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At least 1,333 records · Page 74Linked to original sources
PubMed1985

Evidence for the presence in human plasma of lecithin: cholesterol acyltransferase activity (beta-LCAT) specifically esterifying free cholesterol of combined pre-beta- and beta-lipoproteins. Studies of fish eye disease patients and control subjects.

The present study was undertaken to test our hypothesis that two different lecithin: cholesterol acyltransferase (LCAT) activities exist in normal human plasma, one denoted alpha-LCAT esterifying the free cholesterol of high density lipoproteins (HDL) and the other denoted beta-LCAT acting on the free cholesterol of very low (VLDL) and low (LDL) density lipoproteins. Plasmas depleted of HDL were obtained by means of preparative ultracentrifugation. Incubation at 37 degrees C of these plasma fractions from control subjects and patients with fish eye disease resulted in esterification of the remaining free cholesterol of combined VLDL and LDL (pre-beta- and beta-lipoproteins) in the HDL depleted plasmas. The shapes of the cholesterol esterification rate curves were similar for whole and HDL depleted plasmas from both control subjects and fish eye disease patients. In crosswise mixed incubation experiments with isolated combined VLD and LDL and total lipoprotein depleted plasma from a control subject and a patient with fish eye disease, respectively, esterification of free cholesterol occurred. Incubation of isolated total lipoproteins in plasma from a patient with LCAT deficiency mixed with total lipoprotein depleted plasma from a fish eye disease patient as a source of LCAT caused cholesterol esterification but did not result in normalization of the LCAT deficiency HDL particles, while the amount of normal-sized LDL particles increased. The present results support the hypothesis that a beta-LCAT exists in normal human plasma.

Aged↗
PubMed1987

Inhibitory effect of normal high density lipoproteins on lecithin:cholesterol acyltransferase activity in fish eye disease plasma.

The lecithin:cholesterol acyltransferase (LCAT) activity of lipoprotein depleted normal and fish eye disease (FED) plasma was assayed in a modified Glomset-Wright incubation system where the enzyme was allowed to act on three different normal lipoprotein substrates consisting of an authentic mixture of very low (VLDL), low (LDL) and high (HDL) density lipoproteins to assay total LCAT activity, HDL to assay alpha-LCAT activity and combined VLDL and LDL to assay beta-LCAT activity, respectively. However, using normal plasma depleted of HDL, leaving its combined VLDL and LDL as enzyme substrate, resulted in a more than twofold increase in the LCAT activity of FED plasma from the two patients compared to the activity obtained with HDL present in the incubation mixture, indicating an inhibitory effect of HDL on the beta-LCAT activity present in FED plasma. This inhibitory effect of normal HDL could also be demonstrated by autoincubation of FED plasma mixed with isolated HDL2 or HDL3. Both these HDL subfractions had a pronounced inhibitory effect on the cholesteryl ester formation in FED plasma. The present study thus clearly demonstrates that normal HDL inhibits the beta-LCAT activity present in FED plasma, esterifying the free cholesterol of combined VLDL and LDL, derived from controls as well as from the two FED patients.

Corneal Opacity↗
PubMed1987

Different substrate specificities of plasma lecithin: cholesterol acyl transferase in fish eye disease and Tangier disease.

Esterification of plasma free cholesterol is mediated by lecithin:cholesterol acyl transferase (LCAT). The free cholesterol of plasma high density lipoproteins (HDL) is considered to be the preferred substrate for LCAT. It therefore appeared as a paradox that plasma cholesterol esterification, both in vivo and in vitro, is normal in fish eye disease and Tangier disease, two familial conditions with extremely low plasma HDL levels. Fish eye disease plasma, however, was shown to have LCAT activity primarily acting on combined very low (VLDL) and low (LDL) density lipoproteins, denominated beta-LCAT, while it lacked LCAT activity esterifying HDL cholesterol (alpha-LCAT). Here we show that Tangier plasma, in contrast, has both alpha- and beta-LCAT. Thus, in both fish eye and Tangier diseases it is beta-LCAT that explains the apparent normal plasma cholesterol esterification. We also show that Tangier plasma, having alpha-LCAT activity, normalizes the low cholesteryl ester content as well as the abnormally small size of fish eye disease HDL particles during incubation.

