Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

We report a 39-year-old Japanese man with HDL and apoA-I deficiency as well as data from members of his family. Corneal opacity and a stomatocyte were found but not tonsillar hypertrophy, xanthomas, or splenomegaly. His serum HDL cholesterol, apoA-I, apoA-II, and LDL cholesterol levels were t mg/dL, < 3 mg/dL, 6 mg/dL, and 175 mg/dL, respectively. Plasma triglyceride, phospholipid, apoB, apoC-III, and apoE levels were all within normal limits. Lecithin:cholesterol acyltransferase activity was half of normal, while lipoprotein lipase and hepatic triglyceride lipase activities were within normal limits. ApoA-I deficiency was confirmed by combined isoelectric focusing and sodium dodecyl sulfate-polyacrylamide gel electrophoresis and by an immunoblotting method. We surveyed the apoA-I gene of the patient and five of his family members by direct sequencing after amplification by polymerase chain reaction and found a codon 8 nonsense mutation (TGG --> TAG, Trp --> stop) in exon 3 of the apoA-I gene. The results of a pedigree analysis by DNA sequencing and restricted fragment length polymorphism (Sty I) were consistent with an autosomal codominant trait. Coronary angiography was performed to evaluate coronary atherosclerosis, but no significant luminal narrowing was detected. An intracoronary ultrasound study showed mild intimal hyperplasia in segment 6. In summary, this is a case of apoA-I deficiency without evidence of coronary heart disease.
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PMID:A new case of apoA-I deficiency showing codon 8 nonsense mutation of the apoA-I gene without evidence of coronary heart disease. 758 66

Patients with non-insulin-dependent diabetes mellitus (NIDDM) have a greater risk of developing coronary heart disease than would be expected from a similar degree of hyperlipidemia in nondiabetic populations. Accelerated transfer of cholesteryl esters (CET) from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL), a process that is associated with atherosclerosis, may be a possible explanation for this. CET, plasma lipoprotein concentration, and mass in the fasting and postprandial state have been examined in 31 hyperlipidemic patients with NIDDM before and after 8 weeks of treatment with the hydroxymethylglutaryl (HMG)-coenzyme A (CoA) reductase inhibitor pravastatin in a double-blind, placebo-controlled, parallel group study. Body mass index, glycemic control, and blood pressure remained unaltered during the study period. Compared with placebo, pravastatin decreased fasting serum cholesterol (P < 0.001) and LDL cholesterol (P < 0.002) levels. The high basal CET (34.4 +/- 13.1 nmol.ml-1.h-1) was decreased significantly by pravastatin treatment (27.5 +/- 13.7 nmol.ml-1.h-1, P = 0.013). There was a fall in the total cholesterol, free cholesterol, and phospholipid content of the Sf 0-12, 20-60, and 60-400 lipoproteins (all P = 0.001). Lecithin: cholesterol acyl transferase activity was not altered. The postprandial increase in VLDL cholesterol 5 h after a standardized mixed meal was attenuated after pravastatin treatment (P = 0.011). Inhibition of hepatic cholesterol synthesis with an HMG-CoA reductase inhibitor in hyperlipidemic patients with NIDDM decreased serum cholesterol content of triglyceride-rich lipoprotein, thereby decreasing the transfer of cholesteryl ester from HDL to LDL and VLDL.
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PMID:Effect of treatment with a hydroxymethylglutaryl coenzyme A reductase inhibitor on fasting and postprandial plasma lipoproteins and cholesteryl ester transfer activity in patients with NIDDM. 769 16

