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PubMed1994

Markedly accelerated catabolism of apolipoprotein A-II (ApoA-II) and high density lipoproteins containing ApoA-II in classic lecithin: cholesterol acyltransferase deficiency and fish-eye disease.

Classic (complete) lecithin:cholesterol acyltransferase (LCAT) deficiency and Fish-eye disease (partial LCAT deficiency) are genetic syndromes associated with markedly decreased plasma levels of high density lipoprotein (HDL) cholesterol but not with an increased risk of atherosclerotic cardiovascular disease. We investigated the metabolism of the HDL apolipoproteins (apo) apoA-I and apoA-II in a total of five patients with LCAT deficiency, one with classic LCAT deficiency and four with Fish-eye disease. Plasma levels of apoA-II were decreased to a proportionately greater extent (23% of normal) than apoA-I (30% of normal). In addition, plasma concentrations of HDL particles containing both apoA-I and apoA-II (LpA-I:A-II) were much lower (18% of normal) than those of particles containing only apoA-I (LpA-I) (51% of normal). The metabolic basis for the low levels of apoA-II and LpA-I:A-II was investigated in all five patients using both exogenous radiotracer and endogenous stable isotope labeling techniques. The mean plasma residence time of apoA-I was decreased at 2.08 +/- 0.27 d (controls 4.74 +/- 0.65 days); however, the residence time of apoA-II was even shorter at 1.66 +/- 0.24 d (controls 5.25 +/- 0.61 d). In addition, the catabolism of apoA-I in LpA-I:A-II was substantially faster than that of apoA-I in LpA-I. In summary, genetic syndromes of either complete or partial LCAT deficiency result in low levels of HDL through preferential hypercatabolism of apoA-II and HDL particles containing apoA-II. Because LpA-I has been proposed to be more protective than LpA-I:A-II against atherosclerosis, this selective effect on the metabolism of LpA-I:A-II may provide a potential explanation why patients with classic LCAT deficiency and Fish-eye disease are not at increased risk for premature atherosclerosis despite markedly decreased levels of HDL cholesterol and apoA-I.

Adult↗
PubMed1985

Prematurity and lecithin-cholesterol acyltransferase deficiency in newborn infants.

The occurrence of hyperlipidemia and fat accumulation in certain tissues of premature newborn infants is known. Lecithin-cholesterol acyltransferase (LCAT) catalyzes esterification of free cholesterol and is important in the transport and disposal of lipids. Cord plasma LCAT activity of full-term newborn infants is nearly one-half of that present in the adult plasma. The present study also has found a significant positive correlation between cord plasma LCAT activity and gestational age of the newborn. The ratio of circulating cholesterol ester to free cholesterol was significantly lower only in newborn infants with gestational age less than 32 wk, in comparison to full-term newborn infants or adults. LCAT deficiency and decreased cholesterol ester formation may be responsible for the inadequate lipid clearance in premature newborn infants.

Adult↗
PubMed1997

Acute dyslipoproteinemia induced by interleukin-2: lecithin:cholesteryl acyltransferase, lipoprotein lipase, and hepatic lipase deficiencies.

Recombinant human interleukin-2 (rIL-2) is used to treat refractory cancers. During such treatment, patients develop severe hypocholesterolemia along with striking alterations in the concentration and composition of the circulating lipoproteins. The present study was undertaken to gather information about the pathogenesis of these abnormalities. Patients were studied before-, during- and after a 5-day course of high dose i.v. rIL-2. Whole plasma cholesterol was markedly reduced by rIL-2 administration (52%; P < 0.001), whereas the triglyceride concentration did not change. Thus, the lipoproteins became triglyceride enriched (P = 0.004). Low density lipoprotein cholesterol, apolipoprotein B (apoB), high density lipoprotein cholesterol, and apoA-I concentrations all decreased. Esterified cholesterol levels were markedly reduced. Total plasma apoE increased markedly, and two kinds of abnormal particles appeared: 1) beta-migrating, very low density lipoproteins; and 2) discoidal, apoE- and phospholipid-containing particles with abnormal density and electrophoretic mobility. The activities of two lipoprotein triglyceride hydrolases, lipoprotein lipase and hepatic lipase, fell significantly during treatment and returned promptly to pretreatment levels after rIL-2 was discontinued. Lecithin:cholesteryl acyltransferase (LCAT) activity also decreased significantly (64%) during treatment, but in contrast to the lipases, remained low for at least 5 days after the last dose of rIL-2 (P < 0.001). High dose i.v. rIL-2 induces severe dyslipidemia with deficiencies of both postheparin lipases and acute LCAT deficiency. Most, if not all, of the lipoprotein changes observed are explained by the LCAT deficiency that follows IL-2-induced hepatocellular injury and cholestasis.

