UMLS:C0020473 - FACTA Search

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

Normal cell development depends to a large part on multifunctional proteins that have evolved by recombination of proven modular elements. We now have discovered and characterized in rabbit such a multi-domain protein, and classify it as novel member of the low density lipoprotein (LDL) receptor gene family. The extracellular portion of the approximately 250-kDa membrane protein, termed LR11, contains a cluster of 11 LDL receptor ligand binding repeats, a group of 5 LDL receptor "YWTD" repeats, a large hexarepeat domain of structural elements found in neural cell adhesion molecules, and a domain with similarity to a yeast receptor for vacuolar protein sorting, VPS10. The cytoplasmic domain exhibits features typical of endocytosis-competent coated-pit receptors. The mosaic, and presumably multifunctional, receptor is expressed abundantly in brain, in particular the hippocampus, dentate gyrus, and cerebral cortex, and is present at significant levels in liver, adrenal glands, and testis. Western blotting of tissues and ligand blotting of LR11-transfected cells demonstrated that the novel protein binds apolipoprotein E-containing lipoproteins. In contrast to the LDL receptor, hepatic expression of LR11 is unaffected by hyperlipidemia. The identification of this highly conserved and superbly complex protein offers the opportunity to gain new insights into the emergence of multifunctional mosaic proteins akin to the ever expanding LDL receptor gene family.
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PMID:Elements of neural adhesion molecules and a yeast vacuolar protein sorting receptor are present in a novel mammalian low density lipoprotein receptor family member. 879 46

Multiviriate analysis of epidemiological data has often shown that elevated plasma triglyceride (TG) concentration is not an independent risk factor for coronary heart disease (CHD). However, more recently, subgroup- and meta-analyses have supported an independent association between TG and CHD. The strength of TG to predict the CHD lies in its ability to reflect the presence of atherogenic plasma TG-rich lipoprotein (TRL) remnants. Clinical evidence for the potential atherogenicity of TRL is provided by patients with type III hyperlipoproteinaemia, hepatic lipase deficiency or apolipoprotein E deficiency, who have marked increase in plasma remnant lipoproteins and an increased incidence of CHD. Indirect evidence suggests that the presence of a single epsilon 2 allele may have atherogenic potential by influencing plasma remnant accumulation in the presence of a second environmental or genetic factor. Recent studies have also indicated that the magnitude of postprandial triglyceridaemia is a significant predictor of CHD. Emerging data from angiographic intervention trials have implicated TRL in atherosclerotic disease progression independently of low-density lipoproteins (LDL). Thus, in hypertriglyceridaemic patients, physicians should conduct a thorough clinical evaluation, a family survey, an assessment of associated risk factors and a complete analysis of the plasma lipoprotein profile, in order to assess the atherogenic potential of this hyperlipidaemia.
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PMID:Triglycerides: a risk factor for coronary heart disease. 883 17

To study the pathophysiology of hyperlipidemia in nephrotic syndrome, we compared lipid metabolism in the nephrotic stage (stage 1) and in stage 2, when albuminuria had subsided, in 11 patients with minimal-change disease treated with corticosteroid. High-density lipoprotein (HDL) levels were decreased and HDL contained more cholesterol and triglyceride per unit of protein in stage 1 in the patients than in age-matched healthy controls. The urinary protein level was positively correlated only with low-density lipoprotein (LDL) levels, suggesting that the increased albumin clearance stimulated LDL production. Serum cholesterol levels were positively correlated with apolipoprotein E levels and were negatively correlated with lecithin-cholesterol acyltransferase activity in the nephrotic stage; the opposite correlations were seen in controls. Although triglycerides in HDL had normalized at stage 2, triglycerides in LDL and very-low-density lipoprotein did not return toward normal until stage 3, when serum cholesterol levels were normalized.
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PMID:Lipoprotein derangement during steroid treatment in minimal-change nephrotic syndrome. 885 59

