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)

Cholesteryl ester transfer protein (CETP) transfers cholesteryl ester from high density lipoprotein (HDL) to apo B-containing lipoproteins. The hyperalphalipoproteinemia caused by CETP deficiency is fairly common in Japan and one of the most common mutations in the CETP gene is the splicing defect of the intron 14, the allelic frequency of which has been shown to be 0.0049 in the Japanese general population. Recently, we have reported a missense mutation in exon 15 of the CETP gene (442D:G), showing a dominant effect on the CETP activity and HDL-cholesterol level. In the current study, we determined the frequency of this new mutation in Japanese hyperalphalipoproteinemic (HDL-cholesterol > or = 100 mg/dl) subjects. A rapid and easy screening method for this new mutation was developed using a polymerase chain reaction (PCR)-mediated site-directed mutagenesis. Among 117 Japanese hyperalphalipoproteinemic subjects (HDL-cholesterol; 116.7 +/- 16.5 mg/dl, mean +/- S.D.) without the intron 14 splice defect, three homozygotes (2.5%) and 34 heterozygotes (29.1%) were found to have the 442D:G mutation. The relative allelic frequency of this mutation was calculated to be 0.17. One of the homozygotes for the 442D:G mutation was the patient previously described by us as having hyperalphalipoproteinemia with corneal opacity and coronary heart disease. This was the first reported subject homozygous for the CETP deficiency who also demonstrated atherosclerotic symptoms. In homozygous subjects, CETP activity ranged from 37% to 62% of the normal value, which was consistent with the results obtained from the transient expression experiment previously reported; however, the specific activity of CETP was not as low as expected.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1995 Apr 24
PMID:Frequency of exon 15 missense mutation (442D:G) in cholesteryl ester transfer protein gene in hyperalphalipoproteinemic Japanese subjects. 760 82

We investigated the differences between the hypocholesterolemic effects induced by dietary linoleic acid and those induced by oleic acid in hamsters. Addition of 5% linoleic acid or oleic acid to a 0.1% cholesterol-supplemented diet diminished the increases in plasma total and low density lipoprotein (LDL) cholesterol induced by cholesterol alone. Linoleic acid decreased high density lipoprotein (HDL) cholesterol in comparison with cholesterol alone, whereas oleic acid did not. As compared with a standard diet or a cholesterol-supplemented diet, linoleic acid and oleic acid each prevented hepatic LDL receptor suppression, although linoleic acid was more effective. Oleic acid prevented the increase in plasma cholesteryl ester transfer protein (CETP) activity induced by dietary cholesterol, whereas linoleic acid did not. Neither linoleic acid nor oleic acid altered hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity. Only oleic acid increased hepatic cholesterol 7 alpha-hydroxylase activity. These results suggest that dietary linoleic and oleic acids diminish the cholesterol-induced increases in plasma total and LDL-cholesterol by preventing hepatic LDL receptor suppression, and in the case of oleic acid by also preventing the increase in the plasma CETP activity. These effects on cholesterol 7 alpha-hydroxylase activity may influence bile lipid metabolism.
Atherosclerosis 1995 Apr 24
PMID:Comparison of hypocholesterolemic effects induced by dietary linoleic acid and oleic acid in hamsters. 760 90

