Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To further understand lipoprotein (a) [Lp(a)] and atherosclerosis, we measured serum Lp(a), lipoprotein, and apolipoprotein levels in 55 patients (males, 24-73 years old) on maintenance hemodialysis, and compared them with those of 82 controls (males, 21-81 years old). The serum Lp(a) levels in patients on maintenance hemodialysis were significantly higher than those of the normal controls, while serum total cholesterol (TC), high-density lipoprotein-cholesterol, (HDL-C), HDL2-C, HDL3-C, apolipoprotein (apo) Al, apo All levels, and lecithin-cholesterol acyltransferase (LCAT) activities were significantly (p < 0.05) reduced in the patient group. The frequency distribution of serum Lp(a) levels in the patients was different from that in the control group, and no prognostic tendency of serum Lp(a) levels was noted by the etiology of renal failure as histologically determined by the renal biopsies. In the patient group, we also found that serum Lp(a) levels negatively correlated with serum triglycerides (TG) and total protein (TP) concentrations (p < 0.05), but no correlation was found between the duration of hemodialysis therapy or patient age and the serum levels of TC, TG, apo B and Lp(a) levels when tested for simple regression. Significant (p < 0.05) positive correlations were also found between TP and serum TG, apo B, and LCAT activities. These opposing tendencies of Lp(a) and serum TG, apo B, when measured against TP concentrations, indicate that serum TP levels may not affect serum lipoprotein and Lp(a) levels in the same direction. These data suggest that hemodialysis or end-stage renal disease itself, rather than hypoproteinemia, may hold the key to high serum Lp(a) levels in hemodialysis patients.
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PMID:Serum lipoprotein (a) levels in maintenance hemodialysis patients. 841 89

We investigated the effects of a polymorphic PvuII site in the gene for lecithin:cholesterol acyltransferase (LCAT) on serum high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I) concentrations in a population of 750 pedigreed baboons. We also tested for genotype by diet interactions using data on HDL-C and apo A-I concentrations on two diets (chow and high-cholesterol, saturated fat). A significant (P < 0.001) association between the LCAT genotypes and HDL-C levels was observed. On both diets, animals homozygous for the less common allele had HDL-C levels that averaged 18-19% lower than animals homozygous for the more common allele. HDL-C levels of the heterozygotes were intermediate. The LCAT RFLP accounted for approximately 5% of the variation in HDL-C levels on the two diets. We observed no strong evidence for an LCAT genotype by diet interaction effect.
Atherosclerosis 1993 Jan 25
PMID:A DNA polymorphism for lecithin:cholesterol acyltransferase (LCAT) is associated with high density lipoprotein cholesterol concentrations in baboons. 845 58

A 53-year-old man with a severely reduced HDL cholesterol level, dense corneal opacities, normal renal function, and premature coronary artery disease was investigated together with 16 members of his family. The proband was diagnosed with fish eye disease. As in previously reported patients with fish eye disease, the endogenous plasma cholesterol esterification rate was near normal, yet lecithin:cholesterol acyltransferase (LCAT) activity was almost absent when measured with exogenous HDL analogues used as substrate. Direct sequencing of the LCAT gene revealed two novel missense mutations in exon 1 and exon 4, resulting in the substitution of Pro10 with Gln (P10Q) and Arg135 with Gln (R135Q), respectively. Both missense mutations were located on different alleles. Genetic analysis by polymerase chain reaction revealed 4 carriers of the P10Q and 3 carriers of the R135Q defect. Functional assessment of both missense mutations revealed that when exogenous HDL analogues were used as substrate, the specific activity of rLCAT p10Q was 18% of wild type (WT); however, when LDL was used as substrate, the activity was 146% of WT. By contrast, rLCATR135Q was inactive against both substrates. Thus, we conclude that the LCATR135D mutation is causative for complete LCAT deficiency and that the clinical phenotype of fish eye disease seen in this patient is due to the Pro10 mutation. The presence of premature coronary artery disease in the absence of other risk factors in this new case of fish eye disease raises questions regarding the risk of atherosclerosis, which has previously been reported to be nonexistent.
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PMID:Two novel molecular defects in the LCAT gene are associated with fish eye disease. 862 Mar 46