Estrogen provides beneficial effects on hyperlipidemia in climacteric and elderly women. In this study of 68 women (37 to 67 years old), hepatic triglyceride lipase (HTGL), lipoprotein lipase (LpL) serum lipids and apolipoproteins were analyzed to investigate the effects of estrogen replacement therapy (ERT). After menopause, LpL, total cholesterol, low-density lipoprotein (LDL)-cholesterol, and apolipoprotein B increased. But ERT suppressed total cholesterol, LDL-cholesterol, apolipoprotein B, and especially apolipoprotein E in menopausal women. The mechanism was thought that ERT significantly suppressed HTGL, but LpL was not affected. Estrogen also increases hepatic LDL receptors and accelerates transfer of serum LDL-C (and TC). It was said that HTGL accelerates conversion of intermediate-density lipoprotein (IDL) to LDL. The suppression of HTGL by the ERT may decrease conversion of IDL to LDL and lower LDL-C (and TC). These estrogen's beneficial effects on lipids, may prevent the atherosclerosis. In addition, apolipoprotein E increases senile plaques in senile dementia-Alzheimer's type. The decrease in apolipoprotein E with ERT may be related to cognitive functions of elderly women.
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PMID:Effect of estrogen replacement therapy on hepatic triglyceride lipase, lipoprotein lipase and lipids including apolipoprotein E in climacteric and elderly women. 907 16

We examined the vascular structure and endothelium-dependent relaxation in two genetic models of hypercholesterolemia: apolipoprotein E (apoE)-knockout mice and combined apoE/LDL receptor-double-knockout mice. Intimal area was increased markedly in proximal segments of thoracic aortas from apoE/LDL receptor-knockout mice [0.13 +/- 0.03 (mean +/- SE) mm2] compared with normal (C57BL/6J) mice (0.002 +/- 0.002 mm2, P < .05). Despite intimal thickening, the vascular lumen was not smaller in the aortas of apoE/LDL receptor-knockout mice (0.52 +/- 0.03 mm2) than in normal mice (0.50 +/- 0.03 mm2). In apoE-deficient mice, intimal thickening was minimal or absent, even though the concentration of plasma cholesterol was only modestly less than that in the double-knockout mouse (14.9 +/- 1.1 vs 18.0 +/- 1.2 mmol/L, respectively, P < .05). Relaxation of the aorta was examined in vitro in vascular rings precontracted with U46619. In normal mice, acetylcholine produced relaxation, which was markedly attenuated by the nitric oxide synthase inhibitor NG-nitro-L-arginine (100 microM). Relaxation to acetylcholine and the calcium ionophore A23187 was normal in apoE-deficient mice (in which lesions were minimal) but greatly impaired in the proximal segments of thoracic aortas of apoE/LDL receptor-deficient mice, which contained atherosclerotic lesions. Vasorelaxation to nitroprusside was similar in normal and apoE-knockout mice, with modest but statistically significant impairment in atherosclerotic segments of apoE/LDL receptor-knockout mice. In distal segments of the thoracic aorta of apoE/LDL receptor-deficient mice, atherosclerotic lesions were minimal or absent, and the endothelium-dependent relaxation to acetylcholine and calcium ionophore was normal. Thus, in apoE/LDL receptor-knockout mice (a genetic model of hyperlipidemia), there is vascular remodeling with preservation of the aortic lumen despite marked intimal thickening, with impairment of endothelium-dependent relaxation to receptor- and nonreceptor-mediated agonists. Atherosclerosis may be accelerated in the apoE/LDL receptor-double-knockout mouse compared with the apoE-knockout strain alone. We speculate that other factors, such as the absence of LDL receptors, may contribute to the differences in the extent of atherosclerosis in these two models of hyperlipidemia.
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PMID:Atherosclerosis, vascular remodeling, and impairment of endothelium-dependent relaxation in genetically altered hyperlipidemic mice. 940 99