Cholesterol↗
PubMed1988

Substrate specificity of plasma lecithin: cholesterol acyltransferase in abetalipoproteinemia.

The lecithin: cholesterol acyltransferase (LCAT) activity of lipoprotein-depleted plasma from a patient with abetalipoproteinemia has been assayed in a modified Glomset-Wright incubation system with three different normal lipoprotein substrates consisting of an authentic mixture of very low (VLDL), low (LDL) and high (HDL) density lipoproteins for the assay of total LCAT activity, HDL to assay alpha-LCAT activity and combined VLDL and LDL to assay beta-LCAT activity, respectively. Although reduced to about half the normal control values, both alpha- and beta-LCAT activities were present in the patient's plasma. It has been shown earlier that secretion of LCAT is linked to that of VLDL, but since patients with abetalipoproteinemia cannot form either chylomicrons or VLDL, our results suggest that a secretion of these triglyceride-rich lipoproteins do not seem to be a prerequisite for a basal secretion of beta-LCAT.

Abetalipoproteinemia↗
PubMed1987

Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug-drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1-acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1-acid glycoprotein were increased between 50-85% even at 'therapeutic' doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1-acid glycoprotein.

Glycocholic Acid↗
PubMed1976

Changes in transepidermal water loss and the composition of epidermal lecithin after applications of pure fatty acid triglycerides to skin of essential fatty acid-deficient rats.

The importance of various unsaturated fatty acid triglycerides to the repair of faulty skin barrier function was studied in essential fatty acid-deficient rats. Following cutaneous application of the pure triglycerides for up to 5 days, the hitherto high rate of transepidermal water loss, characteristic of essential fatty acid deficiency in rats, was reduced by the triglycerides of linoleic and gamma-linolenic acids. Incorporation of the applied fatty acids into the lecithin of the epidermis accompanied these changes in water loss, indicating that cutaneously applied triglycerides may be metabolized by the skin and incorporated into complex lipids. Other fatty acid triglycerides, including alpha-linolenic, dihomo-gamma-linolenic, arachidonic and omega-7-heneicosatrienoic acid, did not lower the rate of transepidermal water loss, although all were incorporated into epidermal structural lipids. The non-essential oleic acid also had no effect upon the rate of transepidermal water loss. These data suggest that of the two main essential fatty acids that occur in skin, linoleic acid and arachidonic acid, the former specifically plays an important role in regulating barrier function whereas the later may have a separate function, such as serving as a precursor of prostaglandins.

Animals↗
PubMed1977

Lipoprotein-X: a substrate for lecithin: cholesterol acyltransferase.

The action of lecithin:cholesterol acyltransferase (LCAT) was studied on an abnormal lipoprotein (LP-X) rich in phosphatidylcholine and cholesterol from the plasma of patients with obstructive liver disease. 60 mg LP-X isolated free of other lipoproteins and subsequently labelled with 3H-cholesterol were incubated with 1 mg highly purified enzyme in the presence of albumin. After 45 h at 37 degrees C, the incubation mixture was subjected to zonal ultracentrifugation. 3H-cholesterol and 3H-cholesteryl esters were quantified in each fraction of the zonal gradient. More than 95% of the lipoproteins in this mixture banded in the density range of LP-X with no change in size distribution, but did contain 593 nmoles of newly formed cholesteryl esters. Agarose electrophoresis revealed an alpha-migrating band in addition to the original beta-band. Also on agar, the typically cathode migrating LP-X was changed to anode moving material. These studies indicate that LP-X can serve as a substrate for LCAT.

Acyltransferases↗
PubMed1980

Effect of lipoprotein concentration and lecithin: cholesterol acyltransferase activity on cholesterol esterification in human plasma after plasma exchange.