The concentration of high density lipoproteins (HDL) is inversely related to the risk of atherosclerosis. The two major protein components of HDL are apolipoprotein (apo) A-I and apoA-II. To study the role of apoA-II in lipoprotein metabolism and atherosclerosis, we have developed three lines of C57BL/6 transgenic mice expressing human apoA-II (lines 25.3, 21.5, and 11.1). Northern blot experiments showed that human apoA-II mRNA was present only in the liver of transgenic mice. SDS-polyacrylamide gel electrophoresis and Western blot analysis demonstrated a 17.4-kDa human apoA-II in the HDL fraction of the plasma of transgenic mice. After 3 months on a regular chow, the plasma concentrations of human apoA-II were 21 +/- 4 mg/dl in the 25.3 line, 51 +/- 6 mg/dl in the 21.5 line, and 74 +/- 4 mg/dl in the 11.1 line. The concentration of cholesterol in plasma was significantly lower in transgenic mice than in control mice because of a decrease in HDL cholesterol that was greatest in the line that expressed the most apoA-II (23 mg/dl in the 11.1 line versus 63 mg/dl in control mice). There was also a reduction in the plasma concentration of mouse apoA-I (32 +/- 2, 56 +/- 9, 91 +/- 7, and 111 +/- 2 mg/dl for lines 11.1, 21.5, 25.3, and control mice, respectively) that was inversely correlated with the amount of human apoA-II expressed. Additional changes in plasma lipid/lipoprotein profile noted in line 11.1 that expressed the highest level of human apoA-II include elevated triglyceride, increased proportion of total plasma, and HDL free cholesterol and a marked (>10-fold) reduction in mouse apoA-II. Total endogenous plasma lecithin:cholesterol acyltransferase (LCAT) activity was reduced to a level directly correlated with the degree of increased plasma human apoA-II in the transgenic lines. LCAT activity toward exogenous substrate was, however, only slightly decreased. The biochemical changes in the 11.1 line, which is markedly deficient in plasma apoA-I, an activator for LCAT, are reminiscent of those in patients with partial LCAT deficiency. Feeding the transgenic mice a high fat, high cholesterol diet maintained the mouse apoA-I concentration at a normal level (69 +/- 14 mg/dl in line 11.1 compared with 71 +/- 6 mg/dl in nontransgenic controls) and prevented the appearance of HDL deficiency. All this happened in the presence of a persistently high plasma human apoA-II (96 +/- 14 mg/dl). Paradoxical HDL elevation by high fat diets has been observed in humans and is reproduced in human apoA-II overexpressing transgenic mice but not in control mice. Finally, HDL size and morphology varied substantially in the three transgenic lines, indicating the importance of apoA-II concentration in the modulation of HDL formation. The LCAT and HDL deficiencies observed in this study indicate that apoA-II plays a dynamic role in the regulation of plasma HDL metabolism.
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PMID:Functional lecithin:cholesterol acyltransferase deficiency and high density lipoprotein deficiency in transgenic mice overexpressing human apolipoprotein A-II. 863 92

The oxidation of low density lipoproteins (LDL) has been implicated in the development of atherosclerosis. As a variety of highly reactive lipid peroxidation products can transfer from oxidized LDL to HDL, we evaluated the potential deleterious effects of LDL oxidation on HDL-cholesterol metabolism. To address this issue, we exposed the HDL-containing d > 1.063 g/ml fraction of human plasma to copperoxidized LDL and assessed lecithin:cholesterol acyltransferase (LCAT) activity and apolipoproteinA-I (apoA-I) structure. To determine whether LCAT was directly affected by oxidized LDL, independent of crosslinking of apoA-I, we used an exogenous, [14C]cholesterol-labeled proteoliposome substrate to measure plasma LCAT activity. We observed an inhibition of LCAT activity where copper-oxidized LDL possessing only 2.3 +/- 0.1 and 7.3 +/- 1.4 TBARS produced 24 +/- 3% and 47 +/- 10% reductions in [14C]cholesterol esterification by 1 h, respectively. Copper-oxidized LDL that had been passed through a GF-5 desalting column, while retaining only one-third of its original TBARS, possessed nearly all of its LCAT inhibitory capacity suggesting that the LCAT inhibitory factor(s) was a lipophilic oxidation product. Analysis of polarlipids isolated from copper-oxidized LDL indicated that phospholipid and sterol fractions effectively inhibited LCAT. Copper-oxidized LDL, with as little as 6.3 TBARS, also produced intermolecular crosslinking of apoA-I molecules. Taken together, these data suggest that products of LDL oxidation may adversely affect HDL-cholesterol metabolism by two separate mechanisms: 1) a direct inhibitory effect on LCAT activity and 2) through crosslinking of apoA-I. If occurring in vivo, minimally oxidized LDL may impair cholesteryl ester formation on HDL thereby limiting the ability of HDL to function efficiently in the putative antiatherogenic reverse cholesterol transport pathway.
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PMID:Minimally oxidized LDL is a potent inhibitor of lecithin:cholesterol acyltransferase activity. 872 53

