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:C0020473 (hyperlipidemia)
15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Earlier studies in rats have shown that serum cholesterol levels were significantly lower in rats fed an L-lysine-supplemented ration. This investigation was initiated to determine if the reverse was true. We reasoned that the addition of an incomplete protein to a complete rat ration would bring about an increase in serum lipid levels. This would result from the intermediary metabolic conversion of systemic amin acids not used in protein synthesis. We further postulated that supplementation of the imbalanced protein would obviate the hyperlipidemia. Gelatin was chosen as the incomplete protein since it is deficient in tryptophan, an essential amino acid. Adult male Sprague-Dawley rats fed rations with added gelatin (5, 15 and 25%) for 30 days showed significant increases in serum cholesterol and triglyceride levels. Lipid levels in rats fed L-tryptophan-supplemented diets containing the same levels of gelatin did not differ from those animals fed the control ration. The data indicate that hyperlipidemia results from the feeding of imbalanced protein. Such hyperlipidemia can be obviated by supplementation with the limiting amino acid.
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PMID:Lowering of serum cholesterol and triglyceride levels by balancing amino acid intake in the white rat. 738 89

Thirty male patients with hypersyslipidemia (hyperlipemia involving both total lipids and the different lipemic fractions) were treated for 60 days with clofibrate at the dosage of 2 g/day in two administrations. Following a 15-day interval, treatment was resumed with lysine clofibrate, at the same dosage, for 2 subsequent months. At the end of both treatments, it was recorded a clear-cout reduction in the levels of cholesterol, triglycerides, total lipids and lipoproteins. When comparing the effectiveness of the two treatments, we notice that the activity of the two products is identical, though the effects of lysine clofibrate was more precociously evident than that of clofibrate. The results obtained are particularly interesting: equal doses of the drugs were administered, yet the clofibric acid contained in lysine clofibrate is much less than that cointained in clofibrate. As far as tolerance is concerned, 5 cases treated with clofibrate declared to have suffered of gastro-enteric disturbances, while with lysine clofibrate, only 1 case showed side effects.
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PMID:[Clinical and therapeutic evaluation of a new antilipemic substance]. 745 46

Apolipoprotein (apo) E-deficient transgenic mice develop marked hyperlipidemia and progressive atherosclerotic lesions. To explore whether oxidative modification of lipoproteins is involved in atherogenesis in this murine model, we performed extensive immunocytochemical studies. Atherosclerotic lesions ranging from early fatty streaks to very advanced plaques were examined from the aortic valve region and the thoracic and abdominal aorta. Using guinea pig antisera against malondialdehyde (MDA)-lysine and 4-hydroxynonenal-lysine, two epitopes generated during the oxidative modification of low-density lipoprotein (LDL), we demonstrated the presence of these "oxidation-specific epitopes" in atherosclerotic lesions. In early lesions, oxidation-specific epitopes were found predominantly in macrophage-rich areas, whereas diffuse extracellular staining predominated in necrotic areas of advanced lesions. We have previously shown that autoantibodies against MDA-lysine are present in the circulation of humans and rabbits and that the immunoglobulin fraction extracted from their lesions contains autoantibodies against several "oxidation-specific" epitopes. Sera from apoE-deficient mice also contained circulating autoantibodies to MDA-lysine, and both early and advanced lesions were rich in murine immunoglobulins. Titers of serum autoantibodies were significantly higher in apoE-deficient mice than in C57BL/6 mice. Autoantibodies in murine plasma recognized MDA-lysine epitopes in atherosclerotic lesions of rabbits, and the immunostaining was competitively inhibited by excess human MDA-LDL. Similar findings were obtained by competitive radioimmunoassay. Finally, a morphometric technique was developed and tested in these mice that allows a quantitative assessment of aortic atherosclerosis. These findings suggest that in apoE-deficient mice, lipoprotein oxidation is involved in atherogenesis and that these transgenic mice constitute an appropriate model with which to study the antiatherogenic effect of antioxidant intervention.
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PMID:ApoE-deficient mice are a model of lipoprotein oxidation in atherogenesis. Demonstration of oxidation-specific epitopes in lesions and high titers of autoantibodies to malondialdehyde-lysine in serum. 751 33