In the following report, cynomolgous monkeys, fed atherogenic diets containing either saturated, monounsaturated, polyunsaturated (n-6 Poly) or fish oil (n-3 Poly) fat as 35% of total calories, provide a model for the study of dietary fat effects on plasma lipoproteins and atherosclerosis. We have previously described the ability of polyunsaturated fat diets to lower plasma described the ability of polyunsaturated fat diets to lower plasma high density lipoprotein (HDL) cholesterol levels and alter HDL subpopulation distribution in the primate model. These experiments investigate possible mechanisms responsible for such modifications. Animals fed polyunsaturated fat had significantly lower plasma concentrations of HDL cholesterol, total plasma cholesterol, and apolipoprotein A-I. Such changes were reflected in the distribution of protein among HDL subfractions, with the most remarkable modification in subclass distribution being the preponderance of small HDL particles in the n-3 Poly-fed animals. Striking alterations were also observed in the distribution of phosphatidylcholine (PC) molecular species (diet effect P < 0.0001 for all major molecular species). Phosphatidylcholine isolated from lipoproteins were used to make recombinant HDL (rHDL) particles. The reaction rate of purified lecithin:cholesterol acyltransferase (LCAT) with particles made from n-3 Poly-derived PC was 50% of that determined using rHDL formed with PC from other dietary groups (P < 0.0001). When the distribution of LCAT-derived rHDL cholesteryl esters was analyzed, LCAT demonstrated little selectivity for certain PC molecular species except in n-3 Poly-derived rHDL where 18:2-containing PC was selectively utilized. These data demonstrate that differences in dietary fat intake can significantly alter HDL PC concentration and molecular species distribution. We suggest that diet-induced alterations in HDL PC molecular species modify the type of cholesteryl esters produced during the LCAT reaction thereby affecting the plasma cholesteryl ester pool. We also propose that dietary n-3 Poly affects cholesteryl ester metabolism in part via LCAT by lowering PC (LCAT substrate) availability, altering the rate of the LCAT reaction, and decreasing HDL cholesterol concentrations; however, n-6 Poly dietary fat effects on HDL concentration appear to be through some mechanism other than LCAT.
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PMID:Dietary fatty acid modification of HDL phospholipid molecular species alters lecithin: cholesterol acyltransferase reactivity in cynomolgus monkeys. 775 15

Lecithin cholesterol acyltransferase (LCAT) is a key enzyme of cholesterol metabolism that catalyzes esterification of cholesterol for packaging in high-density lipoprotein (HDL) particles. In this study, we cloned and sequenced LCAT cDNA from baboon, a nonhuman primate model of atherosclerosis. LCAT sequences have been highly conserved over approximately 25 million years since the divergence of the baboon and human lineages. The baboon and human sequences are 97% identical at the nucleotide (nt) level and 98% identical at the amino acid (aa) level. Only 18% of the nt substitutions change the aa sequence (nonsynonymous substitutions). The substitutions between baboon and human LCAT do not alter key functional sites including the interfacial substrate active site, asparagine-linked glycosylation sites, or sites at which rare mutations cause human familial LCAT deficiencies. We also sequenced LCAT cDNA for a less common allele that is associated with higher LCAT activities and altered lipoprotein phenotypes. There were no sequence differences between the two alleles, which suggests that genotypic effects are most likely due to allelic differences in gene expression. The tissue specificity of LCAT expression was investigated using an RNase protection assay calibrated with known amounts of synthetic human LCAT RNA. In a survey of baboon tissues, the highest levels of LCAT mRNA were found in the cerebellum and liver and trace amounts in the ileum, spleen and cerebral cortex.
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PMID:Baboon lecithin cholesterol acyltransferase (LCAT): cDNA sequences of two alleles, evolution, and gene expression. 851 97

Lecithin:cholesterol acyltransferase (LCAT) is a key plasma enzyme in cholesterol and high density lipoprotein (HDL) metabolism. Transgenic rabbits overexpressing human LCAT had 15-fold greater plasma LCAT activity that nontransgenic control rabbits. This degree of overexpression was associated with a 6.7-fold increase in the plasma HDL cholesterol concentration in LCAT transgenic rabbits. On a 0.3% cholesterol diet, the HDL cholesterol concentrations increased from 24 +/- 1 to 39 +/- 3 mg/dl in nontransgenic control rabbits (n = 10; P < 0.05) and increased from 161 +/- 5 to 200 +/- 21 mg/dl (P < 0.001) in the LCAT transgenic rabbits (n = 9). Although the baseline non-HDL concentrations of control (4 +/- 3 mg/dl) and transgenic rabbits (18 +/- 4 mg/dl) were similar, the cholesterol-rich diet raised the non-HDL cholesterol concentrations, reflecting the atherogenic very low density, intermediate density, and low density lipoprotein particles observed by gel filtration chromatography. The non-HDL cholesterol rose to 509 +/- 57 mg/dl in controls compared with only 196 +/- 14 mg/dl in the LCAT transgenic rabbits (P < 0.005). The differences in the plasma lipoprotein response to a cholesterol-rich diet observed in the transgenic rabbits paralleled the susceptibility to developing aortic atherosclerosis. Compared with nontransgenic controls, LCAT transgenic rabbits were protected from diet-induced atherosclerosis with significant reductions determined by both quantitative planimetry (-86%; P < 0.003) and quantitative immunohistochemistry (-93%; P < 0.009). Our results establish the importance of LCAT in the metabolism of both HDL and apolipoprotein B-containing lipoprotein particles with cholesterol feeding and the response to diet-induced atherosclerosis. In addition, these findings identify LCAT as a new target for therapy to prevent atherosclerosis.
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PMID:Overexpression of lecithin:cholesterol acyltransferase in transgenic rabbits prevents diet-induced atherosclerosis. 887 55

Lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes represent a group of rare genetic disorders of HDL metabolism that have been the subject of a large number of clinical, biochemical, and genetic studies. Of special interest are patients with LCAT-related disorders with severe HDL deficiency and the apparent absence of premature atherosclerosis. This finding is inconsistent with the general concept that low HDL cholesterol levels are an obligate risk factor for atherosclerosis. In this review, we describe 36 natural mutations in the LCAT gene that result in either familial LCAT deficiency (FLD) or the milder phenotype known as fish-eye disease (FED). We propose a new classification of the natural mutations of the LCAT gene that are described to date. The defects are divided into four classes based on both the clinical and biochemical characterization of the patient and data that were obtained from the functional assessment of the mutant proteins. We define FLD-associated mutations that underlie a complete or nearly complete loss of LCAT activity due to null mutations (Class 1), and missense mutations (Class 2), respectively. In addition, we distinguish two classes of FED-associated mutations (Classes 3, 4) that underlie a partial impairment of LCAT activity but differ in their lipoprotein substrate specificity. In addition, we review the evidence of atherosclerosis in subjects with LCAT deficiency syndromes. The observation that 6 (all males) of a total of 19 FED subjects suffered from premature CAD (as defined by < 55 years of age and < 60 years of age for women and men, respectively) challenges the earlier assumption that the FED phenotype is not associated with increased risk of CAD. However, premature CAD remains an unusual clinical complication in FLD subjects.
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PMID:The molecular pathology of lecithin:cholesterol acyltransferase (LCAT) deficiency syndromes. 916 40

Lecithin:cholesterol acyltransferase (LCAT) is responsible for the formation of the majority of plasma cholesteryl esters. Familial LCAT deficiency is associated with corneal opacity, anemia and proteinurea and typically results in renal failure in the 4-5th decade; this syndrome is equally characterized by the quasi-absence of plasma LCAT activity with variable enzyme mass and very low levels of plasma cholesteryl esters. In this study, we report detailed analyses of plasma lipids and lipoprotein profile in two sisters (CM and ML) presenting classical homozygous LCAT-deficiency; the younger sibling (CM) had proteinurea from an early age whereas the older sister (ML) has never exhibited renal dysfunction. We investigated the molecular defect in the 45 year-old woman (proband CM) exhibiting all clinical and biochemical features of familial LCAT deficiency: a plasma cholesterol level of 105 mg/dl, of which 95% was unesterified, an HDL-cholesterol of 6.5 mg/dl and an apo A-I level of 52 mg/dl. The proband (CM) displayed a plasma cholesterol esterification rate which corresponded to 2% of normal LCAT activity; plasma LCAT protein concentration was 0.56 microg/ml and equivalent to approximately 10% of normal LCAT mass. Analysis by single strand conformation polymorphism (SSCP) of the PCR products corresponding to exons 4 and 5 of the LCAT gene revealed a visible band shift. Sequence analyses of exons 4 + 5 revealed two separate single point mutations: a C --> T transition replacing Arg147 by Trp and a T --> G transition converting Tyr171 to a stop codon. The presence of these two point mutations was confirmed by restriction enzyme analyses: the C --> T transition abolished a MwoI site whereas the T --> G transition created an AvrII site. The Arg147 mutation was associated with a non-secreted protein. The Tyr171 mutation resulted in formation of a truncated protein lacking the catalytic site. In summary, we have identified an LCAT deficient patient corresponding to a compound heterozygote for the Arg147 --> Trp mutation and a new molecular defect involving a Tyr171 --> Stop mutation in the LCAT gene.
Atherosclerosis 1997 May
PMID:Familial lecithin:cholesterol acyltransferase deficiency: molecular analysis of a compound heterozygote: LCAT (Arg147 --> Trp) and LCAT (Tyr171 --> Stop). 918 Feb 49

Cafestol and kahweol-diterpenes present in unfiltered coffee-strongly raise serum VLDL and LDL cholesterol and slightly reduce HDL cholesterol in humans. The mechanism of action is unknown. We determined whether the coffee diterpenes may affect lipoprotein metabolism via effects on lipid transfer proteins and lecithin:cholesterol acyltransferase in a randomized, double-blind cross-over study with 10 healthy male volunteers. Either cafestol (61-64 mg/day) or a mixture of cafestol (60 mg/day) and kahweol (48-54 mg/day) was given for 28 days. Serum activity levels of cholesterylester transfer protein, phospholipid transfer protein and lecithin:cholesterol acyltransferase were measured using exogenous substrate assays. Relative to baseline values, cafestol raised the mean (+/- S.D.) activity of cholesterylester transfer protein by 18 +/- 12% and of phospholipid transfer protein by 21 +/- 14% (both P < 0.001). Relative to cafestol alone, kahweol had no significant additional effects Lecithin:cholesterol acyltransferase activity was reduced by 11 +/- 12% by cafestol plus kahweol (P = 0.02). It is concluded that the effects of coffee diterpenes on plasma lipoproteins may be connected with changes in serum activity levels of lipid transfer proteins.
Atherosclerosis 1997 Jul 25
PMID:The cholesterol-raising diterpenes from coffee beans increase serum lipid transfer protein activity levels in humans. 924 72

