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)

Cells of early atherosclerotic lesions have an increased content of cholesteryl esters and enhanced rate of cholesterol esterification. The present study was carried out to elucidate whether these changes could be reproduced in a purely in vitro system. Cultures of rabbit aortic medial cells were incubated in a medium containing 10% of either normal rabbit serum (control cells) or serum from rabbits with cholesterol-induced hyperlipidemia (hyperlipidemic cells). The incorporation rate of [1-14C]oleate into cellular cholesteryl esters increased two- to threefold after four hours' incubation with hyperlipidemic serum and remained elevated during the rest of the eight days' study. After seven days' incubation the hyperlipidemic cells incorporated significantly more (+13%) oleate into triglycerides and significantly less (-15%) oleate into phospholipids than did the control cells. Cholesteryl ester content of the hyperlipidemic cells rose steeply for about two days, with a slower rise thereafter. In hyperlipidemic cells the esterified cholesterol content was significantly higher (315 ng/mug DNA) than in the control cells (79 ng/mug DNA). Hyperlipidemic cells showed a slow but significant rise of free cholesterol as well (from 1.15 mug/mug DNA in control to 1.50 mug/mug DNA). The results indicate that lipid changes resembling those in early atherosclerotic lesions can be brought about in vitro 0y treatment of aortic cells with hyperlipidemic serum.
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PMID:Increased cholesterol content and esterification in rabbit aortic medial cells cultured in hyperlipidemic serum. 95 12

Human hepatic lipase (HL) is a 477 residue glycoprotein that hydrolyzes triglycerides from plasma lipoproteins. Familial HL deficiency is a rare recessive disorder that is characterized by premature atherosclerosis and abnormal circulating lipoproteins. While studying the HL gene from the world's index family with HL deficiency, we identified four coding sequence variants of HL, one in each of exons 4, 5, 6, and 8. In this report we present the genetic basis for two new HL gene variants, one in each of exons 3 and 5. All six HL DNA variants are single base pair changes. Two variants (at codons 133 and 202) are diallelic DNA polymorphisms that are silent at the amino acid level. One variant (V73M) is an allele that defines an uncommon HL isoprotein. One variant (N193S) has two alleles of approximately equal frequency in the population that specify two common HL isoproteins. Two variants (S267F and T383M) are rare mutations found to date only in HL deficient subjects and their relatives. Of the six HL variants described to date, only S267F and T383M are associated with hyperlipidemia.
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PMID:Human hepatic lipase mutations and polymorphisms. 130 39

Since the cloning of the human LDL receptor (LDLR) gene, familial hypercholesterolemia (FH) can be diagnosed by recombinant DNA technology either using restriction enzyme mapping to detect major rearrangements of the gene or using restriction fragment length polymorphisms (RFLPs) and linkage analysis in family studies. Genotypes and haplotypes of four RFLPs (StuI, ApaII 5', PvuII, NcoI) were used to study the inheritance of the detective LDLR gene in three families. Diagnosis of FH based on the lipid levels alone was not possible because in these kindreds both parents exhibit elevated lipid levels. However, in two families using haplotype analysis, elevated cholesterol levels in certain relatives could be attributed to the inheritance of a defective LDRL gene and thereby distinguished from hypercholesterolemia due to familial combined hyperlipidemia. In the third family where both hypercholesterolemic parents carried a defective LDLR gene, a case of homozygous FH could be excluded in a child by demonstrating the inheritance of a normal LDLR gene.
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PMID:Diagnosis of familial hypercholesterolemia using DNA haplotype analysis in three large families with two hyperlipidemic parents. 135 52

During the screening of samples obtained from 5 individuals with type III hyperlipidemia, we identified a variant of apolipoprotein (apo) E which exhibited a discrepancy in apo E phenotype showing the E3/E1 isoform on isoelectric focusing (IEF) analysis and E3/E3 on gene analysis. Sequence analysis of the DNA of the proband that was amplified by PCR and subcloned, revealed a single substitution of one lysine (AAG) for one glutamic acid (GAG) at position 146, thereby adding two negatively charged units to apo E3. This defect had been described only for apo E1 to date (Mann et al. (1989) Clin. Res. 37, 520A (abstract)). In this case, PCR-mediated site-directed mutagenesis was used to identify the structural alterations forming the abnormal E1 genotype in the proband's family. Purified apo E1 Lys-146----Glu showed less than 10% of binding activity to apo B, E receptor on human skin fibroblasts compared with apo E3. This substitution demonstrates that Lys-146 is essential for the binding of apo E to the receptor.
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PMID:Apolipoprotein E1 Lys-146----Glu with type III hyperlipoproteinemia. 135 43

