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The plasma lecithins:cholesterol acyltransferase reaction.

Evidence for the existence of a plasma lecithin : cholesterol acyltransferase is reviewed with emphasis not only on the lipid reactants, but also on the lipoprotein "substrates" and "products." The cholesteryl esters of all major lipoprotein classes become labeled when plasma is incubated with cholesterol-(14)C. However, the smaller, lecithin-rich high density lipoproteins appear to be preferred substrates. Most studies of factors that influence the acyltransferase reaction have not adequately distinguished between effects on the enzyme and effects on the lipoprotein substrates. However, the fact that cholesterol esterification is diminished in plasma from eviscerated animals or from patients with reduced liver function suggests that the liver may regulate both the level of the enzyme and that of the substrates. Several indications exist that the acyltransferase reaction is the major source of plasma esterified cholesterol in man. Furthermore, the reaction may have a broader, extracellular function. One possibility is that it plays a role in the transport of cholesterol from peripheral tissues to the liver.

Acyltransferases↗

Role of plasma lecithin:cholesterol acyltransferase in the metabolism of high density lipoproteins.

The role of the plasma lecithin:cholesterol acyltransferase reaction in the esterification of the cholesterol of human and baboon plasma high density lipoproteins has been studied. Human plasma was incubated in vitro, and the initial rate of cholesterol esterification in lipoprotein fractions obtained by chromatography on hydroxylapatite was determined. The rate of esterification was greater in the high density lipoprotein fraction than in the low density lipoprotein fraction. High density lipoproteins from human and baboon plasma were filtered through columns of Sephadex G 200, and the relative concentrations in the effluent of key lipids involved in the acyltransferase reaction were determined. The ratio of esterified to unesterified cholesterol varied across the lipoprotein peak obtained from either type of plasma. The relative concentration of lecithin compared to sphingomyelin also varied across the peaks obtained with human high density lipoproteins. When human or baboon plasma was incubated with cholesterol-(14)C and the high density lipoproteins were filtered through Sephadex, the specific activity of the esterified cholesterol varied across the lipoprotein peak. Similar results were obtained when plasma esterified cholesterol was labeled in vivo by the injection of labeled mevalonate into baboons. The data suggest that the acyltransferase reaction is the major source of the esterified cholesterol of the high density lipoproteins.

Acyltransferases↗

Control of lecithin biosynthesis in erythrocyte membranes.

The detailed relationship between the relative composition of the potential precursor acids, the esterification rates of their CoA thiol ester derivatives, and the relative composition of the fatty acids in the product, lecithin, which was isolated from normal erythrocytes, suggests that in humans the stromal acyltransferases could be the significant enzymatic factor controlling the fatty acid composition at the 2-position of lecithin in erythrocytes.

Acyltransferases↗

Effect of human plasma apolipoproteins on the activity of purified lecithin: cholesterol acyltransferase.

An active preparation of lecithin: cholesterol acyltransferase (LCAT, EC 2.3.1.43) was isolated from human plasma by density ultracentrifugation, high-density lipoprotein affinity chromatography, DEAE-Sepharose and hydroxylapatite chromatography. This enzyme preparation gave a single band on polyacrylamide gel electrophoresis in 8 M urea and on sodium dodecyl sulfate gel electrophoresis. Upon analytical isoelectric focusing the enzyme separated into at least five isoforms with isoelectric points ranging from 5.1 to 5.5. The enzyme with an apparent molecular weight of 66,000 +/- 2,000 was characterized by a high content of glutamic acid, aspartic acid, leucine and glycine and contained approximately 31 moles of glucosamine/10(3) moles of protein and no galactosamine. The purified enzyme, stored at 20-40 microgram/ml at 4 degrees C, had a half-life of 26 +/- 4 days. The effect of purified human plasma apolipoproteins A-I, A-II, C-I, C-II, C-III and D on the activity of purified LCAT was studied, using egg-yolk lecithin (40 microM): cholesterol (10 microM) vesicles prepared in 1.25% ethanol in the absence or presence of 0.5% albumin. Addition of albumin to the incubation mixture nearly doubled the esterification rate of LCAT with A-I as activator (n=4), whereas it inhibited esterification by approximately 35% (n=3) if C-I was the activator. Maximum activation by C-I yielded only 13 +/- 6% (vesicles with albumin) or 42 +/- 5% (vesicles without albumin) of the LCAT activity obtained with A-I. Each of the apoproteins A-II, C-II, C-III and D inhibited the LCAT reaction in the presence of A-I or C-I at concentrations needed for maximal activation. Contrary to previous work, apolipoprotein D does not appear to be an activator of LCAT. LCAT activity is significantly affected by albumin and the apolipoproteins A-II, C-II, C-III, and D.