Ciclosporin (CS-A) has recently been considered a separate risk factor for the development of hyperlipidemia in transplant patients. In the present work, the effect of chronic CS-A administration on serum lipids and its modification using dietary supplementation with LSL 90202, a lysine salt of eicosapentaenoic acid, was studied. Thirty-one male Wistar rats were divided into four groups, receiving (1) 20 mg/kg CS-A in olive oil (CS-A group; n = 8); (2) isovolumetric olive oil (olive oil groups; n = 8); (3) 20 mg/kg CS-A in olive oil plus 20 mg/kg LSL 90202 (CS-A + LSL 20 group;) and (4) 20 mg/kg CS-A in olive oil plus 40 mg/kg LSL 90202 (CS-A+LSL 40 group; n = 8). Both, CS-A and LSL 90202 were given by daily gavage. On day 28, CS-A whole-blood levels and serum levels of total cholesterol, triglyceride, high-density lipoprotein (HDL) cholesterol fractions (HDL, HDL-2, HDL-3, non-HDL), and malondialdehyde were measured. On day 28, the rats given CS-A showed significantly higher cholesterol, triglyceride, and non-HDL cholesterol serum levels than rats given olive oil. Rats given CS-A and LSL 90202 (20 mg/kg) showed significantly lower triglyceride serum levels than rats given CS-A only. Rats given CS-A and LSL 90202 (40 mg/kg) showed significantly lower triglyceride, total cholesterol, and non-HDL cholesterol serum levels than rats given CS-A only. There were no differences in HDL, HDL-2, and HDL-3 cholesterol serum levels between the groups. The CS-A whole-blood levels were not different between groups of animals given CS-A.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of ciclosporin on serum lipids and modification with LSL 90202, a lysine salt of eicosapentaenoic acid. 775 67

A new rare mutant form of apolipoprotein C-II (apoC-II), designated apoC-IISF, was identified in three unrelated hyperlipidemic patients. The first was a Caucasian male with a total cholesterol (TC) of 313 mg/dl and total triglyceride (TG) of 282 mg/dl, the second an African-American female (TC 345 mg/dl, TG 203 mg/dl) and the third, an African-American male (TC 345 mg/dl, TG 1000 mg/dl). Each subject was found to be heterozygous for a G to A substitution in the codon for residue 38, resulting in a Lys for Glu exchange. This accounts for the increased pl value of 5.3. The third patient, in addition to apoC-IISF, had apoC-II2, another charge variant. This was determined by DNA sequencing, confirming the Gln for Lys change at residue 55 previously predicted by analysis of peptide fragments in this laboratory. Similar Michaelis constants of activation and activation energies were observed when the ability of apoC-IISF to activate lipoprotein lipase was compared to normal apoC-II. This indicates that major changes in charge around residue 38 lack effect on the activation properties. The variant may be altered in some other property, such as lipid binding, but since the distribution of apoC-IISF revealed no simple co-inheritance with lipid levels, it is unclear to what extent it plays a role in the observed hyperlipidemia. The presence of other factors acting together with the variant may predispose to elevated lipid levels.
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PMID:Molecular cloning and characteristics of a new apolipoprotein C-II mutant identified in three unrelated individuals with hypercholesterolemia and hypertriglyceridemia. 849 Jun 26

Screening for apolipoprotein (apo) C-II variants in the plasma of 400 students, 600 patients of a cardiological rehabilitation center, and 1200 patients of an outpatient lipid clinic by isoelectric focusing and subsequent anti-apo C-II immunoblotting led to the identification of four individuals whose plasma samples contained an apo C-II isoform with an abnormal isoelectric point. In all cases direct sequencing of PCR-amplified DNA assessed a heterozygous A to C transversion in codon 19 of the apo C-II gene which leads to the replacement of lysine with threonine. Two of the four index patients presented with moderate hypertriglyceridemia; one suffered from severe hyperlipidemia, with triglyceride levels ranging between 180 and 1900 mg/dl, depending on dietary changes. Sequencing of this proband's lipoprotein lipase gene showed no alteration compared to the wild-type sequence. A study in his family revealed that heterozygosity for apo C-II(K19T) is not associated with differences in mean lipid and lipoprotein concentrations. In conclusion, apo C-II(K19T) occurs in Germany at a frequency of approximately 1 in 550. Although this variant is not sufficient to cause hypertriglyceridemia, it may be possible that apo C-II(K19T) cause hypertriglyceridemia in the presence of additional as yet unidentified environmental and/or genetic factors.
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PMID:Electrophoretic screening for human apolipoprotein C-II variants: repeated identification of apolipoprotein C-II(K19T). 852 Sep 70

