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PubMed1996

Potential gene therapy for lecithin-cholesterol acyltransferase (LCAT)-deficient and hypoalphalipoproteinemic patients with adenovirus-mediated transfer of human LCAT gene.

BACKGROUND: Overexpression of human lecithin-cholesterol acyltransferase (LCAT) in transgenic mice results in an increase of the antiatherogenic HDLs. METHODS AND RESULTS: To investigate the potential use of LCAT for gene therapy, a recombinant adenovirus was constructed in which the human LCAT cDNA was expressed under the control of the human cytomegalovirus immediate/early promoter followed by a chimeric intron (AdCMV human LCAT). Human apolipoprotein (apo) A-I transgenic mice infected with AdCMV human LCAT by intravenous injection accumulated reactive LCAT in the plasma. LCAT activity was increased 201-fold in the plasma of mice infected with 1 x 10(6) pfu AdCMV human LCAT, from 45 +/- 2 to 9068 +/- 812 nmol.mL-1.h-1, in comparison with basal LCAT activity measured in control mice, 5 days after injection. Plasma HDL cholesterol levels rose from 117 +/- 12 to 797 +/- 48 mg/dL, and plasma human apo A-I concentrations increased from 247 +/- 14 to 616 +/- 17 mg/dL, in AdCMV human LCAT infected mice compared with control mice. HDL particles were larger and had a different electrophoretic mobility. Studies of cholesterol efflux by incubation of serum with cholesterol-loaded Fu5AH cells showed that serum from AdCMV human LCAT-infected mice promoted a significantly higher efflux than did that of the controls. CONCLUSIONS: These data establish the potential of this approach for treatment of subjects with LCAT gene defects as well as patients with low plasma levels of apo A-I and HDL cholesterol.

Adenoviridae↗
PubMed2000

Inhibitory effects of a lecithinized superoxide dismutase on bleomycin-induced pulmonary fibrosis in mice.

Oxidant/antioxidant imbalance is thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Therefore, antioxidants, such as superoxide dismutase (SOD), are expected to have an inhibitory potential against IPF. To elucidate whether a lecithinized SOD (phosphatidylcholine [PC]-SOD) has the potential to be a new therapeutic agent for IPF, we investigated the inhibitory effects of PC-SOD at doses of 1 mg/kg/d (low dose) and 10 mg/kg/d (high dose) and of methylprednisolone (mPSL) on bleomycin (BLM)-induced pulmonary fibrosis in mice. Histopathologic evaluation and lung hydroxyproline content revealed that the severity of fibrosis was attenuated in mice treated with low-dose PC-SOD, whereas no significant effect was observed in other mice. In bronchoalveolar lavage fluid on Day 1 after treatment with BLM, BLM-induced increases in total cell number, populations of lymphocytes and neutrophils, and expression of messenger RNA for interleukin-1beta and platelet-derived growth factor (PDGF)-A were significantly suppressed in PC-SOD-treated mice. The suppression of PDGF-A expression was significantly greater in mice treated with low-dose PC-SOD than in mice treated with high-dose PC-SOD or mPSL. In summary, this study demonstrated the inhibitory effects of low-dose PC-SOD on the development of pulmonary fibrosis, which indicates the potential usefulness of PC-SOD as a new treatment agent for IPF or at least for BLM-induced pulmonary fibrosis in humans.

Animals↗
PubMed1971

Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: physical and chemical studies of low and high density lipoproteins.

LOW DENSITY LIPOPROTEINS (LDL) AND HIGH DENSITY LIPOPROTEINS (HDL) FROM THE PLASMA OF PATIENTS WITH FAMILIAL LECITHIN: cholesterol acyltransferase (LCAT) deficiency have been characterized by gel filtration, analytical ultracentrifugation, and gel electrophoresis, and their relative content of lipid and protein has been determined. The LDL of d 1.019-1.063 g/ml show marked heterogeneity. A subfraction of the LDL emerges from columns of 2% agarose gel with the void volume, has corrected flotation rates (S(f) degrees ) in the range of 20-400, and contains 4-10 times as much unesterified cholesterol, phosphatidylcholine, and triglyceride per mg protein as normal LDL. A major subfraction of the LDL emerges from the gel in the same general position as normal LDL, but exhibits somewhat higher flotation rates and contains 1.5-3 times as much unesterified cholesterol and phosphatidylcholine and 13 times as much triglyceride per mg protein. The HDL, shown to be heterogeneous in earlier studies, are mainly comprised of molecules which have flotation rates of F(1.20) 3-20, migrate in the alpha(1)-alpha(2) region on electrophoresis, and contain about 12 times as much unesterified cholesterol and 5 times as much phosphatidylcholine per mg protein as normal HDL. Smaller molecules are also detected, which have flotation rates of F(1.20) 0-3, migrate in the prealbumin region on electrophoresis, and contain only slightly more unesterified cholesterol and phosphatidylcholine per mg protein than normal HDL.

