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)

Atherosclerosis is the leading cause of death in industrial societies. In France, 215 men out of 100,000 aged from 25 to 64 years old suffered of a myocardial infarction in 1992 and due to this disease 67 men out of 100,000 died. Hypercholesterolemia corresponding to a high LDL cholesterol level is an important risk factor of myocardial infarction. Nevertheless a low cholesterol level in the HDL fraction (frequently associated with an increase in triglycerides concentrations) is a common abnormality found in patients with confirmed coronary artery disease. Therefore, besides tentatives to reduce triglycerides and LDL cholesterol levels, a therapeutical strategy consists in increasing the serum HDL cholesterol concentration in order to improve the "reverse cholesterol transport". Apo A-I is the major protein of HDL. Studies in mice and rabbits transgenic for human apo A-I showed that overexpression of this protein in these animals resulted in an increase in the HDL cholesterol level. The serum of these animals contents a high concentration of particles containing human apo A-I but not mouse apo A-II (LpA-I) and presents a higher ability to induce cellular cholesterol efflux than the serum of the control mice. These alterations result in a reduction of atherosclerosis development when these animals are submitted to a cholesterol rich diet. Lecithin cholesterol acyl-transferase (LCAT) is a major enzyme in the metabolic cascade leading to the return of cholesterol to the liver. The metabolic role of LCAT is to esterify the free cholesterol of native HDL. Native HDL acquire free cholesterol during the transfer of cholesterol from the cell membrane to the particle during the cellular cholesterol efflux, which is the first step of the "reverse cholesterol transport". Mice and rabbits transgenic for human LCAT have higher HDL-cholesterol levels. Transgenic rabbits but not transgenic mice are protected against diet induced atherosclerosis development. Nevertheless, cholesterol fed mice which are transgenic for both human LCAT and simian cholesteryl ester transfer (CETP) protein do not develop atherosclerosis. This data indicates that over production of LCAT reduces atherosclerosis when CETP is naturally (rabbit) or artificially (CETP transgenic mice) expressed in the animals. Tentatives of gene therapy in mice induced by adenovirus-mediated transfer of human apo A-I and LCAT genes also increased circulating apo A-I and LCAT. Therefore apo A-I and LCAT are two potential targets for gene therapy in patients with atherosclerosis associated with a low HDL cholesterol level.
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PMID:[Reverse cholesterol transport and use of transgenic mice and rabbits to reveal candidate genes for protection against atherosclerosis]. 964 40

Elevated concentrations of plasma cholesterol and triglycerides are characteristic of familial combined hyperlipidemia (FCHL) which may also present with reduced high density lipoprotein (HDL) cholesterol concentrations. Lecithin:cholesterol acyltransferase (LCAT) plays a key role in reverse cholesterol transport by converting unesterified cholesterol to cholesterol ester in the process of maturation of HDL in the presence of its activator, apolipoprotein (apo) A-I. We hypothesised that alterations in LCAT activity or plasma concentrations or gene sequence of apo A-I could influence HDL metabolism in these patients. We studied cholesterol concentrations of high density lipoprotein subfractions and LCAT activity in 25 FCHL subjects and 48 controls. Total HDL (p=0.018) and HDL2 (p=0.008) were significantly decreased in the FCHL group compared with controls. After analyses with adjusted data only HDL2 remained significantly decreased in the FCHL group (p=0.050). The LDLc/HDLc and A-I/HDLc ratios were significantly elevated in the FCHL group (p <0.0001), the latter suggesting the existence of compositional differences in the HDL particles of the FCHL individuals. LCAT activity assessed in the FCHL (19.94+/-3.95 nmol/ml per h) and control (20.13+/-6.86 nmol/ml per h) groups showed no statistically significant differences. A significant positive correlation of LCAT activity with total HDL (r=0.42), HDL3 cholesterol (r=0.46) and apolipoprotein A-I (r=0.47) was observed in affected subjects but not in controls. An association between a Ga(-75)-A variation in the promoter region of the apo A-I gene and elevated concentrations of apo A-I (p=0.009) and apo C-III (p=0.041) was observed. This association was strongly influenced by the status of the subject providing further evidence for a regulatory role of this genetic region in the expression of FCHL. Our data suggests that LCAT activity is normal in FCHL and, therefore, does not account for the abnormalities observed in these patients essentially with regard to the HDL2 subfraction.
Atherosclerosis 1998 Jun
PMID:Evidence against alterations in Lecithin:cholesterol acyltransferase (LCAT) activity in familial combined hyperlipidemia. 969 Sep 23