Amino Acids↗

Effects of cicloxilic acid on secretory function of the liver. II. Effect on biliary secretion of bile acids, cholesterol and lecithin in anesthetised bileduct-cannulated rat.

cis-2-Hydroxy-2-phenyl-cyclohexanecarboxilic acid (cicloxilic acid) increases the output of bile acids and decreases that of cholesterol both in normal and in sodium taurocholate-infused rats; the biliary output of lecithin remains unchanged in normal animals but is increased in taurocholate-treated animals. The increased output of bile acids is interpreted as true stimulation of the bile-forming function of the liver, an activity supposedly mediated by stimulation of the metabolism of cholesterol to bile acids, independent of the drug's hydrocholeretic properties. The changes in the relative molar concentrations of the three micelle-forming bile constituents, namely bile acids, cholesterol, and lecithin, induced by cicloxilic acid lead to an appreciable lowering of the lithogenic index, thus suggesting that the drug may have antilithogenic activity.

Animals↗

Some electrical properties of cerebroside and lecithin bilayer membranes.

Electrical potentials of cerebroside and lecithin bilayers in the presence of Na+, Ca2+, and Sr2+ were measured. Calculated membrane specific resistances were about 10(7) ohm cm2. Calculated transference numbers for Na+, Ca2+, and Sr2+ were between 0.5 and 0.6, and were higher in both membranes than in free solution. Thus membranes are slightly cation selective. Specific conductances and transference numbers were then used to calculate ionic flux of membranes. Sodium ions had a much greater ionic flux in both membranes than calcium and strontium ions. The results indicate that the electrical properties of cerebroside and lecithin bilayer membranes are compatible with the structures of those membranes.

Calcium↗

Effects of dietary lecithin on hormonal and neurobehavioral profiles in normal subjects.

Four normal subjects received lecithin supplements sufficient to elevate serum choline levels 3-fold. Despite persistent hypercholinemia over 48 hours of close observation, no increase was observed in serum ACTH, cortisol, and insulin concentrations, or in free urinary catecholamine excretion. Screening of a large group of other pituitary and gonadal hormones also failed to reveal any influence of lecithin supplements. EEG patterns and results of psychometric tests were also unaltered.

Acetylcholine↗

Abnormal lecithin:cholesterol acyltransferase activation by a human apolipoprotein A-I variant in which a single lysine residue is deleted.

