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PubMed1999

Free cholesterol deposition in the cornea of human apolipoprotein A-II transgenic mice with functional lecithin: cholesterol acyltransferase deficiency.

We have developed several lines of transgenic animals that overexpress different levels of human apolipoprotein A-II (apoA-II). The 11.1 transgenic line has human apoA-II in plasma at threefold the level in normolipidemic humans and a functional lecithin:cholesterol acyltransferase (LCAT) deficiency. The latter is a biochemical phenotype similar to that of fish-eye disease (FED), which is characterized by free cholesterol (FC) and phospholipid accumulation in the cornea, leading to opacity and impaired vision. To assess whether the metabolic alterations in these mice also lead to lipid accumulation in the cornea, we fed them on a long-term regular chow or high-fat/high-cholesterol (HF/HC) diet. The 11.1 transgenic mice showed a moderate accumulation of FC in the cornea, but only when fed the regular chow diet. This FC accumulation was less severe than the accumulation described in FED, which may explain the lack of corneal opacity in these mice. Electron microscopy and immunoblotting analysis of the cornea of 11.1 transgenic mice in comparison to control mice showed (1) a mild but nevertheless more intense intracytoplasmatic lipid particle deposition in the epithelial cells and (2) a decrease of immunoreactive apoA-I in the area of Bowman's layer and at the superficial stroma. The serum capacity to cause cholesterol efflux from rat fibroblasts was decreased in 11.1 transgenic mice, but only in those fed a regular chow diet. We conclude that 11.1 human apoA-II transgenic mice may be a useful model for studies of early lipid deposition in the cornea and its possible prevention.

Animals↗
PubMed1982

Unusual renal biopsy findings in a patient with familial lecithin:cholesterol acyltransferase deficiency.

Familial lecithin:cholesterol acyltransferase deficiency is a rare autosomal recessive disorder associated with significant renal complications. A 16-year-old boy with the typical clinical and laboratory characteristics of this disease had a renal biopsy because of proteinuria and hematuria. The histologic findings were those of membranous glomerulonephritis with very few intracapillar foam cells. Ultrastructural study revealed numerous vacuolated deposits containing irregular profiles of electron-dense membrane-like material predominantly along with the subepithelial aspect of the glomerular basement membranes but also within the basement membranes, the subendothelial space, the mesangium, the capillary lumina, Bowman's capsule, and tubular basement membranes. The unusual aspects of this case are the relative paucity of intraglomerular foam cells and the predominantly subepithelial location of the lipid-like deposits.

Adolescent↗
PubMed1986

Nephropathy of familial lecithin-cholesterol acyltransferase deficiency: report of a case.

A ninth Japanese patient afflicted with lecithin-cholesterol acyltransferase (LCAT) deficiency is described with emphasis on renal pathology. The most striking feature is massive deposition of lipid material in the glomeruli, particularly in the glomerular basement membrane (GBM) and in the mesangial region. The glomerular changes appear to be similar to that seen in some cases with cirrhosis of the liver. Lipid material contains a large amount of apolipoprotein-B detected by immunohistology. In two renal biopsies, taken three years apart, renal pathology is essentially the same and glomerular pathology is most characteristic. It is suggested that lipid deposition in glomeruli in this patient is rather slow. Family study of the present case reveals consanguinous marriages in the previous two generations suggesting the exaggerated gene expression of LCAT deficiency in this family.

Adult↗
PubMed1987

[Corneal opacity as the leading symptom of hereditary lecithin-cholesterol acyltransferase (LCAT) deficiency. Case report and a review of the literature].