Apolipoprotein A-I↗
PubMed1998

Rapid electrophoretic separation of pre-beta-migrating high density lipoproteins using automated PhastSystem: application to analysis of lecithin:cholesterol acyltransferase-deficient plasma.

To identify pre-beta-high density lipoproteins, a rapid two-dimensional separation by electrophoresis (1 hour 30 minutes) was performed on an automated Phast System. This procedure used commercially available polyacrylamide gradient gels (4-15%) and allows sensitive and reproducible results. Pre-beta-1- and pre-beta-2-high density lipoproteins were clearly identified by this method. In addition, our procedure was successfully applied to diagnosis of a patient with familial lecithin:cholesterol acyltransferase deficiency, characterized by the absence of alpha-high density lipoproteins.

Automation↗
PubMed1994

Japanese family with a deficiency of lecithin:cholesterol acyltransferase (LCAT).

We present findings in the ninth known Japanese family with lecithin:cholesterol acyltransferase (LCAT) deficiency. A 54-year-old man (proband) and his 58-year-old brother presented with corneal opacity. Both subjects showed a marked decrease in serum high density lipoprotein (HDL)-cholesterol and in the cholesteryl ester ratio. Although apo A-I and A-II were low, apo E tended to be high. Serum LCAT activity and mass were not detectable. Urinary examination showed microhematuria or proteinuria. Renal function was normal and no anemia was demonstrated, but blood smears showed poikilocytosis with target cells. The serum LCAT activity of the proband's three sons, obligate heterozygotes of LCAT deficiency, was about one-half the normal level, and HDL-cholesterol and apo A-I levels were low normal.

Adult↗
PubMed1986

The basic apolipoprotein A-I in the patients with familial lecithin:cholesterol acyltransferase deficiency.

The apolipoprotein A-I (apo A-I) from the patients with familial lecithin: cholesterol acyltransferase (LCAT) deficiency has been characterized. More than 10% of total serum apo A-I was recovered in the bottom fraction (d greater than 1.21 g/ml) of the patients' sera, while in normal sera, only 4.3 +/- 2.7% (Mean +/- SD) of apo A-I was found in the bottom fraction. The lipoproteins of the sera from the patients were analysed by density gradient ultracentrifugation and by high performance liquid chromatography (HPLC). Our HPLC analysis has revealed that the association of apo A-I with a lipid-poor HDL, observed in the patients, is not due to ultracentrifugal artifacts. The serum apo A-I isoproteins and their relative concentrations in the three patients were analysed by two dimensional electrophoresis. The isoprotein distribution for each of the three patients was as follows: isoproteins 2 and 3; 12.3, 21.2 and 25.7%, suggesting that the basic isoforms (isoproteins 2 and 3) were increased compared to normal controls (3.5 + 2.3%). The profile of apo A-I isoproteins of the bottom fraction was almost the same as that of the patient's HDL, indicating the equivalent affinity of each isoprotein with lipid and/or protein of HDL. These observations are compatible with the suggestion that the reduction of HDL-cholesterol in familial LCAT deficiency may be due to rapid catabolism of HDL, resulting in the increase in the ratio of apo A-I isoprotein 2 and 3 (immature form of isoprotein A-I) to isoprotein 4 and 5 (mature form of apo A-I).

Adult↗
PubMed1988

Familial lecithin: cholesterol acyltransferase (LCAT) deficiency. An updated review Spring 1988.

Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a well-defined inborn error of metabolism, where the enzymatic deficiency (LCAT) has been clarified and also the chromosomal defect (chromosome 16q22) is localized. The disease is to-day known all around the world and 50 patients from 26 families are known to-day. Corneal opacities have been found in all patients and appear early in life. The opacities have a characteristic appearance which makes it rather easy to get the correct diagnosis of this disease. Near the limbus, a pronounced opacity of annular shape resembling a marked arcus lipoides senilis occurs. The opacities are composed of numerous minute grayish dots and are localized to the parenchyma and evenly distributed in all layers of the stroma. In polarized light, crystals that may be cholesterol have been seen in both cornea and the fundus. Excess unesterified cholesterol and phospholipid has been found in cornea. The disease is also characterized by slight anemia and proteinuria and sometimes lipemic plasma, but patients without anemia and proteinuria have also been described. All lipoproteins are abnormal in familial LCAT deficiency. The individual lipoprotein fractions are all heterogeneous and characterized by a higher amount of free cholesterol than normal. Rapidly developing renal insufficiency in adult age often appears in this type of familial renal disease. Kidney transplantation may be necessary. LCAT has now been characterized as a glycoprotein with 416 aminoacids + hydrophobic leader sequence of 24 aminoacids and an apparent Mr of 63 kD. Plans exist to proceed with genomic cloning of the LCAT gene from normal DNA and from various patients.

Chromosomes, Human, Pair 16↗
PubMed2001

[LCAT (lecithin:cholesterol acyltransferase)].

Lecithin:cholesterol acyltransferase (LCAT) is an enzyme which converts free cholesterol of lipoprotein into esterified cholesterol. LCAT plays an important role in lipid metabolism especially in the reverse cholesterol transport system. As LCAT protein is synthesized by the liver, patients with liver disease showed a decreased ratio of cholesteryl ester to total cholesterol. Familial LCAT Deficiency and Fish Eye Disease are disorders that lack LCAT activity congenitally.

Biomarkers↗
PubMed2002

Alterations in erythrocyte membrane lipid and its fragility in a patient with familial lecithin:cholesterol acyltrasferase (LCAT) deficiency.

Lecithin:cholesterol acyltrasferase (LCAT) plays a key role in the cholesterol metabolism-mediated esterification of free cholesterol into the cholesterol ester in normal plasma. Familial LCAT deficiency is frequently associated with anemia. Using biochemical and physiological techniques, the erythrocytes of this patient were investigated to gain an insight into the relationship between the abnormalities of lipid metabolism and erythrocyte membrane fragility. Abnormal erythrocytes, so-called Target cells and/or Knizocytes, were observed at 20% in our patient's erythrocytes. Moreover, the mean corpuscular volume of the patient's cells was 7% greater than that of a normal individual. In the membrane lipids of the patient's erythrocytes, cholesterol and phosphatidylcholine increased, and phosphatidylethanolamine decreased. The electron spin resonance technique with a fatty acid spin probe showed that the membrane fluidity was more elevated than that of normal cells in spite of the increase in cholesterol content and the cholesterol/phospholipid ratio of the membrane of patient's erythrocytes. The patient's abnormally shaped erythrocytes were less deformed than those of the normal individual under high shear stress. The partial depletion of membrane cholesterol from the patient's erythrocytes was demonstrated by incubation with normal plasma with LCAT activity. The increment of transformed erythrocytes during the incubation could be prevented by cholesterol depletion from the patient's erythrocyte membrane. These findings indicate that normochromic anemia of the patient might be caused by erythrocyte fragility resulting from decreased deformity and/or abnormal shape of the cells due to abnormal lipid composition in the membrane.

Adult↗
PubMed2003

Decreased activity of lecithin:cholesterol acyltransferase and hepatic lipase in chronic hypothyroid rats: implications for reverse cholesterol transport.