The rate of cholesterol esterification in plasma, plasma lecithin cholesterol acyltransferase (LCAT) activity and plasma lipoprotein levels have been measured in five subjects who underwent therapeutic plasma exchange to reduce their plasma cholesterol concentration. In the week following the exchange the cholesterol esterification rate and the plasma triglyceride concentration returned rapidly in parallel to pre-exchange levels, while high density lipoprotein (HDL) cholesterol and LCAT activity returned to normal more slowly but also in parallel. The data suggest that the rate-limiting factor for cholesterol esterification in plasma is unlikely to be solely the enzyme levels, but is probably a combination of factors, including the enzyme level and either substrate availabiltiy or product removal. Plasma very low density lipoprotein (VLDL) may either provide substrates for the reaction or provide a means of removing one of the products from the site of reaction.

Adult↗
PubMed2003

Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins.

Insulin resistance and type 2 diabetes mellitus are generally accompanied by low HDL cholesterol and high plasma triglycerides, which are major cardiovascular risk factors. This review describes abnormalities in HDL metabolism and reverse cholesterol transport, i.e. the transport of cholesterol from peripheral cells back to the liver for metabolism and biliary excretion, in insulin resistance and type 2 diabetes mellitus. Several enzymes including lipoprotein lipase (LPL), hepatic lipase (HL) and lecithin: cholesterol acyltransferase (LCAT), as well as cholesteryl ester transfer protein (CETP) and phospholipid transfer protein (PLTP), participate in HDL metabolism and remodelling. Lipoprotein lipase hydrolyses lipoprotein triglycerides, thus providing lipids for HDL formation. Hepatic lipase reduces HDL particle size by hydrolysing its triglycerides and phospholipids. A decreased postheparin plasma LPL/HL ratio is a determinant of low HDL2 cholesterol in insulin resistance. The esterification of free cholesterol by LCAT increases HDL particle size. Plasma cholesterol esterification is unaltered or increased in type 2 diabetes mellitus, probably depending on the extent of triglyceride elevation. Subsequent CETP action results in transfer of cholesteryl esters from HDL towards triglyceride-rich lipoproteins, and is involved in decreasing HDL size. An increased plasma cholesteryl ester transfer is frequently observed in insulin-resistant conditions, and is considered to be a determinant of low HDL cholesterol. Phospholipid transfer protein generates small pre beta-HDL particles that are initial acceptors of cell-derived cholesterol. Its activity in plasma is elevated in insulin resistance and type 2 diabetes mellitus in association with high plasma triglycerides and obesity. In insulin resistance, the ability of plasma to promote cellular cholesterol efflux may be maintained consequent to increases in PLTP activity and pre beta-HDL. However, cellular cholesterol efflux to diabetic plasma is probably impaired. Besides, cellular abnormalities that are in part related to impaired actions of ATP binding cassette transporter 1 and scavenger receptor class B type I are likely to result in diminished cellular cholesterol efflux in the diabetic state. Whether hepatic metabolism of HDL-derived cholesterol and subsequent hepatobiliary transport is altered in insulin resistance and type 2 diabetes mellitus is unknown. Specific CETP inhibitors have been developed that exert major HDL cholesterol-raising effects in humans and retard atherosclerosis in animals. As an increased CETP-mediated cholesteryl ester transfer represents a plausible metabolic intermediate between high triglycerides and low HDL cholesterol, studies are warranted to evaluate the effects of these agents in insulin resistance- and diabetes-associated dyslipidaemia.

Biological Transport↗
PubMed1976

The lecithin: cholesterol acyltransferase reaction, lysolecithin and red cell ageing in blood stored under normal transfusion service conditions.

The lecithin:cholesterol acyltransferase (LCAT) activity and lysolecithin content of human blood stored under standard blood transfusion service conditions at 4 degrees C for 6 weeks has been investigated. Cooling the blood to 4 degrees C rapidly inactivates the LCAT reaction, but the enzyme is not denatured during storage under these conditions. Citrate in the anticoagulant did not activate the LCAT reaction in freshly-taken whole blood. The total phospholipid and total lysolecithin content of whole blood decreased during storage at 4 degrees C for 6 weeks. The lysolecithin content of fresh red cells (2.0-3.0 mumol lysolecithin x 10(-11) per cell) showed no significant change during the storage period.

Acyltransferases↗
PubMed1976

Topological asymmetry of phospholipid metabolism in rat erythrocyte membranes. Evidence for flip-flop of lecithin.

