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)

Six homozygous, 10 heterozygous and 8 unaffected subjects in a CETP deficient family confirmed by CETP gene analysis were studied to characterize serum lipoproteins separated by ultracentrifugation, and to examine the relations between CETP levels and lipoprotein lipid concentration and composition. The serum CETP levels were measured by radioimmunoassay using 125I-labeled monoclonal antibodies (TP2). The serum CETP levels in the homozygotes were undetectable and those in the heterozygotes were significantly lower than those in the unaffected subjects (1.5 +/- 0.1 vs. 2.2 +/- 0.5 microgram/ml, P less than 0.01). In the HDL fraction, esterified cholesterol (EC) levels in the homozygotes were significantly increased (P less than 0.01), and those in the heterozygotes were slightly increased (n.s.), in comparison with those in the unaffected and the normolipidemic controls. The EC levels in the IDL fractions were lower in the homozygotes than in the normolipidemic controls. The EC/triglyceride (TG) molar ratios in IDL, the fraction obtained from the homo- and heterozygotes, were lower than those from the unaffected subjects (P less than 0.01 and less than 0.01, respectively), and the EC/TG ratios in the HDL fraction obtained from the homo- and heterozygotes were higher than those from the unaffected subjects (P less than 0.01 and n.s., respectively). Linear regression analysis showed that positive correlates of the serum CETP levels in all subjects were: IDL-EC (r = 0.463), HDL-TG (r = 0.603) and VLDL- and IDL-EC/TG ratio (r = 0.698 and 0.843).(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1991 Oct
PMID:Serum lipoprotein lipid concentration and composition in homozygous and heterozygous patients with cholesteryl ester transfer protein deficiency. 175 89

Ordinarily, HDL1, a fraction of HDL enriched in apoE, is a minor fraction of plasma, but in human subjects and experimental animals eating diets high in fat and cholesterol and in patients with homozygous familial hypercholesterolemia (HFH) or CETP deficiency, HDL1 (or HDLc) concentrations in plasma are increased. However, little is known about the structures, compositions and metabolic sources of HDL1 in HFH patients. To obtain HDL1 for the study, we surveyed several fractions in the HDL density range for apoE by SDS-PAGE. The ratio of apoE to apoAI in the HDL (d = 1.063-1.21 g/ml) of 8 HFH patients was 0.14 +/- 0.03 compared to 0.03 +/- 0.005 in a control group of 8 normolipidemic subjects (P less than 0.001) suggesting that an apoE-rich fraction indeed was present in increased amounts. ApoE/apoAI ratios of lipoproteins of the density range 1.050-1.090 were even higher at 1.5 and 2.0 in 2 patients compared to 0.4 +/- 0.1 in controls, indicating that this density fraction may be particularly enriched with apoE-rich lipoproteins. By contrast, d = 1.020-1.050 g/ml and d greater than 1.090 fractions contained very little apoE. Therefore, we further characterized the d = 1.050-1.090 g/ml lipoproteins of HFH patients and controls. Fractionation of an d = 1.050-1.090 fraction by concanavalin-A chromatography (CONA) yielded an unbound apoE-rich fraction that contained apoE, apoAI and apoC but no apoB, and a bound LDL-like fraction that contained mostly apoB-100, as determined by SDS-PAGE and by solid phase immunoassays, containing monoclonal antibodies directed against apoB, apoE and apoAI. The apoE/apoAI ratio of the CONA unbound fraction of HFH patients was greater, and the fraction also contained more free cholesterol and phospholipids than the fraction of control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1990 Oct
PMID:Apolipoprotein E-rich HDL in patients with homozygous familial hypercholesterolemia. 212 36

Lipoprotein transport genes have been used to make either transgenic or knockout mice with altered lipoprotein levels and metabolism. These models have provided information in at least three major issues. First, transgenic mice allow to study gene expression regulation. This approach has been helpful in identifying tissue specific expression of two clusters of apolipoprotein genes apo E/CI/CII and apo AI/CIII/AIV. Another example is the identification of a cis-acting region controlling transcription of the CETP gene in response to diet. Second, transgenic mice model provides relevant insights into lipoprotein metabolism: the structural role of human apo AII, the effect of apo AI on HDL subfractions distribution, the contribution of apo CIII to hypertriglyceridemia, and by contrast of apo E in the clearance of atherogenic TG rich lipoproteins, the role of CETP in the balance of LDL and HDL concentration and distribution. Finally, certain strains of mice under specific conditions of diet develop atherosclerotic lesions which have been shown to be reduced in human apo AI transgenic animals. However, the best mouse model for further investigation of human atherosclerosis seems to be apo E knockout mice.
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PMID:[Value of transgenic mouse as model for the study of human lipoprotein metabolism]. 757 8