Familial lecithin: cholesterol acyltransferase (LCAT) deficiency is an inborn error of lipid metabolism clinically characterized by anemia, proteinuria, and corneal opacification. The authors review the literature dealing with 34 biochemically proven and 2 probable cases of LCAT deficiency, and describe the first case from a German-speaking country. Ocular findings were bilateral diffuse nebulous corneal opacification composed of innumerable minute grayish dots throughout the stroma. At the periphery of the cornea these dots increased, forming a ringlike band with indistinct margins. A small lipid deposit was also seen in the retina of the right eye. Vision was 20/20, but glare disability was significantly increased. Corneal opacification was also noticed in all cases of the literature. Anemia was detected at the time of diagnosis in 92% and proteinuria in 76% of the reviewed cases. Corneal opacification is the one absolutely obligatory clinical feature; moreover it is uniform and pathognomonic: a true indicating sign of LCAT deficiency.

Adult↗
PubMed1980

Heterogeneity of human high density lipoprotein: presence of lipoproteins with and without apoE and their roles as substrates for lecithin:cholesterol acyltransferase reaction.

By affinity chromatography on heparin-Sepharose, two classes of lipoproteins were separated from high density lipoproteins (HDL) isolated from patients with primary or secondary lecithin:cholesterol acyltransferase (LCATase; EC 2.3.1.43) deficiency and from normal subjects. The unretained fraction, HDL(A), was characterized by having apoA-I as a major apoprotein; it also contained apoA-II, -C-II, and -C-III but it contained only traces of immunodetectable apoE and no apoB. The retained fraction, HDL(E), had apoE as the major apoprotein; it also contained apoA-I, -A-II, -B, -C-II, and -C-III. The relative concentration of apoA-I increased with increasing density in the HDL(E) subclass. Compared to HDL(A), HDL(E) had a significantly higher cholesterol content and a lower protein concentration. HDL(E) was mainly (90%) contained within the HDL(2) subfraction. Contamination of HDL(E) by low density lipoproteins (LDL) or Lp(a) was minimal on the basis of pre-beta-electrophoretic mobility and absence of albumin, respectively. Contamination by LDL or Lp(a) could be resolved in part by application of HDL(E) to concanavalin A-Sepharose or to heparin-Sepharose with a shallow gradient. When evaluated as substrates for a highly purified LCATase preparation, the initial reaction rates and V(max) obtained with HDL(A) were always higher than those obtained with HDL(E) in any given plasma. However, both HDL subclasses from LCATase-deficient subjects were better substrates than the corresponding HDL subclasses from normal plasma. Also, both HDL(3A) and HDL(3E) isolated from normal HDL(3) were better substrates than the corresponding subclasses isolated from normal HDL(2). The recognition of this compositional and functional heterogeneity within HDL will allow a better understanding of the metabolism of this lipoprotein class.

Apolipoproteins↗
PubMed1997

Disruption of the murine lecithin:cholesterol acyltransferase gene causes impairment of adrenal lipid delivery and up-regulation of scavenger receptor class B type I.

Lecithin:cholesterol acyltransferase (LCAT) is the major determinant of the cholesteryl ester (CE) content of high density lipoprotein (HDL) in plasma. The selective uptake of HDL-CE is postulated to participate in delivery of tissue-derived cholesterol both to the liver and steroidogenic tissues. Recent studies comparing mice with similarly low levels of HDL, due to the absence of either of the two major HDL-associated apolipoproteins apoA-I and apoA-II, suggest that apoA-I is crucial in modulating this process, possibly through interaction with scavenger receptor class B type I (SR-BI). Because of the central role of LCAT in determining the size, lipid composition, and plasma concentration of HDL, we have created LCAT-deficient mice by gene targeting to examine the effect of LCAT deficiency on HDL structure and composition and adrenal cholesterol delivery. The HDL in the LCAT-deficient mice was reduced in its plasma concentration (92%) and CE content (96%). The HDL particles were heterogeneous in size and morphology and included numerous discoidal particles, mimicking those observed in LCAT-deficient humans. The adrenals of the male Lcat (-/-) mice were severely depleted of lipid stores, which was associated with a 2-fold up-regulation of the adrenal SR-BI mRNA. These studies demonstrate that LCAT deficiency, similar to apoA-I deficiency, is associated with a marked decrease in adrenal cholesterol delivery and supports the hypothesis that adrenal SR-BI expression is regulated by the adrenal cholesterol.