Previously, a mutant apolipoprotein (apo) E, apolipoprotein E7 (Glu(244)-->Lys, Glu(245)--->Lys), has been identified in association with hyperlipidemia and atherosclerosis. To investigate the effects of its structural changes on lipoprotein metabolisms and its correlation with atherosclerosis, we characterized this mutant apoE with respect to its receptor-binding, heparin-binding, and lipoprotein association. In a competitive binding assay, apoE7. dimyristoylphosphatidylcholine displayed a defective binding to the low density lipoprotein (LDL) receptor. The concentration of apoE7 required for 50% displacement of (125)I-labeled LDL was 0.223 microg/ml, while that for apoE3 was 0.048 microg/ml. ApoE7 possesses only 23% of normal binding activity. To investigate the lipoprotein preference of apoE7, we determined the relative amounts of apoE7 in plasma lipoprotein fractions obtained by ultracentrifugation or gel filtration. Like human apoE4, apoE7 was preferentially associated with the very low density lipoproteins (VLDL). For determination of heparin-binding activity, apoVLDL was applied to a heparin-Sepharose affinity column and the bound materials were eluted with a salt gradient. The apoE7 was eluted at a higher NaCl concentration (157 mm) than apoE3 (126 mm), indicating that this mutant has a higher affinity for heparin than does apoE3. While the reduced receptor-binding activity indicates delayed clearance of the triglyceride-rich lipoproteins, the preferential association of apoE7 with larger-size lipoproteins and the stronger interaction with heparin may compensate, to some extent, for the delayed clearance of triglyceride-rich lipoproteins. The strong interaction with proteoglycans in the arterial wall seems to be one of the possible explanations for the association of apoE7 with atherosclerosis.-Yamamura, T., L-M. Dong, and A. Yamamoto. Characterization of apolipoprotein E7 (Glu(244)-->Lys, Glu(245)--->Lys), a mutant apolipoprotein E associated with hyperlipidemia and atherosclerosis.
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PMID:Characterization of apolipoprotein E7 (Glu(244)-->Lys, Glu(245)--->Lys), a mutant apolipoprotein E associated with hyperlipidemia and atherosclerosis. 992 54

Factors predisposing to the phenotypic features of familial combined hyperlipidemia have not been clearly defined. In the course of investigating familial coronary artery disease in Utah, we identified a three-generation family in which multiple members were affected with type IIa hyperlipoproteinemia (HLP IIa), type IIb hyperlipoproteinemia (HLP IIb), or type IV hyperlipoproteinemia (HLP IV). Because several family members had relatively severe low-density lipoprotein (LDL) cholesterol elevation, in order to dissect the possible contribution to the plasma lipoprotein abnormalities in this pedigree, we identified a novel point mutation in the low-density lipoprotein receptor (LDLR) gene, a G-to-A transition at nucleotide position 337 in exon 4. This change substituted lysine for glutamic acid at codon 92 (D92K) of the LDL receptor. By means of mutant allele-specific amplification we determined that the mutation co-segregated with elevated cholesterol and LDL cholesterol in the plasma of family members with HLP IIa and HLP IIb, but not with the elevated plasma triglycerides seen in HLP IIb and HLP IV patients. Thus, in families with apparent familial combined hyperlipidemia, a defective LDLR allele and other genetic or environmental factors that elevate plasma triglycerides may account for the multiple lipid phenotypes observed in this kindred.
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PMID:Co-segregation of elevated LDL with a novel mutation (D92K) of the LDL receptor in a kindred with multiple lipoprotein abnormalities. 1080 40