An apolipoprotein (apo) A-I variant that has a relative charge of -1 compared to normal apo-A-I on isoelectric focusing gels has been identified in five unrelated families as a result of screening a large number of individuals. The cause of the electrophoretic abnormality has been examined by analyzing the variant apo-A-I structure. The evidence suggests that a single amino acid, lysine 107, has been deleted in the variant apo-A-I of all affected individuals studied from these families, with the remainder of the variant apo-A-I sequence being unaffected. The deletion of this single basic amino acid residue is sufficient to account for the charge difference between the variant and normal apo-A-I as seen on isoelectric focusing gels. This variant, previously referred to as A-I-Marburg or A-I-Münster-2, can now be designated by the structural abnormality apo-A-I(Lys107----0). The evidence from extensive pedigree analysis suggests the likelihood that the deletion mutant gene is allelic to the normal apo-A-I gene. At the same time, the kindred analyses have failed to yield a lipid abnormality that can be unequivocally related to the presence of this deletion mutant of apo-A-I. However, all subjects expressing apo-A-I(Lys107----0) also express normal apo-A-I, so that any abnormality caused by the variant apo-A-I might be adequately compensated for by the normal apo-A-I. To examine directly the functional consequence of the lysine deletion, the isolated variant was tested in vitro for its ability to activate lecithin:cholesterol acyltransferase, the principal cholesterol-esterifying enzyme in plasma. It was found that apo-A-I(Lys107----0) is deficient in its ability to activate lecithin:cholesterol acyltransferase, having only 40-60% of the cofactor activity of normal apo-A-I. The cofactor activity of the pro-apo-A-I component of the variant was also reduced to about 60% of either normal A-I or normal pro-apo-A-I. The functional defect is probably related to a disruption in the secondary and/or tertiary structure of the protein caused by the deletion of lysine 107 in the primary structure.

Adult↗

Stimulation of lecithin:cholesterol acyl transfer by intravenous injection of heparin.

Intravenous injection of 100 IU heparin per kg body weight caused elevation of the lecithin:cholesterol acyl transfer rate in each one of 11 men, in whom before as well as 5 min and 30 min after heparin application the concentration of unesterified fatty acids in plasma did not reach 0.8 mmol/l. The plasma concentration of unesterified cholesterol in high-density lipoproteins (HDL) increased in parallel at the expense of unesterified cholesterol in very low-density lipoproteins (VLDL) and low-density lipoproteins (LDL). For HDL cholesteryl esters an opposite effect was observed. The results support the hypothesis of a participation of the lecithin:cholesterol acyl transferase (LCAT) in VLDL breakdown.

Cholesterol, HDL↗

[Ferricyanide ion binding sites on the surface of lecithin liposomes].

Interaction of ferricyanide ions with sonicated lecithin liposomes has been studied by (1)H-NMR. Ferricyanide induced shifts have been shown to change along the choline chain of the lecithin head group. The magnitude of the shift decreases as the distance from the positive end of zwitterionic moiety increases. It is concluded that ferricyanide ions bind to the positive charged ammonium groups of the phospholipid.

Binding Sites↗

[Lecithin and sphingomyelin in amniotic fluid in late pregnancy in dairy cows].

Phospholipides were isolated from 26 amniotic fluids of highly pregnant dairy cows and the lecithin : sphingomyelin ratio (the L/S index) was determined; this ratio ranged from 1.9 to 12.0 (mean = 6.5; n = 20), and in other cases only lecithin was clearly detected (n = 6). During the studied period of 249 to 277 days of pregnancy, no significant correlation was found, by the method used, between the age of the foetus and the L/S index in the amniotic fluid. The modifications of the methods in which the concentrations of different phospholipids are used for the determination of the maturity of foetal lungs, are discussed, together with the possibility of using and interpreting the L/S index in cattle.

Amniotic Fluid↗

Failure of single-dose lecithin to alter aspects of central cholinergic activity in Alzheimer's disease.

The effect of a single dose (15 g/70 kg) of lecithin (95% phosphatidylcholine) on several measures of central cholinergic activity (memory, cortisol, prolactin, pulse, blood pressure) was assessed in individuals with Alzheimer's disease. In contrast to the reported effects of physostigmine, a cholinesterase inhibitor, lecithin had no effect on these parameters, despite significant increases in plasma and erythrocyte choline.

Aged↗

Lecithin in Parkinson's disease.