Infection, inflammation and trauma induce marked changes in the plasma levels of a wide variety of proteins (acute phase response), and these changes are mediated by cytokines. The acute phase response is thought to be beneficial to the host. The host's response to injury also results in dramatic alterations in lipid metabolism and circulating lipoprotein levels which are mediated by cytokines. A large number of cytokines including TNF, the interleukins, and the interferons increase serum triglyceride levels. This rapid increase (1-2 h) is predominantly due to an increase in hepatic VLDL secretion while the late increase may be due to a variety of factors including increased hepatic production of VLDL or delayed clearance secondary to a decrease in lipoprotein lipase activity and/or apolipoprotein E levels on VLDL. In animals other than primates, cytokines also increase serum cholesterol levels, most likely by increasing hepatic cholesterol. Cytokines increase hepatic cholesterol synthesis by stimulating HMG CoA reductase gene expression and decrease hepatic cholesterol catabolism by inhibiting cholesterol 7 alpha-hydroxylase, the key enzyme in bile acid synthesis. Injury and/or cytokines also decrease HDL cholesterol levels and induce alterations in the composition of HDL. The content of SAA and apolipoprotein J increase, apolipoprotein A1 may decrease, and the cholesterol ester content decreases while free cholesterol increases. Additionally, key proteins involved in HDL metabolism are altered by cytokines; LCAT activity, hepatic lipase activity, and CETP levels decrease. These changes in lipid and lipoprotein metabolism may be beneficial in a number of ways including: lipoproteins competing with viruses for cellular receptors, apolipoproteins neutralizing viruses, lipoproteins binding and targeting parasites for destruction, apolipoproteins lysing parasites, redistribution of nutrients to cells involved in the immune response and/or tissue repair, and lipoproteins binding toxic agents and neutralizing their harmful effects. Thus, cytokines induce marked changes in lipid metabolism that lead to hyperlipidemia which represents part of the innate immune response and may be beneficial to the host.
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PMID:Beneficial effects of cytokine induced hyperlipidemia. 955 31

The magnitude of serum lipid changes in response to hypolipidemic drugs varies considerably between individuals. These differences may be due to interactions between genetic and environmental factors that effect drug bioavailability or the capacity of the lipid-regulating enzyme and receptor targets to be affected. The apolipoprotein E (apoE) gene locus has been examined in this regard, but reports are conflicting on the effect of its variability on the response to hypolipidemic drugs. We investigated the effect of apoE polymorphism on the serum lipid response to the hepatic hydroxymethyl glutaryl coenzyme A (HMG CoA) reductase inhibitor lovastatin and the fibric acid derivative gemfibrozil. Lipoprotein changes were assessed after 12 weeks of therapy in 106 patients with primary hypercholesterolemia and combined hyperlipidemia treated with lovastastin and in 63 given gemfibrozil therapy. No significant effect of the apoE phenotypes E3/2, E3/3, or E4/3 on the heterogeneity of lipid responses to either drug was found.
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PMID:Lack of interaction of apolipoprotein E phenotype with the lipoprotein response to lovastatin or gemfibrozil in patients with primary hypercholesterolemia. 959 47

We have previously reported that normolipidemic smokers are lipid intolerant due to increased responses of triglyceride-rich lipoproteins (TRL) apolipoprotein B-48, triglyceride (TG), and retinyl esters to a mixed meal compared to non-smokers. To investigate whether postprandial high density lipoprotein (HDL), apolipoprotein A-I (apoA-I), apolipoprotein A-II (apoA-II), and apolipoprotein E (apoE) concentrations or lipid transfer protein activities are affected by cigarette smoking, we investigated 12 male smokers and 12 non-smokers with comparable fasting lipoprotein profile, BMI, and age. Plasma samples obtained after an overnight fast and postprandially were separated by density gradient ultracentrifugation. Postprandial apoA-I, lipoprotein AI-particles (LpA-I), HDL-cholesterol, and HDL apoE concentrations decreased in smokers, but remained unchanged in controls. Concomitantly, cholesterol and apoE concentrations increased significantly in TRL fractions in smokers. Fasting lecithin:cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) activity levels, as well as esterification rates (EST) and phospholipid transfer rates were comparable between the groups. Cholesteryl ester transfer protein (CETP) activity levels were lower in the smokers. Postprandially EST increased, but CETP and PLTP activities deceased in smokers as compared to controls. We conclude, that even healthy, normolipidemic smokers have altered postprandial high density lipoprotein (HDL) cholesterol and apolipoprotein composition, as well as lipid transfer protein activities. The shift of cholesterol and apoE from HDL to the triglyceride-rich lipoprotein (TRL) fraction, together with decreased plasma apoA-I and LpA-I concentrations during alimentary lipemia may indicate impaired reverse cholesterol transport. Both the postprandial increase in TRL and the lowering of HDL may promote atherogenesis in smokers.
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PMID:Decreased postprandial high density lipoprotein cholesterol and apolipoproteins A-I and E in normolipidemic smoking men: relations with lipid transfer proteins and LCAT activities. 968 53