Acyltransferases↗
PubMed1971

Plasma lipoproteins in familial lecithin: cholesterol acyltransferase deficiency: structure of low and high density lipoproteins as revealed by elctron microscopy.

The low density lipoproteins (LDL) of d 1.019-1.063 g/ml of patients with familial lecithin: cholesterol acyltransferase (LCAT) deficiency show marked heterogeneity when viewed with the electron microscope. At least two types of particles are present, one large and the other small. The large particles predominate in a LDL subfraction of large molecular weight isolated by gel filtration on 2% agarose gel. They appear to be flattened structures with diameters mainly in the range of 900-1200 A. The small particles predominate in a LDL subfraction of smaller molecular weight isolated by filtration on the same type of gel. They are 210-250 A in diameter and are similar to normal LDL in size and shape. The high density lipoproteins (HDL) also are heterogeneous. The majority of particles are disc-shaped structures 150-200 A in diameter. The discs are mainly present in stacks which have a periodicity of 50-55 A and a variable length. Each disc appears to be made up of a rosette of smaller globular units 50 A in diameter. The appearance of these large molecular weight HDL contrasts with that of normal HDL, which are 70-100 A in diameter and aggregate in monolayers that show hexagonal packing of particles. A small percentage of the patients' HDL consists of structures 45-60 A in diameter. These predominate in a smaller molecular weight HDL subfraction isolated by gel filtration on Sephadex G200. The particles are present in monolayer aggregates but never form stacked structures similar to those seen in the large molecular weight HDL subfraction.

Adult↗
PubMed1992

Altered epitope expression of human interstitial fluid apolipoprotein A-I reduces its ability to activate lecithin cholesterol acyl transferase.

In human peripheral interstitial fluid, esterification of cholesterol by lecithin cholesterol acyltransferase (LCAT) was found to occur at a rate of only 10% of that in plasma (5.6 +/- 1.8 compared with 55.6 +/- 7.8 nmol/ml per h). Measurement of cholesterol esterification in the presence of excess reconstituted apoA-I HDL (rA-I HDL) revealed an LCAT activity in interstitial fluid of 24% of that in plasma, indicating that the low rate of esterification could not be caused by limiting mass of LCAT enzyme. When plasma was diluted to the same concentration as in interstitial fluid, the percent cholesterol esterification rate was the same as undiluted plasma and significantly higher than that of interstitial fluid. These findings led us to postulate that poor activation of LCAT in interstitial fluid may result from a change in conformation in apoA-I. To test this hypothesis, a monoclonal antibody AI-11 that inhibits apoA-I activation of LCAT was used to measure apoA-I in interstitial fluid and plasma. Antibody AI-11 recognized interstitial fluid apoA-I poorly, whereas a polyclonal antibody recognized interstitial fluid apoA-I normally. Incubation of antibody AI-11 with high density lipoprotein or rA-I HDL inhibited apoA-I activation of LCAT. We conclude that the altered conformation of apoA-I in interstitial fluid may render it a poor activator of LCAT.

Albumins↗
PubMed1995

Expression of human lecithin-cholesterol acyltransferase in transgenic mice. Effect of human apolipoprotein AI and human apolipoprotein all on plasma lipoprotein cholesterol metabolism.

Human (Hu) lecithin-cholesterol acyltransferase (LCAT) is a key enzyme in the plasma metabolism of cholesterol. To assess the effects of increased plasma levels of LCAT, four lines of transgenic mice were created expressing a Hu LCAT gene driven by either its natural or the mouse albumin enhancer promoter. Plasma LCAT activity increased from 1.2- to 1.6-fold higher than that found in control mouse plasma. Lipid profiles, upon comparing Hu LCAT transgenics to control animals, revealed a 20 t0 60% increase in total and cholesteryl esters that were mainly present in HDL. The in vivo substrate specificity of Hu LCAT was assessed by creating animals expressing Hu apo AI + Hu LCAT (HuAI/ LCAT), Hu apo AI + Hu apo AII + Hu LCAT (HuAI/ AII/LCAT), and Hu apo AII + Hu LCAT (HuAII/LCAT). Plasma cholesterol was increased up to 4.2-fold in HuAI/ LCAT transgenic mice and twofold in the HuAI/AII/LCAT transgenic mice, compared with HuAI and HuAI/AII transgenic mice. HDL cholesteryl ester levels were increased more than twofold in both the HuAI/LCAT and HuAI/AII/LCAT mice compared with the HuAI, HuAI/AII, and HuLCAT animals. The HDL particles were predominantly larger in the HuAI/LCAT and the HuAI/AII/LCAT mice compared with those in HuAI, HuAII/LCAT, and HuLCAT animals. The increase in LCAT activity in the HuAI/LCAT and HuAI/AII/LCAT mice was associated with 62 and 27% reductions respectively, in the proportion of Hu apo AI in the pre beta-HDL fraction, when compared with HuAI and HuAI/AII transgenic mice. These data demonstrate that moderate increases in LCAT activity are associated with significant changes in lipoprotein cholesterol levels and that Hu LCAT has a significant preference for HDL containing Hu apo AI.