Pathological and biochemical evidence reviewed favours the hypothesis that the dementia seen in Parkinson's disease, particularly after long-term levodopa therapy, is akin to Alzheimer's disease. We postulate, in late Parkinson's disease, the development of a relative cholinergic deficiency due to the accelerated process of aging and the presence of neurofibrillary tangles (with choline acetyl transferase deficiency.) This process would be enhanced by the imbalance in favour of dopaminergic predominance caused by chronic levodopa therapy, and would partially explain the increase in dementia. As a test of this hypothesis we have given 10 levodopa-treated parkinsonian patients with dementia, a regimen of lecithin (average 20 gms/day). A clear improvement in Kohs block design test of constructive ability was noted with a decrease in the toxic symptoms of confusion, hallucinations and nightmares. In another study lecithin produced a decrease in levodopa-induced abnormal movements, but at the expense of motor performance. These preliminary investigations indicate that the progressive dementia of Parkinson's disease may not be irreversible.

Humans↗

H-2b bound to egg lecithin liposomes: biochemical and functional properties.

Purified H-2b and H-2a molecules were bound to egg lecithin liposomes by a detergent dialysis procedure. Analysis of the liposomes indicated that only 30-50% of bound H-2b is oriented with the hydrophilic, antigenic portion of the molecule toward the outside of the liposome. Saturation of the liposomes occurred at a ratio of 64 molecules of egg lecithin per molecule of H-2b. Liposomes containing H-2 molecules were capable of stimulating spleen cells from primed donors to produce specific, alloreactive, cytotoxic T lymphocytes in vitro. Stimulation was dependent on adherent cells present in the responder spleen cells. Optimal stimulation occurred with highly saturated liposomes and at a ratio of 4-8 micrograms of H-2b per 8 X 10(6) responder cells.

Animals↗

[The effects of glucocorticoid treatment during pregnancy on lecithin synthesis in the fetal rat lung (author's transl)].

In the course of investigations in pregnant rats the authors established that the effect of prednisolone-sodium succinate on the maturation of the fetal lung depends on the dose administered and/or on the time at which it was given. The prednisolone only increased the surface-active lecithin concentration - thus accelerating the functional maturation of the lung - if it was given on the 17th or 18th day of gestation, in a dose of 1.0 mg/kg or 2.0 mg/kg. A dose of 0.5 mg/kg had no effect, while a high dose not only inhibited lecithin synthesis but also caused significant side-effects. The authors point out that the glucocorticoids only have a favorable effect on lung maturation if administered during a certain period in their development, and link this to the maturation process of the specific cortisol receptors in the lung. They also point out the potential danger of glucocorticoids administered to prevent dyspnea and emphasize the importance of determining the lowest effective dose of the various synthetic preparations and/or the optimum time for giving them. They raise the question of whether there is also an ideal time for glucocorticoid treatment in human pregnancies.

Animals↗

Decreased retention of fatty acid conjugated DDT metabolites in rats given injections of heparin, bile salts or lecithin.

Intravenous injections of solutions of heparin, bile salts or lecithin into rats previously intraperitoneally injected with 14C-DDT significantly removed fatty acid conjugated 14C-DDT metabolites retained in their livers and spleens. These 14C-DDT metabolites comprised greater than 90 percent of the radioactivity present in these organs 10 days after the animals were first injected with 14C-DDT. The conjugation of DDT metabolites to fatty acids thus appears to be a primary mechanism by which DDT is ultimately retained in animals and possibly humans. Heparin, bile salts or lecithin might be used as clearing agents for removing these conjugates.

Animals↗

[Comparative study of Lecithin and cephalin exchange between liposomes and mitochondria. Activity measured in the presence and absence of a non-specific carrier protein isolated from rat liver].

Study has been made of the rat liver protein catalyzed exchange of both lecithin and cephalin between liposomes and rat liver mitochondria. It has been shown that the exchange activity of these two phospholipids by the protein is almost the same and is apparently not dependent on the nature of donor liposomes. In contrast the spontaneous exchange activity of the above phospholipids strictly depends on the type of donor liposomes. Moreover, the spontaneous exchange of lecithin at any incubation time appears to be almost 100% higher than that of cephalin.

Animals↗