis of oligosaccharides, it is assumed that the subsequent mutarotation has essentially no effect on the kinetics of the total reaction. Relatively large sampled and long measurement times (slow rate of change in angle of rotation) are necessary for the polarimetric determination of alpha-amylase activity. For these reasons, only urine and duodenal juice are suitable as sample sources. Owing to the absence of coupled reactions and auxilliary enzymes, the polarimetrically determined kinetics are generally more representative of the true kinetics of the amylase reaction, than those obtained with fully enzymic methods; in addition, single determinations by the polarimetric method are less subject to interference by sample components. With measurement times in the order of minutes, the polarimetric method shows excellent linearity, very good proportionality between analytical response and quantity of enzyme, and good precision in series (CV = 1.3%). Comparison of the polarimetric with a chromogenic and a fully enzymic method showed an acceptable correlation (r for each method was about 0.98). T, the polarimetric method shows excellent linearity, very good proportionality between analytical response and quantity of enzyme, and good precision in series (CV = 1.3%). Comparison of the polarimetric with a chromogenic and a fully enzymic method showed an acceptable correlation (r for each method was about 0.98). T, the polarimetric method shows excellent linearity, very good proportionality between analytical response and quantity of enzyme, and good precision in series (CV = 1.3%). Comparison of the polarimetric with a chromogenic and a fully enzymic method showed an acceptable correlation (r for each method was about 0.98). The advantages and disadvantages of the polarimeatric method, with consideration of possible interfering factors, are discussed.