Chronic hypothyroidism is frequently associated with atherosclerosis due to increased cholesterol plasma levels; nevertheless, the contribution of impaired reverse cholesterol transport (RCT) in this process has not been completely elucidated. The aim of this study was to evaluate the effect of thyroidectomy (Htx) upon the main stages of RCT in rats. Plasma lipid alterations induced by thyroidectomy showed a slight, but significant, reduction of total plasma triglycerides, a 300% increase of LDL-cholesterol and a 25% decrease in HDL-cholesterol compared to control rats. We evaluated the first stage of RCT determining 3H-cholesterol efflux in Fu5AH cells. The capacity of HDL obtained from Htx rats to promote cholesterol efflux was similar to that of controls. Lecithin:cholesterol acyltransferase (LCAT) activity, the second stage and the driving force of RCT was 30% lower in Htx animals compared to controls, as determined by reconstituted HDL used as an external substrate. Lipoproteins are remodeled by hepatic lipase; the mean activity of this enzyme in postheparin plasma of Htx animals was reduced by 30% compared to controls, thus suggesting an impaired HDL remodeling by this enzyme in the hypothyroid status. In contrast, lipoprotein lipase activity in the Htx group was unchanged. In summary, this study demonstrates that chronic hypothyroidism in the rat induced an impaired RCT mainly at the cholesterol esterification, and HDL remodeling mediated by hepatic lipase. The latter probably results in an abnormal HDL structure, i.e. phospholipid enrichment, which contributes to decrease HDL-apo AI fractional catabolic rates.

Animals↗
PubMed1992

[A case of familial lecithin: cholesterol acyltransferase deficiency].

Lecithin: cholesterol acyltransferase (LCAT) is an enzyme that catalyzes the esterifying reaction of cholesterol in plasma high density lipoprotein (HDL). Deficiency of LCAT is a rare hereditary disease characterized by several clinical symptoms such as proteinuria, corneal opacity, and anemia due to a shortened life span of erythrocytes. In this communication, we report a case of 40 year-old female patient of LCAT deficiency. She visited a hospital for work-up of proteinuria, corneal opacity and anemia. Activity of her serum LCAT was found to be extremely low, and characteristic changes in plasma lipids due to deficiency of LCAT was observed: those were marked decreases in HDL-cholesterol, degree of esterification in serum cholesterol, and apoprotein A-I, A-II, B and C-II levels. The diagnosis of LCAT deficiency was finally made. We studied about histopathological changes in the patient's kidney, and erythrocyte membrane lipid composition and fluidity. Histopathological findings in renal biopsy were follows: a) Light microscopy showed spherical deposits stained with periodic acid-Schiff in mesangial matrix and adjacent capillary loops, and hyaline deposits in arterioles, b) Electron microscopy showed vacuoles in mesangial matrix and along the glomerular basement membranes. In erythrocyte membrane lipids, increase of cholesterol to phospholipid molar ratio was evident, being accompanied by changes in phospholipid fractions: increase of phosphatidylcholine, and decreases of phosphatidylethanolamine, sphingomyelin and lysophosphatidylcholine. In phospholipid acyl chains, increase of C18:2 and decreased of C18:1 were evident in the patient. Erythrocyte membrane fluidity was found to be decreased in the patient in a measurement by pyrene, probably being related to the changes in membrane lipid composition.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1975

Substrate specificity of lecithin:cholesterol acyltransferase. Esterification of desmosterol, b-sitosterol, and cholecalciferol in human plasma.

Desmosterol and beta-sitosterol were esterified when incubated with normal human plasma. The initial rate of demosterol esterification was 1.7 times faster, and that of beta-sitosterol 0.4 times slower, than the esterification rate of cholesterol. These ratios were found to be almost the same when plasma from different normal individuals was tested. Plasma from a patient with familial lecithin:cholesterol acyltransferase deficiency did not esterify any of the sterols. The esterification of desmosterol and beta-sitosterol was considerably slower in normal plasma in which in vitro cholesterol esterification previously had taken place. The different esterification rates could not be explained by a different affinity of the plasma lipoproteins for the sterols tested. Cholecalciferol added to normal plasma did not become esterified.

Acyltransferases↗
PubMed1991

Partial lecithin:cholesterol acyltransferase (LCAT) deficiency in Balkan endemic nephropathy.