Animals↗
PubMed1996

Hyperalphalipoproteinemia in human lecithin cholesterol acyltransferase transgenic rabbits. In vivo apolipoprotein A-I catabolism is delayed in a gene dose-dependent manner.

Lecithin cholesterol acyltransferase (LCAT) is an enzyme involved in the intravascular metabolism of high density lipoproteins (HDLs). Overexpression of human LCAT (hLCAT) in transgenic rabbits leads to gene dose-dependent increases of total and HDL cholesterol concentrations. To elucidate the mechanisms responsible for this effect, 131I-HDL apoA-I kinetics were assessed in age- and sex-matched groups of rabbits (n=3 each) with high, low, or no hLCAT expression. Mean total and HDL cholesterol concentrations (mg/dl), respectively, were 162+/-18 and 121+/-12 for high expressors (HE), 55+/-6 and 55+/-10 for low expressors (LE), and 29+/-2 and 28+/-4 for controls. Fast protein liquid chromatography analysis of plasma revealed that the HDL of both HE and LE were cholesteryl ester and phospholipid enriched, as compared with controls, with the greatest differences noted between HE and controls. These compositional changes resulted in an incremental shift in apparent HDL particle size which correlated directly with the level of hLCAT expression, such that HE had the largest HDL particles and controls the smallest. In vivo kinetic experiments demonstrated that the fractional catabolic rate(FCR, d(-1)) of apoA-I was slowest in HE (0.328+/-0.03) followed by LE (0.408+/-0.01) and, lastly, by controls (0.528+/-0.04). ApoA-I FCR was inversely associated with HDL cholesterol level (r=-0.851,P<0.01) and hLCAT activity (r=-0.816, P<0.01). These data indicate that fractional catabolic rate is the predominant mechanism by which hLCAT overexpression differentially modulates HDL concentrations in this animal model. We hypothesize that LCAT-induced changes in HDL composition and size ultimately reduce apoA-I catabolism by altering apoA-I conformation and/or HDL particle regeneration.

Animals↗
PubMed1976

Accurate measurement of lecithin and sphingomyelin after ultra-rapid chromatographic separation.

The use of small sandwich chambers containing silica-gel-impregnated glass fibre sheets allows chromatographic separation of lecithin and sphingomyelin in 3 minutes, compared with 45 minutes on conventional silica gel media. Quantitation by measuring the areas of the phospholipid spots after staining with a molybdate stain or 8-anilino-1-naphthylamino sulphonic acid was found to be accurate and more convenient than densitometry. Although slight inaccuracies may be caused by lack of resolution from certain phospholipids, this was not found to be a problem in amniotic fluid analyses as they are either absent or present only in trace quantities. The speed of the technique makes it particularly useful for clinical purposes.

Amniotic Fluid↗
PubMedDate not supplied

Serial measurement of plasma cholesterol and lecithin:cholesterol acyl transferase activity in adults receiving total parenteral nutrition.

The effect of total parenteral nutrition (TPN) containing approximately 800 ml Nutralipid daily on plasma cholesterol and lecithin:cholesterol acyl transferase (LCAT) activity was studied in 11 adult hospital patients. LCAT was assayed using an endogenous (S/N) and an artificial (ASA) substrate to differentiate between altered plasma substrate composition (which would influence the S/N method) and enzyme quantity (measured by the exogenous ASA method). Total cholesterol levels increased significantly during TPN, but generally remained within normal range. In comparison to laboratory reference values, free cholesterol was elevated and high-density lipoprotein cholesterol and ASA LCAT activity was reduced in patients before the start of TPN and remained unaltered by the TPN regime. S/N LCAT activity was normal and not altered by TPN. Since changes in plasma high-density lipoprotein and free cholesterol and ASA LCAT were present in patients before TPN, it must be concluded that they resulted from the underlying disease rather than the TPN per se. Longitudinal analyses showed that during the first 21 days of TPN nine patients showed a further fall in ASA LCAT and a rise in free cholesterol, thereafter ASA LCAT activity rose and free cholesterol fell despite continuation of TPN. It is suggested that ASA is a more reliable indicator of cholesterol esterification than S/N and that change in LCAT activity, although not caused by TPN, was related to the altered plasma lipid profile in the patients studied.