Lecithin:cholesteryl acyl transferase (LCAT) and cholesteryl ester transfer protein (CETP) are key factors in the esterification of cholesterol and the subsequent transfer of cholesteryl ester from high density lipoproteins (HDL) towards very low and low density lipoproteins (VLDL + LDL). Phospholipid transfer protein (PLTP), lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in plasma phospholipid and triglyceride metabolism and also affect HDL. Equivocal changes in plasma cholesteryl ester transfer have been reported in non-insulin-dependent diabetes mellitus (NIDDM). In 16 NIDDM men with plasma triglycerides < or = 4.5 mmol/l and cholesterol < or = 8.0 mmol/l. plasma cholesteryl ester transfer (CET), cholesterol esterification rate, LCAT and PLTP activity levels were higher (P < 0.05 to P < 0.02) in conjunction with higher plasma triglycerides (P < 0.01) and lower HDL cholesterol and cholesteryl ester levels (P < 0.05) compared to 16 matched healthy men. Multiple stepwise regression analysis demonstrated that CET was positively related to VLDL + LDL cholesterol (P < 0.001), triglycerides (P = 0.001), PLTP activity (P = 0.007) and CETP activity (P = 0.008, multiple r = 0.94). NIDDM had no effect on CET, independently from these parameters. HDL cholesteryl ester was negatively related to CET (P= 0.017), HL activity (P = 0.033) and NIDDM (P = 0.047) and positively to LCAT activity levels (P = 0.034, multiple r = 0.68). It is concluded that the elevated CET in plasma from NIDDM patients is associated with higher plasma triglycerides and PLTP activity levels. Furthermore, our data suggest that in normo- and moderately dyslipidaemic subjects PLTP and CETP activity levels per se may influence the rate of cholesteryl ester transfer in plasma. Plasma cholesteryl ester transfer appears to be a determinant of HDL cholesteryl ester, but other factors are likely to contribute to lower HDL cholesteryl ester levels in NIDDM.
Atherosclerosis 1998 Sep
PMID:Elevated plasma cholesteryl ester transfer in NIDDM: relationships with apolipoprotein B-containing lipoproteins and phospholipid transfer protein. 973 17

Lecithin: cholesterolacyltransferase (LCAT) transacylates the fatty acid at the sn-2 position of lecithin to the 3beta-OH group of cholesterol forming lysolecithin and the majority of cholesteryl ester found in plasma. LCAT participates in the reverse cholesterol transport pathway in man where it esterifies tissue-derived cholesterol following efflux from peripheral cells into HDL. Only 38 unique mutations in the human LCAT gene have been reported worldwide. Our French female proband presented with corneal opacity and no detectable plasma LCAT activity using either endogenous or exogenous assays. Her total plasma cholesterol and HDL cholesterol were low (2.34 mmol/l and 0.184 mmol/l, respectively) with a very high cholesterol/cholesteryl ester molar ratio (10.9:1). Plasma triglycerides were 0.470 mmol/l with low apo B (40.5 mg/dl), apo A-I (14.7 mg/dl), apo A-II (6.8 mg/dl) and apo E (2.1 mg/dl) levels. Plasma lipoprotein analysis by ultracentrifugation showed very low HDL concentrations and a characteristic shift of the lipoprotein profile towards larger, less dense particles. No proteinuria, renal dysfunction or signs of atherosclerosis were noted at age 45. Sequence analysis of her LCAT gene showed a novel homozygous TG-deletion at residues 138-139 that resulted in a frameshift causing the generation of a stop codon and premature termination of the LCAT protein at amino acid residue 144. Western blotting of the patient's plasma using a polyclonal IgY primary antibody against human LCAT failed to demonstrate the presence of a truncated LCAT protein. A 53 bp mismatched PCR primer was designed to generate an Fsp 1 restriction site in the wild type sequence of exon 4 where the mutation occurred. The 155 bp PCR product from the wild type allele produced a 103 bp and 52 bp fragment with Fsp 1 and no cleavage products with the mutant allele thus permitting rapid screening for this novel mutation.
Atherosclerosis 1999 Sep
PMID:Classical LCAT deficiency resulting from a novel homozygous dinucleotide deletion in exon 4 of the human lecithin: cholesterol acyltransferase gene causing a frameshift and stop codon at residue 144. 1048 97