The role of lipid abnormalities has been also implicated in the progression of renal diseases. The search for lipid abnormalities in Balkan endemic nephropathy (BEN) has roused sporadic interest and has not been fully elucidated. This study was performed in 54 healthy subjects from the families affected with BEN (group A), 18 members from non-affected families living in the same location (group B), and 25 control subjects (group C). Lipid profiles and lecithin:cholesterol acyltransferase (LCAT) were determined in each subject. The most striking distinction between the groups was that of the LCAT activity, which was abnormally low in group A (39 +/- 2), significantly different (P less than 0.0001) from that of the other groups. Thirty individuals from group A were those accounting for the low LCAT activity (A1). This group had a significantly lower total cholesterol and free cholesterol than all of the other subjects. The entire group A subjects had a significantly lower percentage of free cholesterol than the other two groups. There was no significant difference in HDL cholesterol between any of the groups, but group A1 had significantly higher HDL than group C (P less than 0.04). What emerges from our study is that a certain proportion of subjects from BEN families have a peculiar form of lipid abnormalities associated with an abnormal LCAT activity. At present we have no explanation for these findings. We believe that these changes may have an important role in the pathogenesis of BEN.

Adult↗
PubMed1991

Lecithin cholesterol acyltransferase deficiency: ultrastructural examination of sequential renal biopsies.

We present the renal biopsy findings in two brothers with nephrotic syndrome and lecithin:cholesterol acyltransferase deficiency. Mesangial expansion and capillary wall thickening were accompanied by numerous extracellular osmiophilic membranes within round lucent spaces, by round lamellar deposits, and by amorphous deposits containing thread-like structures with cross-striations. A second biopsy in one of the brothers, when he had developed renal insufficiency 8 yr later, showed increased mesangial and capillary wall thickening. The deposits, which had been in predominantly subepithelial and intramembranous locations, were now in a more prominent subendothelial location. The subepithelial localization of the deposits seen on initial examination may be related to their cationic charge, perhaps with binding to glomerular polyanion, and to uptake by glomerular epithelial cells. The accumulation of lipid is associated with progressive mesangial and glomerular sclerosis.

Adolescent↗
PubMedDate not supplied

[Comparative lecithin-cholesterol-acyltransferase deficiency in the blood of newborn infants. Comparison of the esterifying activity of neonatal and maternal blood].

On the basis of data obtained in studies on the accumulation of cholesterol in erythrocytes of newlorns, the hypothesis is advanced on the deficiency of lecithin-cholesterol-acetyl transferase (LCAT) in the newborn children. A decrease in the rate of the LCAT-reaction was shown in funic blood using the specially developed system "LP-infranatante", the constituents of which were isolated from blood plasma of both newborns and of their mothers by ultracentrifugation at a density 1.21 g/ml and 40.000 rpm. The following factors were considered as possible determinants of the decrease in the rate of cholesterol esterification in blood plasma of newborns: 1) insufficiency in LCAT, 2) alteration in the composition of the substrate lipoproteins (lipoproteins of high density).

Cholesterol Esters↗
PubMed1989

Lecithin:cholesterol acyltransferase-induced transformation of HepG2 lipoproteins.

Previous studies with the human hepatoblastoma-derived HepG2 cell line in this laboratory have shown that these cells produce high density lipoproteins (HDL) that are similar to HDL isolated from patients with familial lecithin:cholesterol acyltransferase (LCAT) deficiency. Experiments were, therefore, performed to determine whether HepG2 HDL could be transformed into plasma-like particles by incubation with LCAT. Concentrated HepG2 lipoproteins (d less than 1.235 g/ml) were incubated with purified LCAT or lipoprotein-deficient plasma (LPDP) for 4, 12, or 24 h at 37 degrees C. HDL isolated from control samples possessed excess phospholipid and unesterified cholesterol relative to plasma HDL and appeared as a mixed population of small spherical (7.8 +/- 1.3 nm) and larger discoidal particles (17.7 +/- 4.9 nm long axis) by electron microscopy. Nondenaturing gradient gel analysis (GGE) of control HDL showed major peaks banding at 7.4, 10.0, 11.1, 12.2, and 14.7 nm. Following 4-h LCAT and 12-h LPDP incubations, HepG2 HDL were mostly spherical by electron microscopy and showed major peaks at 10.1 and 8.1 nm (LCAT) and 10.0 and 8.4 nm (LPDP) by GGE; the particle size distribution was similar to that of plasma HDL. In addition, the chemical composition of HepG2 HDL at these incubation times approximated that of plasma HDL. Molar increases in HDL cholesteryl ester were accompanied by equimolar decreases in phospholipid and unesterified cholesterol. HepG2 low density lipoproteins (LDL) isolated from control samples showed a prominent protein band at 25.6 nm with GGE. Active LPDP or LCAT incubations resulted in the appearance of additional protein bands at 24.6 and 24.1 nm. No morphological changes were observed with electron microscopy. Chemical analysis indicated that the LDL cholesteryl ester formed was insufficient to account for phospholipid lost, suggesting that LCAT phospholipase activity occurred without concomitant cholesterol esterification.