Adrenal Glands↗
PubMed2002

Oxidative stress is markedly elevated in lecithin:cholesterol acyltransferase-deficient mice and is paradoxically reversed in the apolipoprotein E knockout background in association with a reduction in atherosclerosis.

Complete lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare cause of severe hypoalphalipoproteinemia, but the affected subjects are surprisingly not particularly prone to premature coronary heart disease. We studied oxidative stress in lcat-/- mice and their cross-breed with apolipoprotein-E knockout mice (apoE-/-xlcat-/-) by measuring vascular ring superoxide production and plasma phospholipid (PL)-bound F2-isoprostane levels and their relationship with aortic atherosclerosis. Compared with wild type control (lcat+/+), lcat-/- and lcat+/- mice showed a 4.9- (p = 0.003) and a 2.1-fold (p = 0.04) increase in plasma PL-F2-isoprostane levels, respectively. There was also a 3.6- (p < 0.0001) and 2.9-fold (p = 0.003) increase in the area under the curve for the aortic ring superoxide excursion by lucigenin-derived chemiluminescence. A comparison of apoE-/-xlcat+/+ mice with wild type control mice showed a more modest 2.1- (p = 0.04) and 2.2-fold (p < 0.00001) increase in these respective markers. Surprisingly, the apoE-/-xlcat-/- mice showed a paradoxical normalization in both oxidation markers. Furthermore, by fast protein liquid chromatography separation, we observed an associated retention and redistribution of serum paraoxonase activities to the non-high density lipoprotein fractions in both the apoE-/-xlcat-/- and apoE-/-xlcat+/- mice. Aortic atherosclerotic lesions in male apoE-/-xlcat-/- and apoE-/-xlcat+/- mice were reduced by 52 (p = 0.02) and 24% (p = 0.46), respectively. Our data suggest that LCAT-deficient mice are associated with an increased oxidative stress that is paradoxically reversed in a hyperlipidemic background, possibly due to the redistribution of paraoxonase. This modulation of oxidative stress may in part contribute to the reduced atherosclerosis seen in the apoE-/- xlcat-/- mice.

Alleles↗
PubMed2003

Hypertriglyceridemia in lecithin-cholesterol acyltransferase-deficient mice is associated with hepatic overproduction of triglycerides, increased lipogenesis, and improved glucose tolerance.

Lecithin-cholesterol acyltransferase deficiency is frequently associated with hypertriglyceridemia (HTG) in animal models and humans. We investigated the mechanism of HTG in the ldlr-/- x lcat-/- (double knockout (dko)) mice using the ldlr-/- x lcat+/+ (knock-out (ko)) littermates as control. Mean fasting triglyceride (TG) levels in the dko mice were elevated 1.75-fold compared with their controls (p < 0.002). Both the very low density lipoprotein and the low density lipoprotein/intermediate density lipoprotein fractions separated by fast protein liquid chromatography were TG-enriched in the dko mice. In vitro lipolysis assay revealed that the dko mouse very low density lipoprotein (d < 1.019 g/ml) fraction separated by ultracentrifugation was a more efficient substrate for lipolysis by exogenous bovine lipoprotein lipase. Post-heparin lipoprotein lipase activity was reduced by 61% in the dko mice. Hepatic TG production rate, determined after intravenous Triton WR1339 injection, was increased 8-fold in the dko mice. Hepatic mRNA levels of sterol regulatory element binding protein-1 (srebp-1) and its target genes acetyl-CoA carboxylase-1 (acc-1), fatty acid synthase (fas), and stearoyl-CoA desaturase-1 (scd-1) were significantly elevated in the dko mice compared with the ko control. The hepatic mRNA levels of LXRalpha (lxralpha) and its target genes including angiopoietin-like protein 3 (angptl-3) in the dko mice were unchanged. Fasting glucose and insulin levels were reduced by 31 and 42%, respectively in the dko mice, in conjunction with a 49% reduction in hepatic pepck-1 mRNA (p = 0.014). Both the HTG and the improved fasting glucose phenotype seen in the dko mice are at least in part attributable to an up-regulation of the hepatic srebp-1c gene.