The enzyme lecithin cholesterol acyl transferase is responsible for the synthesis of most of the cholesteryl esters in plasma, and therefore plays a key role in lipoprotein metabolism. The relationship between the structure and function of lecithin cholesterol acyl transferase has been extensively studied in the past years, and new data appeared in 1999 documenting the substrate specificity and physiological role of lecithin cholesterol acyl transferase. The discovery of natural mutants, together with the proposal of a three-dimensional model for the enzyme, has provided new tools to unravel the function of specific residues of lecithin cholesterol acyl transferase. The use of transgenic animals and the production of knock-out lecithin cholesterol acyl transferase mice has further contributed to the understanding of the lecithin cholesterol acyl transferase 'in vivo' function. Evidence for a protective role of lecithin cholesterol acyl transferase against the development of atherosclerosis through the hydrolysis of oxidized lipids was recently proposed. Lecithin cholesterol acyl transferase patterns in several pathologies were further clarified. These newer developments are reviewed here.
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PMID:Structure and function of lecithin cholesterol acyl transferase: new insights from structural predictions and animal models. 1078 77

Hypertriglyceridemia is a complex pathological entity strongly connected to low HDL-C levels but controversially related to the risk of coronary artery disease. In this study, we evaluated the main steps of the antiatherogenic pathway called reverse cholesterol transport in a group of patients with primary hypertriglyceridemia and low HDL-C levels in comparison to normotriglyceridemic subjects with or without hypoalphalipoproteinemia. In patients with primary hypertriglyceridemia, low HDL-C levels were accompanied by decreased apo A-I and apo A-II concentrations. These reductions were manifested by a selective reduction in LpA-I:A-II particles. In addition, apo C-III Lp non B was found to be elevated and HDL lipid percentage composition showed a triglyceride enrichment and cholesterol depletion. The capacity of serum samples from hypertriglyceridemic patients to promote cellular cholesterol efflux was reduced, as evidenced by using two different cellular models, Fu5AH and J774 cells. This impaired cholesterol efflux promotion was also corroborated by incubations of isolated HDL fractions with Fu5AH cells. Lecithin:cholesterol acyltransferase (LCAT) activity, the driving force of reverse cholesterol transport, showed a tendency towards lower values in hypertriglyceridemic patients, but this difference was not statistically significant. Additionally, cholesteryl ester transfer protein (CETP) activity was increased in this group of patients. Therefore, hypertriglyceridemia was found to induce quantitative and qualitative alterations in HDL and its subclasses and, consequently, in some steps of reverse cholesterol transport. The abnormalities found in this antiatherogenic pathway and its promoters could constitute a possible connection between hypertriglyceridemia and atherosclerosis.
Atherosclerosis 2000 Sep
PMID:Alterations in the main steps of reverse cholesterol transport in male patients with primary hypertriglyceridemia and low HDL-cholesterol levels. 1099 54

Growth hormone (GH) deficiency and acromegaly may be associated with increased cardiovascular risk. Little is known about alterations in high density lipoproteins (HDL) in these conditions. Lecithin:cholesterol acyl transferase (LCAT) has the ability to esterify free cholesterol (FC) in HDL. Cholesteryl ester transfer protein (CETP) is able to transfer cholesteryl esters (CE) from HDL to very low and low density lipoproteins (VLDL and LDL). During phospholipid transfer protein (PLTP)-mediated HDL remodelling, small pre beta-HDL particles are generated which serve as acceptors for cellular cholesterol and provide the initial LCAT-substrate. We documented plasma lipids, LCAT, CETP and PLTP activity levels as well as plasma cholesterol esterification (EST) and cholesteryl ester transfer (CET) in 12 adult men with acquired GH deficiency, 12 acromegalic men and 24 healthy male subjects. All GH deficient and acromegalic patients received conventional hormonal replacement therapy if necessary. VLDL + LDL cholesterol and plasma triglycerides were higher in GH deficient (P < 0.01 and P < 0.05) and acromegalic patients (P < 0.05 and P < 0.01) than in healthy subjects. HDL cholesterol and HDL CE were lower (P < 0.05 for both) and the HDL FC/CE ratio was higher (P < 0.01) in these patient groups compared to healthy subjects. Plasma LCAT, CETP and PLTP activity levels were lower in acromegalic patients (P < 0.01 for all) and CETP activity was lower in GH deficient patients (P < 0.01) compared to healthy subjects. Plasma EST and CET were decreased in both acromegalic (P < 0.01 for both) and GH deficient patients (P < 0.05 for both). Multiple regression analysis demonstrated independent negative relationships of plasma insulin-like growth factor I with plasma LCAT (P = 0.0001), CETP (P = 0.009) and PLTP activity levels (P = 0.021). Plasma LCAT (P = 0.0001) and CETP activity (P = 0.0001) were also negatively associated with (substitution therapy for) adrenal insufficiency. In conclusion, GH deficient and acromegalic patients show abnormalities in HDL, consistent with impaired LCAT action. Decreases in plasma EST and CET in such patients, as well as a low PLTP activity in acromegaly suggest that reverse cholesterol transport may be impaired, contributing to increased cardiovascular risk.
Atherosclerosis 2000 Dec
PMID:Low plasma lecithin:cholesterol acyltransferase and lipid transfer protein activities in growth hormone deficient and acromegalic men: role in altered high density lipoproteins. 1116 39