We have identified the molecular basis for familial lipoprotein lipase (LPL) deficiency in two unrelated families with the syndrome of familial hyperchylomicronemia. All 10 exons of the LPL gene were amplified from the two probands' genomic DNA by polymerase chain reaction. In family 1 of French descent, direct sequencing of the amplification products revealed that the patient was heterozygous for two missense mutations, Gly188----Glu (in exon 5) and Asp250----Asn (in exon 6). In family 2 of Italian descent, sequencing of multiple amplification products cloned in plasmids indicated that the patient was a compound heterozygote harboring two mutations, Arg243----His and Asp250----Asn, both in exon 6. Studies using polymerase chain reaction, restriction enzyme digestion (the Gly188----Glu mutation disrupts an Ava II site, the Arg243----His mutation, a Hha I site, and the Asp250----Asn mutation, a Taq I site), and allele-specific oligonucleotide hybridization confirmed that the patients were indeed compound heterozygous for the respective mutations. LPL constructs carrying the three mutations were expressed individually in Cos cells. All three mutant LPLs were synthesized and secreted efficiently; one (Asp250----Asn) had minimal (approximately 5%) catalytic activity and the other two were totally inactive. The three mutations occurred in highly conserved regions of the LPL gene. The fact that the newly identified Asp250----Asn mutation produced an almost totally inactive LPL and the location of this residue with respect to the three-dimensional structure of the highly homologous human pancreatic lipase suggest that Asp250 may be involved in a charge interaction with an alpha-helix in the amino terminal region of LPL. The occurrence of this mutation in two unrelated families of different ancestries (French and Italian) indicates either two independent mutational events affecting unrelated individuals or a common shared ancestral allele. Screening for the Asp250----Asn mutation should be included in future genetic epidemiology studies on LPL deficiency and familial combined hyperlipidemia.
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PMID:A missense (Asp250----Asn) mutation in the lipoprotein lipase gene in two unrelated families with familial lipoprotein lipase deficiency. 161 66

Diabetic patients who develop proteinuria show a marked increase in cardiovascular morbidity and mortality. The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain, in part, obscure. However, there is now evidence that renal disease clusters in families and that genetic factors may be of central importance in determining susceptibility. Predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. Interestingly, fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first clinical signs of renal involvement are the appearance of microalbuminuria and a small elevation in arterial pressure. Mesangial expansion accompanies these changes. Microalbuminuria is associated with abnormalities of lipoprotein profiles and higher Na+/Li+ countertransport rates. The environmental changes brought about by diabetes could lead in susceptible individuals to increased systemic and intraglomerular pressures on the one hand and to mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities may further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered, involving reduction in renal function, further hypertension, proteinuria, glomerular obsolence and hyperlipidaemia, and eventually end-stage renal failure or premature cardiovascular death.
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PMID:Risk factors for renal and cardiovascular disease in diabetic patients. 165 64

Previously, we reported a case with type I hyperlipidemia due to a lipid interface recognition deficiency in lipoprotein lipase (LPL) (1). The LPL from postheparin plasma of this patient did not hydrolyze TritonX-100-triolein or very low density lipoprotein-triolein but did hydrolyze tributyrin and LysoPC-triolein substrates. Sequence analysis of the probands DNA revealed a heterozygous nucleotide change: a C----G transversion at position of 1595, resulting in changing the codon for Ser447 to a stop codon. Expression studies of this mutant LPLcDNA in Cos-1 cells produced and secreted considerable amounts of LPL mass in the culture media. The mutated LPL hydrolyzed much less TritonX-100-triolein than wild type LPL, whereas hydrolysis of tributyrin and LysoPC--triolein was the same with both the mutant and wild type LPL. These results suggest that this mutation might be responsible for the property of the LPL with a defect in lipid interface recognition in the type I patient we reported.
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PMID:A heterozygous mutation (the codon for Ser447----a stop codon) in lipoprotein lipase contributes to a defect in lipid interface recognition in a case with type I hyperlipidemia. 173 1