Adult↗
PubMed1978

Scanning electron microscopy of the spreading of barium sulfate suspensions on the gastric mucosa of the rat. Effect of wetting agents, bile salt and lecithine.

Scanning electron microscopy was performed on the rat stomach mucosa after application of BaSO4 and three barium-containing commercial contrast media. The degree of flocculation was assessed; flocculation could be prevented by using synthetic wetting agents and by physiologic, natural emulsifiers, sodium taurocholate and lecithine.

Animals↗
PubMed1978

Lecithine as an adjuvant in resorption of contrast medium in oral cholecystography.

No or poor filling of the gallbladder was obtained in 21 patients at cholecystography. They were re-examined after 10 days of later with the addition of lecithine to the contrast medium. The filling of the gallbladder, which was without abnormality, was improved in all cases. The mechanism of this effect is discussed.

Adjuvants, Pharmaceutic↗
PubMed1989

Canadian collaborative study of tetrahydroaminoacridine (THA) and lecithin treatment of Alzheimer's disease: effect on mood.

Several lines of evidence have implicated acetylcholine (ACh) as one of the neurotransmitters found to be decreased in Alzheimer's disease (AD). Various methods of cholinergic augmentation have been attempted, with mixed results. Tetrahydroaminoacridine (THA), an acetylcholinesterase inhibitor, is currently being investigated at the McGill Centre for Studies in Aging. Preliminary uncontrolled data from a 10-week clinical trial of THA and lecithin, reported elsewhere, suggest a clinically modest but statistically significant beneficial effect on cognition, although problems exist with side effects, particularly gastrointestinal. Since the suggestion by Janowsky in 1972 that cholinergic neurotransmission may exert an inhibitory or depressant effect on mood, the evidence accumulated in the literature has been inconclusive. We undertook to assess several potential pretreatment correlates of depressive symptoms in AD and to monitor the course of these symptoms during the 10 week treatment period, using the Geriatric Depression Scale (GDS) of Brink and Yesavage. Pretreatment GDS scores were found to correlate with degree of overall disability and dementia as measured by the Rapid Disability Rating Scale (RDRS) and the Mini Mental State Examination (MMS), respectively. GDS scores over the treatment period did not change to a statistically significant degree. The meaning of these results is discussed, particularly with reference to the difficulty of diagnosis and measurement of depression in the setting of dementia.

Aged↗
PubMedDate not supplied

Quantitative EEG during a double-blind trial of THA and lecithin in patients with Alzheimer's disease.

Quantitative electroencephalography (EEG) was performed on eight of ten Alzheimer patients in a double-blind, inpatient-outpatient tetrahydroaminoacridine (THA) and lecithin trial. Neuropsychological measures were related to EEG activity. Patient baseline dominant parietal rhythms (DPRs) and power spectral distributions differed significantly from controls. Severity of cognitive impairment was related to the degree of parietal slowing. Inpatient THA treatment resulted in increased DPR frequency in six of eight patients. Four of eight inpatients demonstrated reduced power in the delta and theta bands. During the outpatient long-term treatment phase, six of the patients were able to continue. Three of these improved significantly on tests of cognition. Two of these improved patients demonstrated DPRs with increased frequency. One of these patients also showed a decrease in slow-wave activity. Thus, THA may accelerate DPRs while reducing power in the slower EEG bands. However, there appears to be only a tentative coupling between individual quantitative EEG measures and cognitive performance associated with THA administration.

Aged↗
PubMed1975

Amniotic fluid lecithin to sphingomyelin ration of 3.5 and fetal pulmonary maturity.

The clinical outcome of 118 pregnancies assessed by amniotic fluid lecithin to sphingomyelin concentration (L/S) ratio within 2 days of delivery is presented. It has been observed that the critical L/S ratio for pulmonary function is 3.5 in that no infant born with an L/ S ratio greater than 3.5 has had respiratory distress syndrome (RDS). Below an L/S ratio of 3.5, the risk and severity of RDS is inversely related to the L/S ratio. An L/S ratio smaller than 3.5 has the same prognostic value in infants born between 30 and 34 weeks gestation as it has in infants born between 35 and 38 weeks gestation. Under these conditions the relation between L/S ratio and RDS is independent of gestational age.

