Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0020473 (hyperlipidemia)
 15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A family with three heterozygote and two homozygote carriers of the rare apolipoprotein E1 isoform was detected by isoelectric focusing. One of the homozygous patients had type III hyperlipidemia, while the other showed normolipemic dysbetalipoproteinemia. Restriction fragment length analysis as well as allele specific oligonucleotides were used to identify the structural alterations forming the abnormal epsilon 1 genotype. Comparison with the most common epsilon 3 allele showed that two base exchanges A for G in codon 127 and T for G in codon 158 (Asp for Gly and Cys for Arg, respectively) are responsible for the amino acid substitution which causes the charge shift observed in isoelectric focusing. The same defects have been described in the only previously characterized apoE1 (Weisgraber et al. 1984. J. Clin. Invest. 73: 1024-1033). In addition to the study by Weisgraber and coworkers, who reported on a heterozygous patient, we here describe the metabolic and clinical consequences of a homozygosity for this rare allele. Changes in lipoprotein metabolism, as well as in clinical phenotypes, were exactly identical to those seen in patients homozygous for the epsilon 2 allele, which has in common with the epsilon 1 allele the mutation in codon 158, but lacks the substitution in codon 127. In addition, lipoprotein profiles of the epsilon 3/epsilon 1 heterozygotes were indistinguishable from those of epsilon 3/epsilon 2 heterozygotes. Therefore, we conclude that the additional mutation in codon 127 that characterizes the epsilon 1 allele is of no functional importance in vivo.
 ...
PMID:Normolipemic dysbetalipoproteinemia and hyperlipoproteinemia type III in subjects homozygous for a rare genetic apolipoprotein E variant (apoE1). 197

Familial defective apolipoprotein B-100 (FDB) is a recently identified, dominantly inherited genetic disorder, which leads to increased serum concentration of low density lipoprotein (LDL) cholesterol with reduced affinity for the LDL receptor. This disorder is associated with a G to A mutation in exon 26 of the apolipoprotein B (apo B) gene which creates a substitution of glutamine for arginine in the codon for amino acid 3500. We have searched for this mutation in 374 unrelated individuals with hyperlipidaemia from the United Kingdom, and in 371 unrelated individuals with a primary clinical diagnosis of atherosclerosis from the United Kingdom and Scandinavia. Ten individuals, 9 from the U.K. and 1 from Denmark, were identified. The frequency of the mutation was 3% in individuals classified clinically as having familial hypercholesterolaemia (FH) and 3% in individuals with type IIa hyperlipidaemia without FH, and was not found in patients with types IIb and III hyperlipidaemia. The mutation was rare in individuals with a primary clinical diagnosis of atherosclerosis. Plasma lipid levels and clinical characteristics of the ten patients identified in the present study are similar to those reported for heterozygous FH. Thus, in our study, FDB is associated with moderate to severe hypercholesterolaemia, and appears to be a serious disorder causing premature cardiovascular disease. Individuals with this mutation can be identified unambiguously using routine molecular screening techniques.
 ...
PMID:Familial defective apolipoprotein B-100: detection in the United Kingdom and Scandinavia, and clinical characteristics of ten cases. 231 Apr 29

Homozygosity for the apolipoprotein (apo) E variant apoE2(158 Arg----Cys) invariably gives rise to dysbetalipoproteinemia, and when associated with obesity or a gene for hyperlipidemia, results in type III hyperlipoproteinemia. The association of the E2/2 phenotype with type IV/V hyperlipoproteinemia rather than type III hyperlipoproteinemia in identical twin brothers led us to investigate the primary structure of their apoE. Lipoprotein electrophoresis on agarose gels confirmed the presence of increased very low density lipoproteins (VLDL) and chylomicrons but little, if any, beta-VLDL, indicating that these subjects did not have dysbetalipoproteinemia. When the apoE from these twins was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis on a system that can distinguish apoE2(158 Arg----Cys) from all other known apoE variants, it gave rise to two components. One had the unique mobility of apoE2(158 Arg----Cys), and one migrated in the position of the other variants of apoE (and normal apoE3), indicating that the brothers were heterozygous for apoE2(158 Arg----Cys) and a second apoE2 isoform. Cysteamine modification and isoelectric focusing showed that, like apoE2(158 Arg----Cys), the second apoE2 isoform also contained two cysteine residues. The structural mutation in the second apoE2 isoform was determined by peptide sequencing. Like normal apoE3, this variant had arginine at position 158, but differed from apoE3 by the substitution of cysteine for arginine at position 228. Total apoE isolated from the brothers had the same receptor-binding activity in a competitive binding assay as a 1:1 mixture of normal apoE3 and apoE2(158 Arg----Cys).(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Apolipoprotein E2-Dunedin (228 Arg replaced by Cys): an apolipoprotein E2 variant with normal receptor-binding activity. 234 12