Acetyl-CoA Carboxylase↗
PubMed2006

Structural differences between wild-type and fish eye disease mutant of lecithin:cholesterol acyltransferase.

Fluorescence spectroscopy has been used to investigate the conformational changes that occur upon binding of wild type (WT) and mutant (Thr123Ile) lecithin:cholesterol acyltransferase (LCAT) to the potential substrates (dioleoyl-phosphatidyl choline [DOPC] and high density lipoprotein [HDL]). For a detailed analysis of structural differences between WT and mutant LCAT, we performed decompositional analysis of a set of tryptophan fluorescence spectra, measured at increasing concentrations of external quenchers (acrylamide and KI). The data obtained show that Thr123Ile mutation in LCAT leads to a conformation that is likely to be more rigid (less mobile/flexible) than that of the WT protein with a redistribution of charged residues around exposed tryptophan fluorophores. We propose that the redistribution of charged residues in mutant LCAT may be a major factor responsible for the dramatically reduced activity of the enzyme with HDL and reconstituted high density lipoprotein (rHDL).

Amino Acid Substitution↗
PubMed1987

Hereditary lecithin-cholesterol acyltransferase deficiency. Case report of a German patient.

Lecithin-cholesterol acyltransferase (LCAT) deficiency was first described in a Norwegian family as an inborn error of metabolism. Altogether, 35 patients in 18 families have been identified. The authors report the first German patient, who presented with the characteristic clinical features of corneal opacity, proteinuria, and mild anemia. Renal biopsy revealed foam cells and an increased mesangial matrix in the glomeruli. Confirmation of the clinical diagnosis of LCAT deficiency was obtained by plasma enzyme and lipid analyses. Functional LCAT activity was not detected in incubated plasma by chemical or radiochemical methods, although rocket immunoelectrophoresis indicated that the patient had about one-third of normal LCAT mass. In keeping with other reports of LCAT deficiency, apoE-rich discoidal particles were seen in the patient's high-density lipoprotein fraction by electron microscopic examination.

Adult↗
PubMed1999

Metabolism of oxidized phosphatidylcholines formed in oxidized low density lipoprotein by lecithin-cholesterol acyltransferase.

The possible involvement of lecithin-cholesterol acyltransferase (LCAT) in the metabolism of oxidized phosphatidylcholine (PC) in plasma was investigated. A variety of oxidized products are formed from PC following oxidation of low density lipoproteins (LDL). A significant increase in LDL oxidation levels in patients with familial LCAT deficiency (FLD) has been previously demonstrated by a sensitive sandwich ELISA for oxidized LDL using the monoclonal antibody DLH3 which recognizes oxidized products of PC. In the present study, we found that LCAT produces various metabolites from oxidized PC and that oxidized PC molecules in LDL particles serve as substrates. When the neutral lipid fraction was separated by TLC after the incubation of oxidized 1-palmitoyl-2-[1-14C]linoleoyl PC with human plasma, a number of radioactive bands were formed in addition to cholesteryl ester. These products were not formed from native 1-palmitoyl-2-[1-14C]linoleoyl PC. Plasma from FLD patients also failed to form the additional products from oxidized PC. The addition of dithio-bis(nitrobenzoate) (DTNB), an LCAT inhibitor, or the inactivation of LCAT activity by treating the plasma at 56 degrees C for 30 min abolished the generation of these products from oxidized PC. The activity was recovered in the high density lipoprotein (HDL) fraction but not in the LDL fraction separated from normal plasma. When 1-palmitoyl-2-[1-14C](9-oxononanoyl) PC and 1-stearoyl-2-[1-14C](5-oxovaleroyl)PC, PC oxidation products that contain short chain aldehydes, were incubated with human plasma, radioactive products in the neutral lipid fraction were observed on TLC. LDL containing oxidized PC was measured by sandwich ELISA using an anti-apolipoprotein B antibody and DLH3. The reconstituted oxidized PC-LDL particles were found to have lost their ability to bind DLH3 upon incubation with HDL, while the reactivity of the reconstituted oxidized PC-LDL remained unchanged in the presence of DTNB. These results suggest that LCAT is capable of metabolizing a variety of oxidized products of PC and preventing the accumulation of oxidized PC in circulating LDL particles.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2002

Histopathology of corneal changes in lecithin-cholesterol acyltransferase deficiency.