Comparative studies indicate that plasma cholesteryl ester (CE) composition is correlated with susceptibility to atherosclerosis. We previously showed that the lecithin:cholesterol acyltransferases (LCATs) of susceptible species such as rabbit, pig, and chicken (group I) differ in their substrate and positional specificities from the LCATs of resistant species such as rat and mouse (group II). However, the relative importance of enzyme specificity and substrate phosphatidylcholine (PC) composition in determining the CE composition is not known. To address this, we analyzed the molecular species composition of plasma PC in the same 14 vertebrates in which we previously studied the CE composition and LCAT specificity. The utilization of native PC species by LCAT was studied by determining the loss of each PC after incubation of plasma at 37 degrees C. The major contributor for LCAT reaction was either 16:0-18:2 PC or 18:0-18:2 PC in all species except dog, in which it was 18:0-20:4 PC. The formation of 20:4 CE correlated more with the consumption of 18:0-20:4 PC in group I, and with the consumption of 16:0-20:4 PC in group II. The group II enzymes exhibited higher selectivity for sn-2-20:4 PCs, whereas the group I enzymes showed preference for sn-2-18:2 PCs. The synthesis of high percentage of 20:4 CE in dog plasma was found to be due to the presence of unusually high concentration of 18:0-20:4 PC, rather than due to enzyme selectivity. These results show that the PC molecular species composition, especially the concentrations of sn-2-20:4 phosphatidylcholines has profound influence on plasma CE composition, and possibly on atherogenic risk.
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PMID:Comparative studies on the substrate specificity of lecithin:cholesterol acyltransferase towards the molecular species of phosphatidylcholine in the plasma of 14 vertebrates. 882 Jan 7

Lipid apheresis, a recently described procedure for the elimination of lipid but not apolipoproteins from plasma, was applied to normocholesterolaemic and hypercholesterolaemic roosters. Lipid apheresis resulted in an immediate reduction in plasma unesterified cholesterol concentration, which was sustained for 150 min. The reduction in unesterified cholesterol concentration was higher in the normocholesterolaemic animals than in the hypercholesterolaemic animals. Lipid apheresis induced changes in the ratio of plasma unesterified to total cholesterol in normocholesterolamic animals but not in hypercholesterolaemic animals. In hypercholesterolaemic animals, lecithin-cholesterol acyltransferase (LCAT) activity was not affected by lipid apheresis, whereas in normocholesterolaemic animals LCAT activity was acutely reduced for 150 min after lipid apheresis. Saturated LCAT kinetics occurred in the hypercholesterolaemic animals but not in the normocholesterolaemic animals. LCAT obeyed Michaelis-Menten kinetics. After lipid apheresis, there was a pool of unesterified cholesterol that was available as substrate for LCAT to a greater extent in hypercholesterolaemic animals than in normocholesterolaemic animals. These observations may have important implications for lipid apheresis as a treatment for atherosclerosis.
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PMID:Lecithin-cholesterol acyltransferase activity in normocholesterolaemic and hypercholesterolaemic roosters: modulation by lipid apheresis. 908 57

Iron overload, with its associated toxic effects, has serious health consequences and results in damage to the liver, heart and other organs. Salicylate may be used as the lipophilic carrier, transporting more iron into hepatocytes. In this study, we examined the effect of the combined administration of these compounds on plasma lipid profile and lipoprotein composition, as well as on hepatic lipid concentration. Male Spraque-Dawley rats were injected i.p. with Fe (15 mg/kg weight). This injection was repeated 24 h later with a gavage of sodium salicylate (700 mg/kg). Control rats received 0.9% NaCl only. The peroxidation indices TBARS (P < 0.001) and conjugated dienes (P < 0.05) significantly increased in the blood (50 and 122%, respectively) and liver (333 and 101%, respectively) of Fe salicylate-treated rats. Concomitantly, blood and liver arachidonic acid content was diminished by iron treatment. In parallel, the plasma lipid profile was markedly affected in Fe-salicylate treated-rats. Lower plasma concentrations of total cholesterol (25%, P < 0.0001) cholesteryl ester, (34%, P < 0.001) and high-density lipoprotein-cholesterol (50%, P < 0.001) were observed. Lipoprotein composition analysis revealed enrichment of free cholesterol and depletion of cholesterol ester in very low-density, intermediate-density, low-density and high-density (HDL2, HDL3) lipoproteins. Furthermore, SDS-polyacrylamide gel electrophoresis revealed several alterations in the apolipoprotein distribution of these lipoproteins. The activity of lecithin:cholesterol acyltransferase was unchanged and could not account for the reduction of cholesterol esterification. As for the plasma, the liver exhibited a significant (P < 0.001) decrease in total cholesterol (2.42 +/- 0.07 versus 1.89 +/- 0.06 mg/g liver), essentially due to a reduction in cholesteryl ester (0.93 +/- 0.07 versus 0.51 +/- 0.03 mg/g, P < 0.001). Again, the activity of ACAT (dpm/mg microsomal protein) was not lower (12,700 +/- 1250) than that of controls (9650 +/- 1080). Thus, the iron-salicylate was able to induce peroxidation and to profoundly affect the intravascular and intrahepatic lipid, and plasma lipoprotein metabolism. Additional work is needed to elucidate the mechanisms involved in the underlying lipid and lipoprotein abnormalities.
Atherosclerosis 1997 Mar 21
PMID:Iron-salicylate complex induces peroxidation, alters hepatic lipid profile and affects plasma lipoprotein composition. 910 57