1. The distribution of phospholipids between inside and outside of rat erythrocyte membranes was studied by incubating the cells with phospholipase A2 from Naja naja venom and sphingomyelinase from Staphylococcus aureus. 2. Choline-containing phospholipids were found to comprise the majority of the outer layer of the membrane. 3. The incorporation of radioactive fatty acids into phospholipids occurred predominantly at the inside of the membrane. 4. Exchange of phospholipids between red cell membranes and plasma lipoproteins occurred at the outside of the membrane. 5. Indications were found for a rather slow flip-flop of lecithin across the membrane.

Animals↗
PubMed1984

Apolipoprotein A-IGiessen (Pro143----Arg). A mutant that is defective in activating lecithin:cholesterol acyltransferase.

Apolipoprotein A-IGiessen is a variant form of apo A-I that is displaced from the corresponding normal A-I isoforms on isoelectric focusing gels by a single charge unit towards the cathode [Utermann et al. (1982) J. Biol. Chem. 257, 501-507]. Three subjects heterozygous for the variant were detected in one family. The percentage of the total A-I in plasma represented by the A-IGiessen in these subjects ranged over 25-30%. The variant and normal major A-I isoforms from the proband (Y.J.) were purified by preparative isoelectric focusing and cleaved with CNBr. Analytical focusing of CNBr fragments demonstrated a charge difference between CB3Giessen and normal CB3. Sequence analysis of CB3Giessen revealed that a proline existing in normal A-I was replaced by an arginine in the variant A-I at residue 143. The ability of the mutant A-I to activate purified lecithin:cholesterol acyltransferase was determined in vitro. The cofactor activity of [Arg143]apolipoprotein A-I was about 60-70% of that demonstrated by control A-I. Residue 143 is in a putative beta-turn between two of the repeating amphiphilic helices in apolipoprotein A-I and may be a critical determinant of the protein's structure and function.

Amino Acid Sequence↗
PubMed1986

Isolation and properties of porcine lecithin:cholesterol acyltransferase.

Lecithin: cholesterol acyltransferase (LCAT, phosphatidylcholine: sterol O-acyltransferase, EC 2.3.1.43) was purified approximately 20 000-fold from pig plasma by ultracentrifugation, phenyl-Sepharose and hydroxyapatite chromatography. Purified LCAT had an apparent relative molecular mass of 69 000 +/- 2000. By isoelectrofocusing it separated into five or six bands with pI values ranging from pH 4.9 to 5.2. The amino acid composition was similar to that of the human enzyme. An antibody against pig LCAT was prepared in goat. The antibody reacted against pig LCAT and gave a reaction of partial identity with human LCAT. Incubation of pig plasma or purified enzyme with the antibody virtually inhibited LCAT activity. The same amount of antibody inactivated only 62% of the LCAT activity in human serum. Pig and human LCAT were activated to the same extent by either human or pig apolipoprotein A-I (apo-A-I) using small liposomes as substrate. Human apoA-I, however, caused a higher esterification rate for both enzymes. Using apoA-I and small liposomes as a substrate, the addition of apoC-II up to 4 micrograms/ml had no effect on the LCAT reaction, but above this concentration LCAT was inhibited. Small liposomes with phosphatidylcholine/cholesterol molar ratios of 3:1 up to 8.4:1 did not show any significant differences in the LCAT reaction, when used as substrates in the presence of various amounts of apoA-I and albumin. In contrast, the LCAT activity was significantly reduced by liposomes with phosphatidylcholine/cholesterol molar ratios below 3:1.

Animals↗
PubMed1995

Tissue-specific expression of the human gene for lecithin: cholesterol acyltransferase in transgenic mice alters blood lipids, lipoproteins and lipases towards a less atherogenic profile.