An underlying cause of type III hyperlipoproteinemia is the presence of variant forms of apolipoprotein (apo) E that are defective in binding to apo B,E low density lipoprotein receptors. This disorder is associated almost exclusively with the apo E2/2 phenotype. However, structural and functional heterogeneity have been demonstrated within this phenotype. The apo E2(Arg158----Cys) variant, displaying 1% of normal apo E3 binding activity, is the most defective known form. In this study, we describe a method in which a pair of 19-mer synthetic oligonucleotide probes were used to distinguish between DNA coding for arginine or cysteine at position 158 in apo E. The specificity of the probes was demonstrated by using DNA from subjects whose apo E protein sequence or phenotype was known. The probes were used to screen a French-Canadian population of 34 apo E2/2 subjects to determine the frequency of the apo E2(Arg158----Cys) variant. All 34 subjects, most of whom displayed clinical or biochemical features of type III hyperlipoproteinemia, were found to be homozygous for apo E2(Arg158----Cys), strongly suggesting that this variant is the most common form of apo E2 within this ethnic and clinical population. In addition, the utility of this approach in detecting new apo E mutants was demonstrated when DNA from one of the apo E3/3 control subjects, whose family has a history of hyperlipidemia and coronary artery disease, reacted with both probes. This result suggests that this subject is heterozygous for normal apo E3 and a new apo E3 variant that is likely to be functionally equivalent to apo E2(Arg158----Cys).
 ...
PMID:Apolipoprotein E2(Arg158----Cys) frequency in a hyperlipidemic French-Canadian population of apolipoprotein E2/2 subjects. Determination by synthetic oligonucleotide probes. 291 21

Genetic polymorphism and rare mutants of apolipoproteins occur in humans. The polymorphism of apolipoprotein E (apoE) is controlled by three common alleles, epsilon 2, epsilon 3, and epsilon 4, which code for proteins that differ in lipoprotein receptor binding activity, or in their catabolism in vivo, or both. This may explain the observed significant effects of the apoE alleles on the phenotypic variance of plasma lipoprotein concentrations in different ethnic groups and, moreover, the involvement of apoE alleles in the pathogenesis of multifactorial forms of hyperlipidaemia, for example, hypertriglyceridaemia, familial type III hyperlipidaemia (apoE-2 Arg-158----Cys) and polygenic hypercholesterolaemia (apoE-4 Cys-112----Arg). A further polymorphic gene locus controls the concentrations of the Lp(a) lipoprotein complex in plasma, which may vary from less than 1 mg/dl to greater than 200 mg/dl between different individuals. This lipoprotein contains two different polypeptides, apoB-100 and the Lp(a) glycoprotein. The Lp(a) glycoprotein exhibits genetic polymorphism which is controlled by a series of autosomal alleles at a single locus and which is associated with lipoprotein concentrations in plasma. This suggests that the same gene locus is involved in determining Lp(a) glycoprotein phenotypes and Lp(a) lipoprotein concentrations in plasma. Thus, there is evidence that variability in apolipoprotein genes relates to the normal variance of lipoprotein concentrations in the population and that this variability is a major genetic factor in multifactorial forms of hyperlipidaemia.
 ...
PMID:Apolipoproteins, quantitative lipoprotein traits and multifactorial hyperlipidaemia. 296

The primary structure of apolipoprotein E (apo E) was investigated in seven type III hyperlipoproteinemic patients with the apo E-2/2 phenotype. Six of the patients had identical two-dimensional tryptic peptide maps. These differed from the normal apo E3 map by the altered mobility of a single peptide. Amino acid analysis and sequencing showed that apo E2 in these patients had a substitution of 158 Arg----Cys. The presence of this mutation in six of the seven type III patients confirms that this is the most common form of apo E2. The seventh type III patient had a unique map with a new peptide resulting from a substitution of 136 Arg----Ser. He was heterozygous for this and for the more common apo E2 (158 Arg----Cys) variant. His very low-density lipoprotein contained approximately five times more apo E2 (136 Arg----Ser) than apo E2 (158 Arg----Cys), as determined by cysteamine treatment and peptide mapping. This new apo E2 mutant thus appears to contribute significantly to the patient's hyperlipidemia.
 ...
PMID:Apolipoprotein E2-Christchurch (136 Arg----Ser). New variant of human apolipoprotein E in a patient with type III hyperlipoproteinemia. 303 59