We investigated the effects of simvastatin on plasma levels of lipoprotein subfractions, cholesterol esterification rates and activities of cholesteryl ester transfer protein in 28 patients with type II hyperlipoproteinemia (i.e., nonfamilial hyperlipoproteinemia type IIa and type IIb, and heterozygous familial hypercholesterolemia (FH)). Plasma levels of VLDL-cholesterol (C) and VLDL-triglyceride (TG) were significantly reduced overall by 12.9 +/- 58.0% (mean +/- S.D.; P < 0.05) and 4.2 +/- 54.2% (P < 0.05) respectively, but not in FH. Plasma levels of IDL-C and IDLT-G were decreased overall by 23.2 +/- 47.5% (P < 0.001) and 12.3 +/- 49.7% (P < 0.05), respectively, again mainly due to decreases seen in nonfamilial type II hyperlipoproteinemia. Plasma levels of LDL1 (1.019 < d < 1.045)-C and LDL1-TG were significantly reduced by 33.1 +/- 12.9% (P < 0.001) and 23.3 +/- 24.7% (P < 0.001), respectively. Plasma levels of LDL2 (1.045 < d < 1.063)-C were significantly reduced by 22.9 +/- 18.1% (P < 0.001) overall but not in FH. Gradient PAGE showed no consistent changes in the distribution of LDL particles. Thus, plasma levels of all apo B-containing lipoprotein subfractions were reduced by simvastatin, but its effects varied among the three subgroups. Cholesterol esterification rates were suppressed by 9.3 +/- 19.7% (P < 0.01) and activities of cholesteryl ester transfer protein were reduced by 30.6 +/- 21.5% (P < 0.001). Changes in CETP activity and in plasma levels of cholesterol in lipoprotein subfractions were not correlated. Thus, the changes in distribution of lipoprotein subfractions were not due mainly to CETP suppression.
Atherosclerosis 1995 Apr 24
PMID:Effects of simvastatin on plasma lipoprotein subfractions, cholesterol esterification rate, and cholesteryl ester transfer protein in type II hyperlipoproteinemia. 760 91

Transfer processes in plasma are determinant in cholesterol metabolism. In many species, including man, there is an alternative route for the disposal of cholesteryl esters (CE) in HDL via transfer to VLDL in exchange for triglycerides (TG), a process dependent on a hydrophobic 74 kDa glycoprotein called cholesteryl ester transfer protein (CETP). In vivo, cholesteryl esters transferred from HDL will contribute to LDL, to which VLDL is converted. Although the prevention of CE accumulation in HDL may enhance the ability of HDL to take up more cholesterol from tissues, high rates of transfer may also increase the risk for atheroma by increasing formation of atherogenic lipoproteins. Conversely, CE retained within HDL, if returned directly to the liver, would be expected to be beneficial. Moreover, in most conditions predisposing to atheroma, CETP activity is raised; whereas species with low or absent CETP activity are at low risk for atherosclerosis.
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PMID:[Transfer of plasma cholesterol and atherosclerosis]. 780 46

Recent studies in transgenic mice provide strong evidence for a direct anti-atherogenic role of high-density lipoproteins (HDL) and highlight the importance of multiple gene interactions in the regulation of HDL levels. Plasma lipid transfer processes mediated by cholesteryl ester transfer protein (CETP) have a major impact on HDL levels, as revealed in studies of human genetic CETP deficiency and CETP transgenic mice. Subsequent to the discovery of an intron 14 CETP gene splicing defect, several new CETP gene mutations have been discovered recently in Japanese and other populations. One of these is an exon 15 missense mutation, changing amino acid 442 of CETP from aspartate to glycine. Population studies in Japan indicate that CETP gene mutations are sufficiently common to have a significant influence on HDL levels in the general population. Studies in transgenic mice show that CETP expression results in decreased levels of HDL cholesterol, but that the effects of CETP on HDL apolipoprotein A-I (apoA-I) content and size show important modulation by co-expression with transgenes encoding human apoA-I, apoC-III and apoA-II. In addition to the apparent antiatherogenic phenotype of human genetic CETP deficiency, high level expression of CETP in transgenic mice leads to accelerated atherosclerosis, illustrating the pro-atherogenic potential of CETP expression.
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PMID:Plasma cholesteryl ester transfer protein and high-density lipoproteins: new insights from molecular genetic studies. 783 31