Amniocentesis↗
PubMed1995

Dietary nucleotides enhance plasma lecithin cholesterol acyl transferase activity and apolipoprotein A-IV concentration in preterm newborn infants.

The activity of lecithin cholesterol acyl transferase (LCAT), a key enzyme in lipoprotein metabolism, is low in newborn preterm infants. It has been suggested that a normal gastrointestinal function might be necessary to induce a postnatal increase of LCAT activity because apoproteins A-I and A-IV (apoA-I and apoA-IV) synthesized in considerable amounts in the intestine are known activators of LCAT. Dietary nucleotides have been reported to enhance intestinal growth and maturation; therefore, we hypothesized that nucleotide supplementation to formulas for preterm infants may influence LCAT activity. To investigate this hypothesis, two groups of preterm infants were fed either a nucleotide-free formula or a nucleotide-supplemented formula during the first month of life. The plasma LCAT activity, plasma levels of apoA-I and apoA-IV, plasma cholesteryl esters, and plasma fatty acid composition of cholesteryl esters and phospholipids were then determined. Infants receiving nucleotides had higher LCAT activities and apoA-IV levels than those receiving the nucleotide-free formula for a few weeks. The changes in apoA-IV levels were highly correlated with those of the LCAT activities. However, there were no significant correlations between changes in LCAT activity and plasma cholesteryl esters or phospholipids. These findings indicate that nucleotide supplementation to formulas for preterm infants may improve dietary lipid tolerance by enhancing plasma LCAT activity, probably as a result of an increase in apoA-IV plasma concentrations; they also suggest that nucleotides may enhance apoA-IV synthesis in the intestine during the neonatal period.

Apolipoprotein A-I↗
PubMed1996

Visual acuity and fatty acid status of term infants fed human milk and formulas with and without docosahexaenoate and arachidonate from egg yolk lecithin.

Preterm infants fed formulas with docosahexaenoic acid (DHA, 22:6n-3) during the interval equivalent to the last intrauterine trimester and beyond have higher circulating DHA and transiently higher visual acuity compared with infants fed formulas containing linolenic acid. In term infants several nonrandomized studies of infants receiving DHA from human milk suggest a relationship between DHA status and acuity, but the evidence for a cause-and-effect relationship is mixed. In the present study, term infants were randomly assigned to a standard term formula (n = 20) or the same formula with egg yolk lecithin to provide DHA (0.1%) and arachidonic acid (AA, 20:4n-6, 0.43%) (n = 19) at levels reported in milk of American women. A third group of infants was breast fed for > or = 3 mo (n = 19). Grating visual acuity (Teller Acuity Card procedure) and plasma and red blood cell (RBC) phosphatidylcholine (PC) and phosphatidylethanolamine (PE) DHA and AA were determined at corrected ages of 2, 4, 6, 9 (acuity only), and 12 mo past term = 40 wk postmenstrual age (PMA). At 2 mo breast-fed infants and infants fed the supplemented formula had higher grating acuity than term infants fed standard formula. As in preterm infants, the increase was transient. Plasma PC DHA and AA and RBC PE AA increased by 2 mo in supplemented infants, but RBC PE DHA in supplemented infants was not higher than in controls until 4 mo and beyond. Despite normal intrauterine accumulation of DHA and AA, infants fed formula with 2% linolenic acid and 0.1% DHA had better 2-mo visual acuity than infants fed formula with 2% linolenic acid.

Arachidonic Acid↗
PubMed1978

Effect of hypophysectomy of cholesteryl ester synthesis and hydrolysis in testes and on serum lecithin-cholesterol acyltransferase activity in rats.

Studies are reported of the effect of hypophysectomy on cholesterol esterase activity of testicular tissue and serum lecithin-cholesterol acyltransferase (LCAT) activity in rats. The testes of male Sprague-Dawley rats of 200-255 g were excised from animals sacrificed at 3, 7, and 15 days after hypophysectomy. Assays for cholesterol-esterifying and hydrolytic activities of the testicular tissues of these animals, compared to control animals, showed that hypophysectomy decreased both cholesteryl ester synthesis and hydrolysis. Hydrolytic activity was affected to a greater extent than esterifying activity. LCAT activity was significantly decreased by hypophysectomy compared to that of control animals. Although serum LCAT and testicular cholesterol esterase activities were decreased, the overall effect of hypophysectomy produced an increase in the level of serum cholesterol and cholesteryl esters. It is suggested that the role of essential fatty acids (EFA) in testicular function is related to the utilization of cholesteryl esters in androgen synthesis.

Animals↗