Lecithin: cholesterol acyltransferase (LCAT) (EC 2.3.1.43) is generally assumed to participate in reverse cholesterol transport, i.e., cholesterol transport from peripheral tissues to the liver. LCAT is secreted by the liver and transported in plasma mostly associated with high density lipoprotein. It catalyzes the esterification of cholesterol, mainly high density lipoprotein cholesterol, and produces cholesteryl ester and lysolecithin. Transgenic mice overexpression human LCAT on a C57BL/6 background have elevated high density lipoprotein cholesterol and markedly reduced low and very low density lipoprotein cholesterol and triglyceride levels in plasma, suggesting that such mice may be less susceptible to diet-induced atherosclerosis than isogenic nontransgenic controls. To determine if the apparent anti-atherogenic lipoprotein profile of the LCAT transgenics reduced their susceptibility to atherogenesis, the atherosclerotic lesions developing in transgenic LCAT mice and controls when fed an atherogenic diet were compared by histology and morphometry. Histological examination of the aortas from mice fed a high fat diet for 12, 17 and 22 weeks revealed that the aortic lesions were no smaller or less developed in the transgenic LCAT mice than in the C57BL/6 controls. After 17 weeks there were significantly more "fatty streaks" in the transgenic mice than in the controls. Thus, overexpression of human LCAT in transgenic mice, in spite of their very favourable blood lipoprotein and lipid profile, does not protect against development of atherosclerosis.
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PMID:Mice overexpressing human lecithin: cholesterol acyltransferase are not protected against diet-induced atherosclerosis. 939 57

Lecithin:cholesterol acyltransferase (LCAT) is an enzyme well known for its involvement in the intravascular metabolism of high density lipoproteins; however, its role in the regulation of apolipoprotein (apo) B-containing lipoproteins remains elusive. The present study was designed to investigate the metabolic mechanisms responsible for the differential lipoprotein response observed between cholesterol-fed hLCAT transgenic and control rabbits. 131I-labeled HDL apoA-I and 125I-labeled LDL kinetics were assessed in age- and sex-matched groups of rabbits with high (HE), low (LE), or no hLCAT expression after 6 weeks on a 0.3% cholesterol diet. In HE, the mean total cholesterol concentration on this diet, mg/dl (230 +/- 50), was not significantly different from that of either LE (313 +/- 46) or controls (332 +/- 52) due to the elevated level of HDL-C observed in HE (127 +/- 19), as compared with both LE (100 +/- 33) and controls (31 +/- 4). In contrast, the mean nonHDL-C concentration for HE (103 +/- 33) was much lower than that for either LE (213 +/- 39) or controls (301 +/- 55). FPLC analysis of plasma confirmed that HDL was the predominant lipoprotein class in HE on the cholesterol diet, whereas cholesteryl ester-rich, apoB-containing lipoproteins characterized the plasma of LE and, most notably, of controls. In vivo kinetic experiments demonstrated that the differences in HDL levels noted between the three groups were attributable to distinctive rates of apoA-I catabolism, with the mean fractional catabolic rate (FCR, d-1) of apoA-I slowest in HE (0.282 +/- 0.03), followed by LE (0.340 +/- 0.01) and controls (0.496 +/- 0.04). A similar, but opposite, pattern was observed for nonHDL-C levels and LDL metabolism (h-1), such that HE had the lowest nonHDL-C levels with the fastest rate of clearance (0.131 +/- 0.027), followed by LE (0.057 +/- 0.009) and controls (0.031 +/- 0.001). Strong correlations were noted between LCAT activity and both apoA-I (r= -0.868, P < 0.01) and LDL (r = 0.670, P = 0.06) FCR, indicating that LCAT activity played a major role in the mediation of lipoprotein metabolism. In summary, these data are the first to show that LCAT overexpression can regulate both LDL and HDL metabolism in cholesterol-fed rabbits and provide a potential explanation for the prevention of diet-induced atherosclerosis observed in our previous study.
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PMID:Overexpression of human lecithin:cholesterol acyltransferase in cholesterol-fed rabbits: LDL metabolism and HDL metabolism are affected in a gene dose-dependent manner. 945 77


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