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

Familial hypercholesterolemia (FH) is a disorder of LDL receptor abnormalities, and the resultant high-LDL-cholesterolemia produces atherosclerosis. More than 150 different mutations in the LDL receptor gene have been reported in the world. Seven variants of the LDL receptor gene have been identified in our laboratory. These seven mutants in 85 patients from 31 families accounted for only 15.5% of the FH cases. LDL receptor gene abnormalities are highly heterogenous in Japan, and the variation of the LDL receptor mutant may determine the severity of hypercholesterolemia and coronary heart disease in FH. A serum HDL above 60 mg/dl is a negative risk factor for coronary atherosclerosis. We found that familial hyperalphalipoproteinemia can be produced by CETP deficiency due to a CETP gene. Two common mutants of the CETP gene produce a CETP deficiency and resultant antiatherogenic lipoprotein pattern (i.e. hyper-HDL-cholesterolemia and hypo-LDL-cholesterolemia), and the frequency of the mutant allele is more than 1 in 10 subjects in Japan. Finally, we found unique patients with double heterozygotes of FH and CETP deficiency. We found 16 double heterozygotes of the LDL receptor gene and CETP gene. Four of the 16 patients showed myocardial infarction and 4 showed angina pectoris. These findings suggest that the atherogenicity of hyper-LDL-cholesterolemia in FH is more powerful than antiatherogenicity of hyper-HDL-cholesterolemia in CETP deficiency.
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PMID:[Molecular genetics of cholesterol transport and cholesterol reverse transport disorders (familial hypercholesterolemia and CETP deficiency), and coronary heart disease]. 773 14

Plasma CETP plays an important role in the reverse cholesterol transport system in conjunction with lecithin:cholesterol acyltransferase (LCAT). CETP mediates transfer of cholesteryl ester from HDL to apo B containing lipoproteins and also mediates transfer of triglyceride from VLDL and IDL to HDL. In this review, molecular characteristics, mechanism of lipid transfer, site of synthesis, factors regulating production and activity of CETP and lipoprotein abnormalities in CETP deficiency were described. High activity of CETP is considered to promote atherosclerosis, because the lipoprotein changes resulting from CETP activity are completely atherogenic and animals who have low CETP activity are resistant to atherosclerosis.
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PMID:[Cholesterol ester transfer protein (CETP)]. 785 6

It had been found that Beijing ducks (BD) have a high level of HDL (70%), high LCAT but very low CETP activity and will not develop atherosclerosis on an atherogenic diet, suggesting that cholesterol ester is mainly carried by HDL and metabolized through an HDL receptor pathway in the liver. However, evidence of this receptor's existence in the liver is not yet complete. In this paper, the HDL receptor in BD liver has been studied. Our experiments showed: 1) ApoE-free 125I-HDL could bind specifically to duck hepatic cell membrane with high affinity (Kd = 9.6 micrograms/ml) and was saturable (Bmax = 8.9 micrograms/mg cell membrane protein) at room temperature. 2) Competitive inhibition studies with unlabelled duck, human, rat and chick HDL and duck apo AI and its liposomes formed with PC or DMPC could inhibit the binding of 125I-HDL to duck hepatic cell membranes, but LDL, apo E and their liposomes with PC or DMPC could not with the exception of duck LDL. 3) The receptor could recognize apo AI but not apo B or E. 4) Both phosphorylase A2 and pronase could inhibit the binding activity. The above results give strong evidence for the existence of a specific HDL receptor pathway in the duck liver, supporting our hypothesis that CE in Beijing ducks is metabolized directly through the hepatic HDL receptor instead of being transferred back to VLDL and LDL, then through the LDL receptor pathway. This unique way of metabolizing CE may be behind the Beijing duck's antiatherogenicity.
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PMID:Studies on the HDL receptors. I: Evidence for the existence of HDL receptors in Beijing duck liver. 800 64