PURPOSE: Lecithin-cholesterol acyltransferase (LCAT) deficiency is a rare entity. This dyslipoproteinemia may lead to corneal opacity, renal failure, and arteriosclerosis. METHODS: Presentation of a 66-year-old man with bilateral corneal opacification due to LCAT deficiency caused by a single-nucleotide exchange in codon 123 of gene. An extracapsular cataract extraction combined with full-thickness corneal transplantation was performed. The corneal specimen was analyzed by light and transmission electron microscopy. RESULTS: All stromal layers showed extracellular vacuoles with acid mucopolysaccharide contents measuring up to 2.5 microm. Amyloid deposits measuring up to 12 microm in diameter were detected in the stroma and especially predescemetally. CONCLUSION: To our knowledge, this is the first histologic description of secondary amyloidosis in a full-thickness corneal specimen with LCAT deficiency. The disease is associated with anemia, proteinuria, a lack of plasma high-density lipoprotein, and the presence of target cells. Bilateral corneal opacification is a characteristic of the disease and may allow early detection of homozygous LCAT deficiency by the ophthalmologist.

Aged↗
PubMed1978

Familial lecithin: cholesterol acyltransferase deficiency complicated with unconjugated hyperbilirubinemia and peripheral neuropathy. The first reported cases in the Far East.

Three Japanese patients with lecithin: cholesterol acyltransferase (LCAT) deficiency, the offspring of a consanguineous marriage, are described. In addition to the characteristic clinical and laboratory findings of the disease, our patients had hitherto unreported manifestations, namely unconjugated hyperbilirubinemia, peripheral neuropathy and marked hypocholesterolemia. Although the mechanism of the unconjugated hyperbilirubinemia is not clear, the role of impaired hepatic bilirubin uridine-diphosphate-glucuronyl transferase activity combined with another unknown factor(s) was postulated. Non-random assortment was observed between LCAT deficiency and haptoglobin types, as previously reported. The discovery of Japanese patients with LCAT deficiency indicates that the distribution of this hereditary metabolic disorder is not confined to the Western hemisphere.

Adult↗
PubMed1985

Evidence for deficiency of high density lipoprotein lecithin: cholesterol acyltransferase activity (alpha-LCAT) in fish eye disease.

In a rare familial condition, fish eye disease, there is a low relative content of cholesteryl esters in the plasma high density lipoproteins (HDL) but a normal content of these lipids in the very low (VLDL) and low (LDL) density lipoproteins. Lecithin: cholesterol acyltransferase (LCAT) is the enzyme which mediates the esterification of free cholesterol in the plasma lipoproteins. In the present investigation, isolated HDL from our two fish eye disease patients were found to be excellent substrates during in vitro incubations with normal LCAT as present in lipoprotein depleted plasma from control subjects. Almost all free cholesterol of these HDL fractions became esterified and concomitantly the abnormally small fish eye disease HDL particles increased to a size in the range of that of normal HDL particles. Lipoprotein depleted plasma from fish eye disease, however, lacked the property of normal plasma to esterify the free cholesterol of HDL isolated from plasma of fish eye disease patients or control subjects. These results have led to the formulation of a new concept implying that two different LCAT activities exist in normal plasma. One of these activities, denoted alpha-LCAT, is specific for HDL (alpha-lipoproteins) and the other, beta-LCAT, is specific for VLDL-LDL (pre beta- and beta-lipoproteins). Fish eye disease according to this notion is classified as an alpha-LCAT deficiency in contrast to the classical LCAT deficiency which probably lacks both alpha- and beta-LCAT activities.