The effect of a bile acid sequestrant, cholebine (3 g/day), on plasma lipoprotein subfractions was investigated in 16 patients with type II hyperlipoproteinemia. Activities of low density lipoprotein (LDL)-receptor and activities of lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) were assayed to address the mechanism of cholebine-induced changes in plasma lipoprotein subfractions. Twelve weeks of treatment with cholebine reduced plasma levels of total cholesterol (TC) and LDL-cholesterol (C) by 8.3 +/- 8.1% (mean +/- S.D.) and 14.4 +/- 11.9%, respectively (P < 0.001), but did not affect plasma levels of high density lipoprotein (HDL)-C. Cholebine significantly reduced plasma levels of LDL1-C (1.019 < d < 1.045) by 22.9 +/- 18.9% (P < 0.001) but did not affect plasma levels of very low density lipoprotein (VLDL)-C, intermediate density lipoprotein (IDL)-C, LDL2-C (1.045 < d < 1.063), HDL2-C, and HDL3-C (d > 1.125). Gradient polyacrylamide gel electrophoresis (PAGE) revealed that cholebine reduced large LDL in plasma but had almost no effects on small LDL and HDL subfractions. Cholebine did not alter the activities of LCAT and CETP. LDL-receptor activities of cultured lymphocytes negatively correlated with the reduction in plasma levels of LDL-C (r = -0.500, P < 0.05), IDL-C (r = -0.581, P < 0.02), and LDL1-C (r = -0.610, P < 0.01), respectively. Thus, cholebine seems to reduce further the plasma levels of IDL and large, light LDL in patients with lower LDL-receptor activities. We conclude that cholebine only reduces plasma levels of large, light LDL. This may be due to the stimulation of hepatic LDL-receptor activity.
Atherosclerosis 1997 Mar 21
PMID:Specific reduction of plasma large, light low-density lipoprotein by a bile acid sequestering resin, cholebine (MCI-196) in type II hyperlipoproteinemia. 910 67

Fish-eye disease (FED) in humans is characterized by corneal opacities and markedly decreased plasma concentrations of high-density lipoprotein (HDL) cholesterol, apolipoprotein (apo) AI, and apo All, but no tendency to precocious atherosclerosis is present. To elucidate this paradox, the structure of HDL, the potential of serum to promote cholesterol efflux from cultured cells, and the in vivo metabolism of HDL were examined in a 53-year-old woman with a FED syndrome in association with a markedly decreased lecithin:cholesterol acyltransferase (LCAT) activity in HDL due to a mutation of the LCAT gene (Arg158 --> Cys). HDLs isolated by ultracentrifugation were small and enriched in unesterified cholesterol and phospholipids at the expense of cholesteryl esters and proteins. The apolipoprotein content showed an enrichment in apo E and apo AIV, whereas apo AI and apo All were dramatically reduced. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting using specific antibodies showed that the apo E was free or covalently bound to apo All. These particles analyzed by electron microscopy were small and round lipoproteins with a size similar to the smallest fraction of normal HDL3. The potential capacity of the serum to promote efflux from the cells was approximately 40% of control serum levels, but FED HDLs were as efficient as control HDLs in promoting cholesterol efflux from cells. To assess the metabolism of HDL apolipoproteins, in vivo apolipoprotein kinetic studies were performed using endogenous labeling techniques in the patient with FED and three control subjects. All subjects were administered D3-labeled leucine by primed constant infusion for up to 10 hours. The fractional synthetic rates (FSRs) of apo AI and apo All in the patient were 0.674 and 0.594 per day, clearly higher than in controls, 0.210 +/- 0.053 and 0.148 +/- 0.014 per day for apo AI and apo All, respectively. Apo AI and apo All production rates in the patient with FED were normal, 11.32 and 2.62 mg/kg x d, respectively, as compared with those in normal subjects, 11.45 +/- 1.23 and 2.68 +/- 0.17 mg/kg x d. These data established that hypoalphalipoproteinemia in FED was caused by marked hypercatabolism of apo AI and apo All. This hypercatabolism could be the consequence of structural abnormalities due to the selective LCAT deficiency. In conclusion, two steps of reverse cholesterol transport, cholesterol efflux and apo-HDL metabolism, appeared particularly efficient. This efficiency could participate in the absence of premature atherosclerosis in FED patients as regards the low HDL level.
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PMID:Fish-eye disease: structural and in vivo metabolic abnormalities of high-density lipoproteins. 916 Aug 10


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