The mechanism whereby alcohol increases high-density lipoprotein cholesterol (HDL-C) levels is unclear. Lipoprotein lipase (LPL), hepatic lipase (HL), cholesteryl ester transfer protein (CETP) and lecithin:cholesterol acyltransferase (LCAT) act on lipoprotein metabolism. The purpose of the present study is to determine which one or what combination of these factors is responsible for the rise in HDL-C levels following alcohol ingestion. After 3 weeks of abstinence, 12 men consumed 0.5 g/kg bw of alcohol per day for 4 weeks; 13 abstaining men served as controls. Mean plasma total cholesterol (TC) levels were unchanged in either group throughout the study. Among the alcohol consumers, plasma triglycerides (TG), HDL-C, apolipoprotein (apo) A-I and A-II levels increased significantly after 3 weeks of alcohol loading but were unchanged in the control group. High-density lipoprotein3 cholesterol (HDL3-C) levels increased significantly in the alcohol consumers after 4 weeks of alcohol loading whereas high-density lipoprotein2 cholesterol (HDL2-C) levels were unaffected. In the controls, neither HDL2-C nor HDL3-C changed significantly. Post-heparin plasma (PHP) LPL activity and mass increased significantly (P < 0.01) after the alcohol ingestion (controls remained unchanged) without changing LPL specific activity. HL, CETP and LCAT activities were unaffected in both groups. We conclude that of the factors considered, LPL contributed the most to the alcohol-induced rise in HDL-C.
Atherosclerosis 1994 Nov
PMID:Effects of alcohol on lipoprotein lipase, hepatic lipase, cholesteryl ester transfer protein, and lecithin:cholesterol acyltransferase in high-density lipoprotein cholesterol elevation. 784 Aug 18

Probucol lowers total and LDL cholesterol levels, and also lowers HDL cholesterol levels. Probucol is able to lower cholesterol levels in homozygous patients with familial hypercholesterolemia as well as in heterozygous patients. In heterozygous familial hypercholesterolemia, probucol lowered total cholesterol levels by 22%, LDL-cholesterol levels by 17%, and HDL-cholesterol levels by 40%, respectively. The lowering HDL cholesterol levels by probucol may reflect increased reverse cholesterol transport. Probucol increases cholesteryl ester transfer protein concentration, and diminishes HDL particle size. Probucol has been reported to retard and even regress atherosclerosis in animal models and to diminish tendinous xanthomas in man. Its lowering LDL-cholesterol levels, activation of reverse cholesterol transport process, and antioxidant effects may cause an antiatherogenic action.
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PMID:[Probucol treatment of hyperlipidemia]. 785 23

We investigated the role of cholesteryl ester transfer protein (CETP) in hamsters by using a monoclonal antibody (MAb) that inhibited hamster CETP activity. MAbs were prepared against partially purified human CETP and screened for inhibiton of 3H-cholesteryl oleate (CE) transfer from LDL to HDL in the presence of human plasma bottom fraction (d > 1.21 g/ml). Antibody 1C4 inhibited CE transfer activity in both human plasma bottom fraction (IC50 = approximately 4 micrograms/ml) and in whole plasma from male Golden Syrian hamsters (IC50 = approximately 30 micrograms/ml). Purified MAb 1C4 was injected into chow- and cholesterol-fed hamsters, and blood was collected for analysis of plasma CETP activity and HDL lipid composition. Plasma CETP activity was inhibited by 70%-80% at all and HDL lipid composition. Plasma CETP activity was inhibited by 70%-80% at all times up to 24 h following injection of 500 micrograms MAb 1C4 (approximately 3.7 mg/kg). The amount of antibody required for 50% inhibition at 24 h post-injection was 200 micrograms (approximately 1.5 mg/kg). Inhibition of hamster CETP activity in vivo increased hamster HDL cholesterol by 33% (P < 0.0001), increased HDL-CE by 31% (P < 0.0001) and decreased HDL-triglyceride by 42% (P < 0.0001) (n = 36) as determined following isolation of HDL by ultracentrifugation. An increase in HDL cholesterol and a redistribution of cholesterol to a larger HDL particle were also observed following fast protein liquid chromatography (FPLC) gel filtration of plasma lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1994 Sep 30
PMID:Inhibition of cholesteryl ester transfer protein activity in hamsters alters HDL lipid composition. 785 64