Aged↗
PubMed1993

Postabsorptive retinyl palmitate removal is retarded in lecithin-cholesterol acyltransferase deficiency.

Postabsorption fat clearance of intestinal lipoproteins indicated by retinyl palmitate was studied in two siblings with the classical lecithin-cholesterol acyltransferase (LCAT) deficiency and in a control group of 21 healthy subjects with similar apoprotein E 3/3 phenotype. Relatively high pre- and postabsorptive cholesterol esterification percentage of chylomicrons suggested that acyl coenzyme A:cholesterol acyltransferase activity was not inhibited. Postabsorptive levels of plasma lipids increased and decreased roughly similarly in the cases and controls with the postabsorptive peak values at about 4 h. Plasma total and chylomicron levels of retinyl palmitate were not affected by LCAT deficiency, while the removal of the vitamin from very low and intermediate density lipoproteins was clearly reduced so that the peak concentrations, values under the response curves and the time of the peak concentrations were markedly higher than in the controls. The long-lasting circulation of chylomicron remnants of density < 1.006-1.019 g ml-1 may have some clinical significance because postabsorptive lipoproteins are suspected to have atherogenic potentiality.

Aged↗
PubMed1995

Lecithin-cholesterol acyltransferase deficiency presenting with acute pancreatitis: effect of infusion of normal plasma on triglyceride-rich lipoproteins.

A 38-year-old Asian man presented with acute pancreatitis, marked hypertriglyceridaemia and macroproteinuria, 20 years after the diagnosis of lecithin-cholesterol acyltransferase (LCAT) deficiency. After recovery, he exhibited macroproteinuria and chylomicronaemia despite treatment with a very-low-fat diet. Infusion of normal plasma significantly increased the proportion of cholesterol esters in the patient's plasma and significantly lowered chylomicron-triglyceride levels, but not proteinuria. We conclude that renal dysfunction may be a late manifestation of LCAT deficiency and that it may lead to severe chylomicronaemia and acute pancreatitis. Infusion of normal plasma corrects the dyslipidaemia in LCAT deficiency, but in the short term does not improve renal function.

Acute Disease↗
PubMed1981

Lecithin-cholesterol-acyltransferase deficiency: autosomal recessive transmission in a large kindred.

Thirty-four members of a single Sardinian kindred with lecithin-cholesterol-acyltransferase deficiency have been studied. The kindred spans four generations and the parents of the two affected siblings are blood relatives. Segregation of the acyltransferase deficiency gene in the family clearly demonstrated an autosomal recessive mode of inheritance. Thirteen family members, including all obligate heterozygotes, had roughly half-normal acyltransferase activities (mean +/- S.D. = 0.39 +/- 0.06 mU/ml) when compared to 17 intrafamilial controls and spouses (mean +/- S.D. = 0.72 +/- 0.09 mU/ml) and 40 blood donors from Marburg/Lahn (mean +/- S.D. =0.76 +/- 0.1 mU/ml). Characterization of the heterozygotes did not reveal abnormalities in their plasma lipoproteins. LCAT deficiency and the beta-thalassaemia trait coexisting in this kindred segregated independently.

Consanguinity↗
PubMed1975

Genetics of LCAT (lecithin: cholesterol acyltransferase) deficiency.

Since 1967 a syndrome characterized by renal disease, normochromic anaemia and corneal opacities has been described in 7 members of 3 different Norweigan families. The patients have low levels of esterified cholesterol and lack LCAT (lecithin: cholesterol acyltransferase) activity in plasma. The genetic basis of the disorder seems to be the presence of a LCAT deficiency gene in double dose. This gene is probably the result of a single mutational event. Linkage studies revealed non-random assortment between LCTA deficiency and serum haptoglobin (Hp) types. After Hp subtyping a combined lod score of 3-41 at a recombination fraction of 0-00 was obtained. Association was revealed between the LCAT deficiency gene and the Hp-1S gene. We propose that the LCAT gene is situated close to the alpha-haptoglobin locus on chromosome no. 16.

Acyltransferases↗