Lecithin:cholesterol acyltransferase (LCAT) is a key enzyme in the reverse cholesterol pathway but its role in lipid metabolism is still unclear. We have generated mice transgenic for a 7-kb genomic DNA fragment comprising the 6 exons and 5 introns of the LCAT gene with 1932 bp of 5' flanking and 908 bp of 3' flanking sequences. One line had integrated about 30 copies and expressed about 40-fold increased LCAT activity in a human test system. The expression showed correct tissue specificity of the human LCAT gene. Increased LCAT activity resulted in a decrease of plasma triacylglycerols below 50% of fasting controls. This reduction was seen in all lipoprotein fractions. Lipoprotein lipase activity did not change significantly, whereas hepatic triacylglycerol lipase increased markedly. Plasma total cholesterol was similar in fasting transgenic and control mice, but low-density lipoprotein and very low-density lipoprotein cholesterol were reduced to about 50%. High-density lipoprotein cholesterol increased about 20%, accompanied by a correspondingly increased size and a higher cholesterol efflux-stimulating activity of transgenic LCAT high-density lipoprotein. Both apolipoprotein A-I and A-II plasma concentrations increased in transgenic mice. Plasma triacylglycerol and cholesteryl ester fatty acid distribution showed an increased proportion of palmitic acid, whereas oleic, linoleic and arachidonic acid decreased, thus resembling more closely the human situation. Overexpression of the human LCAT gene provokes major changes in plasma lipoprotein and apolipoprotein concentrations, resulting in a less atherogenic plasma lipoprotein profile through a reduction in atherogenic and an increase in anti-atherogenic lipoproteins.

Animals↗
PubMed1997

Structural and functional properties of the 154-171 wild-type and variant peptides of human lecithin-cholesterol acyltransferase.

The 154-171 segment of the human lecithin-cholesterol acyltransferase (LCAT) enzyme was identified as the most stable amphipathic helix in the LCAT sequence. Its mean hydrophobicity, hydrophobic moment and its orientation at a lipid/water interface are similar to those of some of the helical repeats of apolipoprotein A-IV and E. This domain was therefore proposed as a candidate peptide accounting for the association between LCAT and its lipid substrate. To investigate this hypothesis we synthesized the LCAT-(154-171)-peptide, two variants containing the natural Y156N and R158C mutations and a variant with increased hydrophobicity through Y156I, L160I, L163I and Y171W substitutions. The structural and lipid-binding properties of these synthetic peptides were investigated by turbidity, fluorescence, electron microscopy and circular dichroism. The wild-type peptide, the R158C variant in its dimeric form, as well as the more hydrophobic peptide, associated with phospholipids, whereas the Y156N and the R158C variant in its monomeric form did not. However, only the complexes generated with the hydrophobic variant were stable enough to resist dissociation during gel filtration. The wild-type peptide and hydrophobic variant formed discoidal complexes with dimyristoylglycerophosphocholine (Myr2GroPCho) as shown by negative staining electron microscopy. Comparison of the properties of the wild-type and hydrophobic variant LCAT-(154-171)-peptide stresses the contribution of the hydrophobic face of the amphipathic helix to the formation and stabilization of the peptide/lipid complexes. This is further confirmed by the decreased affinity of the Y156N variant peptide for lipids, as this mutation decreased the mean hydrophobicity of the hydrophobic face of the amphipathic helix. These results support the hypothesis that the 154-171 segment of LCAT might be involved in the interaction of the enzyme with its lipid substrate and suggest that the decreased activity of the Y156N natural LCAT mutant might result from a decreased affinity of this mutant for lipids.

Amino Acid Sequence↗
PubMed1987

The structural gene for lecithin:cholesterol acyl transferase (LCAT) maps to 16q22.

We have used a cDNA clone for human lecithin:cholesterol acyl transferase (LCAT) and Southern blotting techniques to identify the human LCAT gene in DNA from a series of rodent X human somatic cell hybrids. Our results are compatible with the location of the gene on human chromosome 16, and this has been confirmed using in situ hybridization of the LCAT cDNA to human metaphase chromosomes. These results confirm the earlier studies on LCAT-deficient patients, indicating that the structural gene for LCAT is on human chromosome 16q22.

Animals↗
PubMed1975

Palmitic acid and lecithin measurements in amniotic fluid.

A method is described for the rapid and quantitative estimation of total amniotic fluid palmitic acid. Palmitic acid and lecithin were measured in 140 samples of amniotic fluid in normal and abnormal pregnancy, and the correlation coefficient between the two parameters was 0.93. It is concluded that amniotic fluid palmitic acid measurements are of value in the prenatal determination of fetal pulmonary maturity.

Amniocentesis↗