In this study, we present clinical feature of a novel case with homozygous apolipoprotein (apo) E5. The patient was a 53-year-old Japanese woman. She was from a small island off the coast of Kagoshima Prefecture, Japan. Her parents were first degree cousins. No corneal opacification, xanthomatosis, lymphadenopathy, or hepatosplenomegaly was observed. There have been no signs of clinically overt atherosclerosis to date. Her serum total cholesterol, triglycerides (TG) and high-density lipoprotein (HDL)-cholesterol levels were 11.6, 6.1 and 1.2 mmol/l, respectively, and apo A-I, A-II, B, C-II, C-III and E levels were 121, 34.8, 269, 10.4, 25.7 and 10.3 mg/dl, respectively. Serum lipoprotein profile analyzed by agarose gel electrophoresis and differential staining revealed markedly increased cholesterol and TG in both beta and prebeta-migrated lipoproteins, whereas alpha-migrated lipoprotein showed decreased cholesterol. Her apo E isoform analyzed by isoelectric focusing (IEF) was found to be homozygous apo E5. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis of her apo E and lipoprotein lipase (LPL) genes revealed that she had a homozygous apo E (Glu3-->Lys) and heterozygous LPL variant Ser447 to Ter. Her son and daughter, both of whom had hyperlipidemia, were found to have apo E3/5 phenotype. Direct sequencing analysis of her apo E gene confirmed a homozygous one nucleotide change: G to A at nucleotide position of 2836 in the exon 3, resulting in Glu3-->Lys mutation. This is the first report of lipids and lipoprotein profiles in patients with homozygous apo E5 (Glu3-->Lys).
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PMID:A case of hyperlipidemia with homozygous apolipoprotein E5 (Glu3-->Lys). 1206 56

Plasma apolipoprotein E (apoE) is a 34-kDa polymorphic protein which has atheroprotective actions by clearing remnant lipoproteins and sequestering excess cellular cholesterol. Low or dysfunctional apoE is a risk factor for hyperlipidaemia and atherosclerosis, and for restenosis after angioplasty. Here, in short-term studies designed to establish proof-of-principle, we investigate whether encapsulated recombinant Chinese hamster ovary (CHO) cells can secrete wild-type apoE3 protein in vitro and then determine whether peritoneal implantation of the microcapsules into apoE-deficient (apoE(-/-)) mice reduces their hypercholesterolaemia. Recombinant CHO-E3 cells were encapsulated into either alginate poly-l-lysine or alginate polyethyleneimine/polybrene microspheres. After verifying stability and apoE3 secretion, the beads were then implanted into the peritoneal cavity of apoE(-/-) mice; levels of plasma apoE3, cholesterol and lipoproteins were monitored for up to 14 days post-implantation. Encapsulated CHO-E3 cells continued to secrete apoE3 protein throughout a 60-day study period in vitro, though levels declined after 14 days. This cell-derived apoE3 was biologically active. When conditioned medium from encapsulated CHO-E3 cells was incubated with cultured cells pre-labelled with [(3)H]-cholesterol, efflux of cholesterol was two to four times greater than with normal medium (at 8 h, for example, 7.4+/-0.3% vs. 2.4+/-0.2% of cellular cholesterol; P<0.001). Moreover, when secreted apoE3 was injected intraperitoneally into apoE(-/-) mice, apoE3 was detected in plasma and the hyperlipidaemia improved. Similarly, when alginate polyethyleneimine/polybrene capsules were implanted into the peritoneum of apoE(-/-) mice, apoE3 was secreted into plasma and at 7 days total cholesterol was reduced, while atheroprotective high-density lipoprotein (HDL) increased. In a second study, apoE was detectable in plasma of five mice treated with alginate poly-l-lysine beads, 4 and 7 days post-implantation, though not at day 14. Furthermore, their hypercholesterolaemia was reduced, while HDL was clearly elevated in all mice at days 4 and 7 (from 18.4+/-6.2% of total lipoproteins to 31.1+/-6.8% at 7 days; P<0.001); however, these had rebounded by day 14, possibly due to the emergence of anti-apoE antibodies. We conclude that microencapsulated apoE-secreting cells have the potential to ameliorate the hyperlipidaemia of apoE deficiency, but that the technology must be improved to become a feasible therapeutic to treat atherosclerosis.
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PMID:Apolipoprotein E delivery by peritoneal implantation of encapsulated recombinant cells improves the hyperlipidaemic profile in apoE-deficient mice. 1562 88


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