A large family is reported with familial hepatic triglyceride lipase (HTGL) deficiency and with the coexistence of reduced lipoprotein lipase (LPL) similar to the heterozygote state of LPL deficiency. The proband was initially detected because of hypertriglyceridemia and chylomicronemia. He was later demonstrated to have beta-VLDL despite an apo E3/E3 phenotype and the lack of stigmata of type III hyperlipoproteinemia. The proband had no HTGL activity in postheparin plasma. Two of his half-sisters had very low HTGL activity (39 and 31 nmol free fatty acids/min/ml; normal adult female greater than 44). His son and daughters had decreased HTGL activity (normal male and preadolescent female greater than 102), which would be expected in obligate heterozygotes for HTGL deficiency. Low HTGL activity was associated with LDL particles which were larger and more buoyant. Several family members, including the proband, had reduced LPL activity and mass less than that circumscribed by the 95% confidence-interval ellipse for normal subjects and had hyperlipidemia similar to that described in heterozygote relatives of patients with LPL deficiency. All the sibs with hyperlipidemia had a reduced LPL activity and mass, while subjects with isolated reduced HTGL (with normal LPL activity) had normal lipid phenotypes. Analysis of genomic DNA from these subjects by restriction-enzyme digestion revealed no major abnormalities in the structure of either the HTGL or the LPL gene. Compound heterozygotes for HTGL and LPL deficiency show lipoprotein physiological characteristics typical for HTGL deficiency, while their variable lipid phenotype is typical for LPL deficiency.
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PMID:Coexistence of abnormalities of hepatic lipase and lipoprotein lipase in a large family. 196 4

The precise pathogenesis of human diabetic kidney disease and the factors responsible for the susceptibility to it remain to be established. However, there is now evidence that renal disease clusters in families and that genetic factors are of central importance in determining liability. A predisposition to arterial hypertension has been suggested as playing a contributory role in the development of kidney disease. Genetically controlled hypertrophic processes may be implicated in the susceptibility to arterial wall damage and glomerular injury in diabetes. This suggestion derives from the observation that the fibroblasts of patients with diabetic nephropathy show a higher Na+/H+ antiport activity and a greater 3H-thymidine incorporation into DNA than fibroblasts of diabetic patients without nephropathy. The first sign of renal damage is the appearance of microalbuminuria and of a small elevation in arterial pressure, changes associated with significant mesangial expansion. Microalbuminuria is associated with abnormalities of lipoprotein profiles possibly as a consequence of insulin-resistance-induced hyperinsulinemia. It could be postulated that the environmental changes brought about by diabetes lead in susceptible individuals to increased systemic and intraglomerular pressure on the one hand and mesangial expansion on the other. These two processes would cause proteinuria and glomerulosclerosis. Lipid abnormalities would further aggravate the renal histological damage and, in combination with hypertension, contribute to the accelerated atherosclerosis typical of patients with diabetic kidney disease. A vicious circle would thus be triggered of reduction in renal function, more hypertension, more proteinuria, more glomerular obsolence, more hyperlipidemia and eventually end-stage renal failure or premature cardiovascular death.
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PMID:Mechanisms of diabetic renal and cardiovascular disease. 207 90

The basic and clinical studies that are expected to influence future laboratory medicine were presented by five speakers in the symposium held at the National Cardiovascular Center, in Osaka on January 27, 1990. Dr. Y. Katayama reported a new method for analyzing glycated protein by HPLC and the data on the positive error caused by superoxide anion in the value of fructosamine. Dr. Y. Harano described a sensitive method for enzyme immunoassay of apoprotein B and discussed cases of diabetes mellitus, hyperlipidaemia and hypo-apoprotein B with respect to the apoprotein B level. Dr. T. Noguchi reported the excellent results in DNA analysis of pyruvate kinase. Dr. N. Taniguchi presented a basic study on superoxide dismutase and noted the increased activity of this enzyme in certain diseases. The assay of this enzyme activity can now be routinely performed. Dr. H. Matsuo, the last speaker in this symposium, had received the Gakusiin award in 1989 for his studies on atrial natriuretic hormone (ANH). He outlined the history of ANH study developed in his laboratory. ANH also will be added to routine assay. We, the chairmen in this symposium, added comments concerning useful modern techniques for the clinical chemistry and the role of the clinical laboratory in large hospitals.
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PMID:[Progress in clinical chemistry]. 223 44


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