We investigated the interaction between genetic and environmental factors in the regulation of plasma HDL cholesterol concentration by determining TaqI and EcoN I restriction fragment length polymorphisms at the cholesteryl ester transfer protein (CETP) gene locus in 93 male alcohol drinkers and 82 control men. The highest plasma CETP activity and the lowest HDL cholesterol concentration were in the control subjects who were homozygous for the presence of the TaqI B restriction site (genotype 1-1). The lowest CETP activity and the highest HDL cholesterol among the control subjects were in those with genotype 2-2. These associations were, however, evident only in the non-smokers (P = 0.03 for CETP activity and P = 0.05 for HDL cholesterol). The non-smoking control subjects with genotype 1-1 had 19% higher CETP activity and 16% lower HDL cholesterol than those with genotype 2-2 (mean +/- S.D., 113 +/- 25 nmol/h/ml and 1.16 +/- 0.30 mmol/l vs. 95 +/- 16 nmol/h/ml and 1.38 +/- 0.34 mmol/l, respectively), and CETP activity and HDL cholesterol were negatively correlated (r = -0.280, P = 0.03, n = 59). The alcohol drinkers had 30% lower CETP activity (P < 0.001) and 48% higher HDL cholesterol (P < 0.001) than the controls. CETP activity was not affected by the TaqI B genotype in the alcohol drinkers. The lowest HDL cholesterol was in subjects with genotype 1-1 (1.68 +/- 0.60 mmol/l), but those with genotype 2-2 had lower HDL cholesterol than those with genotype 1-2 (1.78 +/- 0.59 and 1.93 +/- 0.66 mmol/l, respectively). The data of the alcohol drinkers fitted better with the quadratic regression model than with the linear one, suggesting a trend towards a curved relationship between the TaqI B genotype and HDL cholesterol in both the non-smoking and smoking alcohol drinkers. Total, LDL or VLDL cholesterol, total or VLDL triglycerides did not differ between the TaqI B genotypes either in the alcohol drinkers or the controls. Lipid and lipoprotein levels and CETP activities were likewise similar in the TaqI A and EcoN I polymorphisms. Our data indicate that CETP TaqI B polymorphism is related to plasma CETP activity and HDL cholesterol concentration in non-smoking men, but these associations are affected by smoking and alcohol drinking.
Atherosclerosis 1994 Sep 30
PMID:Relation of polymorphisms in the cholesteryl ester transfer protein gene to transfer protein activity and plasma lipoprotein levels in alcohol drinkers. 785 68

Plasma triglyceride (TG)-rich lipoproteins are related to high density lipoprotein (HDL)-cholesterol and risk of coronary artery disease (CAD). Two major hypotheses on the role of HDL in the development of CAD have been proposed: a 'causalist' view assigns a protective effect against atherosclerosis to HDL and a 'non-causalist' view states that HDL do not interfere directly with development of atheroma but reflect metabolism of TG-rich lipoproteins. HDL exist as two major subfractions: small, lipid-poor, dense HDL3, and larger, lipid-rich, less dense HDL2, with variable levels of total-HDL cholesterol. Rapid lipolysis of TG-rich lipoproteins produces increased lipid uptake, formation of HDL2 and may protect the arterial wall; delayed lipolysis increases transfer of TG from TG-rich lipoproteins into HDL. Cholesteryl ester transfer protein (CETP) catalyzes lipid exchange and may be the mechanism for switching 'good cholesterol' into 'bad cholesterol'. According to this view, the driving force for the switch is the metabolism of TG-rich lipoproteins. Rapid clearance of TG-rich lipoproteins promotes formation of HDL2, low levels of TG-rich lipoproteins prevent transfer of HDL-cholesteryl esters into TG-rich lipoproteins keeping HDL-cholesterol high. The net effect is antiatherogenic. Accumulation of TG-rich lipoproteins leads to transfer of cholesteryl esters from HDL into lipoprotein fractions associated with high CAD risk.
Atherosclerosis 1994 Oct
PMID:Triglyceride-rich lipoproteins and atherosclerosis. 785 79


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