We investigated the effects of 12 weeks of bezafibrate treatment on plasma lipoprotein subfraction levels and on activities of LCAT and CETP in 25 patients with hyperlipoproteinemia. Bezafibrate reduced plasma levels of VLDL-TC and VLDL-TG by 69% and 66% (P < 0.001) and plasma levels of IDL-TC and IDL-TG were decreased by 37% and 31% (P < 0.01). Bezafibrate had no significant effects on plasma levels of LDL1 (1.019 < d < 1.045)-TC and LDL1-TG in the study population as a whole but significantly increased the plasma level of LDL1-TC in the subgroup of 9 patients with type IV hyperlipoproteinemia. Bezafibrate reduced plasma levels of LDL2 (1.045 < d < 1.063)-TC, LDL2-TG by 48% and 44% (P < 0.001) in both type II and type IV hyperlipoproteinemic patients. Gradient polyacrylamide gel electrophoresis revealed a decrease in small LDL particles. Bezafibrate did not affect the plasma level of HDL2-TC but reduced the HDL2-TG concentration significantly (P < 0.001). Bezafibrate increased the plasma level of HDL3-TC by 37% and reduced the HDL3-TG level significantly by 20% (P < 0.001). Gradient polyacrylamide gel electrophoresis revealed an increase in HDL3a and a decrease in HDL2a. Bezafibrate suppressed the activities of LCAT and CETP by 21% (P < 0.001) and 17% (P < 0.01), respectively. The bezafibrate-induced decrease in plasma levels of small, heavy LDL might be related to its inhibition of LCAT and CETP activities which resulted in suppression of heteroexchange of HDL-EC with triglyceride in large, light LDL. The bezafibrate-induced increase in large HDL3 (HDL3a) could not be explained solely by its suppression of LCAT and CETP activities. The decrease of plasma small, heavy LDL as well as TG-rich lipoproteins by bezafibrate seems to be beneficial for prevention of atherosclerotic diseases.
Atherosclerosis 1994 Apr
PMID:Effects of bezafibrate therapy on subfractions of plasma low-density lipoprotein and high-density lipoprotein, and on activities of lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in patients with hyperlipoproteinemia. 806 Mar 79

Lipoprotein Lp(a) is a pluri-molecular complex rich in cholesterol and composed of an LDL (low-density lipoprotein) particle to which is attached a large glycoprotein, apolipoprotein(a) (apo(a)). Numerous epidemiological studies have established a strong correlation between plasma levels of Lp(a) and the premature development of atheromatous vascular disease in man, an association which has subsequently been confirmed by the detection of Lp(a) in human atherosclerotic plaques. Furthermore, a marked structural resemblance has been demonstrated between apo(a) and plasminogen, a key protein of the fibrinolytic system and responsible for dissolution of blood clots. This discovery has provided evidence, for the first time, that Lp(a) might constitute an important link between atherosclerosis and thrombosis. Intense research effort is now underway to provide further understanding of (I) the structural organisation of the Lp(a) particle; (II) the molecular genetics of apo(a); (III) the processes involved in the synthesis, assembly intravascular metabolism and degradation of Lp(a) and apo(a); (IV) the nature of the interactions of Lp(a) and apo(a) with cellular and non-cellular components of the arterial wall; (V) the role of Lp(a) in fibrinolysis, and (VI) the relationship between Lp(a) and certain metabolic disorders such as familial hypercholesterolemia. These fascinating questions will be examined in the light of studies of different models of transgenic mce expressing human apo(a) alone, or both apo(a) and apo B100. In man, CETP assures the transfer of cholesteryl ester from high-density lipoproteins (HDL) to lipoproteins containing apo-B, and notably VLDL, IDL and LDL.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Lipoprotein Lp(a) and CETP (cholesterol ester transfer protein): contribution of transgenic mice]. 807 82

Alterations in core lipid composition of lipoproteins in noninsulin-dependent diabetes mellitus (NIDDM) patients have suggested that the heteroexchange of neutral lipids between HDL and the apo B-containing lipoproteins may be enhanced. For this reason, we studied cholesteryl ester transfer (CET) in ten sulfonylurea-treated patients with stable NIDDM. CET measured in all NIDDM subjects with an assay of mass transfer was significantly greater than that of controls at 1 and 2 h (P < 0.001); the transfer of radiolabeled CE also was increased in a subset of four of the NIDDM group (NIDDM k = 0.21 +/- 0.04 vs. control k = 0.10 +/- 0.05; P < 0.05). A weak correlation was demonstrable between the mass of CE transferred at 1 h and diabetic control expressed as plasma fructosamine (r = 0.58, P < 0.09). To characterize this disturbance in CET further, the donor (HDL + VHDL) and acceptor (VLDL + LDL) lipoprotein fractions were isolated by ultracentrifugation at d 1.063 g/ml from NIDDM and control plasma and a series of recombination experiments were performed. Combining NIDDM acceptor with control donor fractions that contained HDL and CETP and not the combination of NIDDM donor and control acceptor lipoproteins resulted in an accelerated CET response identical to that observed in NIDDM whole plasma. This observation indicated that the abnormality in CET in NIDDM was associated with the VLDL + LDL fraction.(ABSTRACT TRUNCATED AT 250 WORDS)
Atherosclerosis 1993 Dec
PMID:Accelerated cholesteryl ester transfer in noninsulin-dependent diabetes mellitus. 814 51


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