The effect of diets containing soybean proteins substituting a significant portion of meat proteins was studied in patients with hyperlipidemia, type IIa, and in experiments on rats. It was found that soybean proteins included into the diet induced blood plasma amino acid imbalance, changed the excretion of some amino acids with urine, and significantly diminished the blood plasma cholesterol level. In the experiments on rats a reduced rate was noted in the low-density lipoprotein apoprotein formation and high-density lipoprotein apoprotein regeneration in the blood plasma. It is suggested that the hypocholesterolemic effect of soybean proteins is caused by decreased apoprotein E synthesis and metabolism due to low levels of blood plasma lysine and arginine.
 ...
PMID:[Clinico-experimental approaches to studying the hypocholesteremic action of soy proteins]. 370 42

Rats fed a semipurified diet containing casein developed higher levels of circulating triglycerides and cholesterol than animals fed a soy protein-containing diet. The increased serum lipid levels in non-fasted rats were associated largely with the d less than 1.006 g/ml lipoprotein particles (e.g. chylomicrons or very low density-like lipoproteins). In addition, casein-fed rats exhibited higher levels of circulating insulin and depressed hepatic 7 alpha-hydroxylase levels compared to soy-fed rats. Supplementation of the casein diet with arginine, to give an arginine/lysine ratio comparable to that in the soy diet, resulted in a reduction of d less than 1.006 g/ml lipids, a reduction in serum insulin levels and an elevation in hepatic 7 alpha-hydroxylase activity. Supplementation of the soy diet with lysine also resulted in modification of these parameters toward those observed with casein diets, albeit the effects were less dramatic. The results suggest that the hyperlipidemia associated with feeding casein-based diet is associated with decreased rates of clearance of chylomicron-like lipoproteins and their component triglycerides and cholesterol. Furthermore, this is largely prevented by addition of arginine to diets containing casein as the sole protein source.
 ...
PMID:Effects of casein and soy protein on hepatic and serum lipids and lipoprotein lipid distributions in the rat. 393 24

It was found that polyarginine (Mr 40 000-60 000) is a strong inhibitor of the lipoprotein lipase activity in vivo and in vitro. The inhibitory effect in vivo was observed after a single intravenous injection of 0.85-3.5 mg/kg to rabbits, that in vitro at the polypeptide concentration of greater than or equal to 2.5 micrograms/ml. Within the first few hours after intravenous injection of polyarginine hyperlipidemia occurred with an obvious increase in the plasma triglyceride and VLDL fractions and a slight decrease of the LDL and HDL fractions. These changes typical for reduced lipoprotein lipolysis were due to the formation of a polyarginine-heparin complex, on the one hand, and to the formation of a polyarginine-enzyme complex devoid of the lipolytic properties, on the other. The inhibitory effect of polyarginine on lipoprotein lipase is related to the whole polypeptide molecule or its large fragment, since arginine and metformine (bi-guanidine compound) have no effect on the enzyme activity.
 ...
PMID:[Inhibition of lipoprotein lipolysis by polyarginine and evaluation of the mechanism of its interaction with lipoprotein lipase]. 400 23

Feeding diets with 4% L-lysine to the chick produces an elevation of plasma lipids which does not occur when feeding an excess of any other amino acid. Experiments were conducted to determine whether lysine-induced hyperlipidemia is secondary to the antagonistic effect of lysine on arginine or to the anorexia which accompanies lysine feeding, and in addition, whether the lysine-induced hypercholesterolemia is affected by chick age. In all experiments gain and food intake were reduced by feeding chicks 4% lysine. Plasma cholesterol and triglyceride were elevated, but high-density-lipoprotein cholesterol, as a percentage of total, was reduced. Addition of dietary arginine up to 4% failed to reverse the depression in performance and elevation of plasma lipids. Pair-feeding the control diet to the amount consumed by lysine-fed chicks did not elevate plasma lipids above control levels. Thus, lysine-induced hyperlipidemia is not mediated by the antagonistic effect of lysine on arginine nor by the effect of lysine on food intake. The high-lysine diet prevented the normal decline in plasma cholesterol expected with advancing age of chicks. Preliminary results suggested that excess lysine stimulated cholesterol biosynthesis.
 ...
PMID:Effect of excess dietary lysine on plasma lipids of the chick. 641 75


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>