Adult↗
PubMed1989

Detection of vesicular lipoproteins in lecithin:cholesterol acyltransferase-deficient plasma by 1H-NMR spectroscopy.

The proton NMR spectra of the N-methyl choline region of normal and lecithin:cholesterol acyltransferase (LCAT)-deficient lipoproteins and of egg yolk phosphatidylcholine-cholesterol 55:45 (mol %) vesicle mixtures have been examined in the presence and absence of manganous sulfate as a line-broadening reagent. Manganous ions quenched all of the signal arising from normal lipoproteins and only part of the vesicle signal corresponding to the outer monolayer. There was no net loss of vesicular phospholipid when vesicles were added to normal lipoproteins and as little as 5% (or 100 micrograms) of the vesicular phospholipid could be detected and quantitated in the mixture of lipoproteins. Similar experiments performed on plasma lipoproteins from an LCAT-deficient patient indicated that 42% of the phospholipid was associated with vesicular lipoproteins. These experiments demonstrate that this technique can be used to detect and quantify small amounts of vesicular structures directly in a mixture of micellar lipoproteins.

Humans↗
PubMed1989

Lipoprotein abnormalities associated with lipopolysaccharide-induced lecithin: cholesterol acyltransferase and lipase deficiency.

Density gradient ultracentrifugation was used to isolate and characterize the plasma lipoproteins from African green monkeys before and 24 and 48 h after subcutaneous injection of 300 micrograms/kg lipopolysaccharide (LPS) to induce an acute phase response. Compared with 0 h values, reductions occurred in plasma cholesterol (39%), high density lipoprotein (HDL) cholesterol (54%), lecithin:cholesterol acyltransferase (LCAT) activity (55%), and post-heparin plasma lipase activity (68%) 48 h after LPS injection while plasma triglyceride concentrations increased 700%. Cholesterol distribution among lipoproteins shifted from 7 to 41% in very low density lipoproteins (VLDL), 65 to 38% in low density lipoproteins (LDL), and 28 to 21% in HDL after LPS injection. At 48 h after LPS injection, all lipoprotein classes were relatively enriched in phospholipid and triglyceride and depleted of cholesteryl ester. The plasma concentration of all chemical constituents in VLDL was increased 3-9-fold within 48 h after LPS injection. By negative stain electron microscopy, HDL were discoidal in shape while VLDL and LDL appeared to have excess surface material present. Even though total HDL protein concentration in plasma was unaffected, the plasma mass of the smallest HDL subfractions (HDL3b,c) doubled while the mass of intermediate-sized subfractions (HDL3a) was dramatically decreased within 24 h after treatment. HDL became enriched in apoE, acquired apoSAA, and became depleted of apoA-I, A-II, and Cs by 48 h after LPS injection while apoB-100 remained the major apoprotein of VLDL and LDL. We conclude that administration of LPS to monkeys prevents normal intravascular metabolism of lipoproteins and results in the accumulation of relatively nascent forms of lipoproteins in plasma. These immature lipoproteins resemble those isolated from the recirculating perfusion of African green monkey livers, which are relatively deficient of LCAT activity and those isolated from the plasma of patients with familial LCAT deficiency.

Animals↗