We have recently reported a new apolipoprotein (apo) A-I variant (apo A-I(Zaragoza) L144R) in a Spanish family with HDL-C levels below the 5th percentile for age and sex and low apo A-I concentrations. All the apo A-I(Zaragoza) subjects were heterozygous and none of them showed evidence of coronary artery disease (CAD). Mean plasma HDL-C, apo A-I, and apo A-II levels were lower in apo A-I(Zaragoza) carriers as compared to control subjects (40, 60, and 50%, respectively). Lipid composition analysis revealed that apo A-I(Zaragoza) carriers had HDL particles with a higher percentage of HDL triglyceride and a lower percentage of HDL esterified cholesterol as compared to those of control subjects. Lecithin:cholesterol acyltransferase (LCAT) activity and cholesterol esterification rate of apo A-I(Zaragoza) carriers were normal. Apo A-I and apo A-II metabolic studies were performed on two heterozygous apo A-I(Zaragoza) carriers and on six control subjects. We used a primed constant infusion of [5,5,5-2H3]leucine and HDL apo A-I and apo A-II tracer/tracee ratios were determined by gas chromatography mass spectrometry and fitted to a monoexponential equation using SAAM II software. Both subjects carrying apo A-I(Zaragoza) variant showed mean apo A-I fractional catabolic rate (FCR) values more than two-fold higher than mean FCR values of their controls (0.470+/-0.0792 vs. 0.207+/-0.0635 x day(-1), respectively). Apo A-I secretion rate (SR) of apo A-I(Zaragoza) subjects was slightly increased compared with controls (17.32+/-0.226 vs. 12.76+/-3.918 mg x kg(-l) x day(-1), respectively). Apo A-II FCR was also markedly elevated in both subjects with apo A-I(Zaragoza) when compared with controls (0.366+/-0.1450 vs. 0.171+/-0.0333 x day(-1), respectively) and apo A-II SR was normal (2.31+/-0.517 vs. 2.1+/-0.684 mg x kg(-l) x day(-1), respectively). Our results show that the apo A-I(Zaragoza) variant results in heterozygosis in abnormal HDL particle composition and in enhanced catabolism of apo A-I and apo A-II without affecting significantly the secretion rates of these apolipoproteins and the LCAT activation.
Atherosclerosis 2001 Feb 15
PMID:Enhanced fractional catabolic rate of apo A-I and apo A-II in heterozygous subjects for apo A-I(Zaragoza) (L144R). 1125 62

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.
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PMID:Decreased activity of lecithin:cholesterol acyltransferase and hepatic lipase in chronic hypothyroid rats: implications for reverse cholesterol transport. 1284 43

Lecithin cholesterol acyltransferase (LCAT) is a key enzyme in the metabolism of high density lipoprotein (HDL), which has been found inversely correlated with atherosclerosis. Adenovirus mediated overexpression of human LCAT (hLCAT) in hamsters resulted in increased levels of plasma total cholesterol, HDL cholesterol, phospholipids and enlarged particle size of HDL. It also increased cholesterol and total bile acid concentrations in bile. Hepatic mRNA level of cholesterol 7alpha-hydroxylase increased 2.7-fold in hamsters. However, such effects were not observed in mice in a parallel experiment. This study suggests that overexpression of hLCAT in hamsters facilitated reverse cholesterol transport. Similar metabolic changes in humans might modify atherogenic risk.
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PMID:Increased plasma HDL cholesterol levels and biliary cholesterol excretion in hamster by LCAT overexpression. 1525 33


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