Mice lacking hepatic lipase have been reported to express mild hyperlipidemia characterized by increased concentrations of large high density lipoproteins, but normal concentrations of lipoproteins containing apolipoprotein B. Whereas hepatic lipase has been implicated in the clearance and processing of chylomicron remnants in rats, no such defect was found in these mice. We have further characterized the abnormal lipoprotein phenotype in young hepatic lipase-deficient mice and have found more pronounced elevations of high density lipoproteins associated in particular with a 5-fold increase in plasma concentrations of apolipoprotein E. In addition, there was a reduction in the concentration of low density lipoproteins containing apolipoprotein B-100 and B-48 relative to precursor lipoproteins of lower density and a pronounced deficiency of apolipoprotein B-containing low density lipoproteins with density exceeding 1.029 g/mL. Conversion of radiolabeled rabbit intermediate density lipoproteins to low density lipoproteins was reduced by 6-fold as compared with wild-type mice. Although clearance of cholesteryl ester-labeled chylomicrons from the blood was unimpaired in the deficient mice, that of chylomicron remnants was reduced. Furthermore, endocytosis of chylomicron cholesteryl esters into liver cells occurred more rapidly than in wild-type mice. The unimpaired hepatic clearance of injected chylomicron particles in hepatic lipase-deficient mice may be the result of greater acquisition of apoE from high density lipoproteins during remnant formation. These studies thus demonstrate a critical role for mouse hepatic lipase in the formation of small, dense low density lipoproteins, as well as participation in the normal clearance and processing of chylomicron remnants.
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PMID:Metabolism of lipoproteins containing apolipoprotein B in hepatic lipase-deficient mice. 971 27

Abnormal interaction between low density lipoprotein receptors (LDLR) and their ligands, apolipoprotein E and B, causes decreased catabolism of lipoproteins which carry these apolipoproteins (VLDL, IDL and/or LDL) and thereby increased plasma concentrations of these. In familial hypercholesterolemia (FH), abnormal interaction is due to mutations in the LDLR gene, and in type III hyperlipidemia due to mutations in the apo E gene. A few mutations in the apolipoprotein B (apo B) gene have been described, of which the apo B-3,500Arg-Gln seems by far the most frequent, that causes defective binding to normal LDLR. The metabolic disorder associated with these mutations has been named familial defective apolipoprotein B-100 (FDB). The frequency of the apo B-3,500Arg-Gln mutation is particularly high in Central Europe (Switzerland) with lower frequencies south of the Alpes, in Russia and in Scandinavia. We found an incidence of 1/1250 of the mutation in Denmark (III), employing a DNA based assay optimized to allow detection of the mutation in very small amounts of DNA (I). Since other mutations in the receptor binding domain of the apo B-100 have been described, we developed another DNA based assay, employing DGGE technique, to screen for other mutations in the region of amino acid 3,456 to 3,553 (II). However, no other mutations but the apo B-3,500Arg-Gln have so far been detected in Danish hypercholesterolemic patients. In a study of 5 Danish families with FDB (46 heterozygous FDB patients and 57 unaffected relatives) we found that FDB patients had significantly increased mean cholesterol and LDL cholesterol concentrations, but with a wide range of variation and with approximately 30% having cholesterol concentrations below the 95th percentile for the general population (IV). This was confirmed in a compilation of data on 205 FDB patients from the Netherlands, Germany and Denmark (V). In this study we also compared the biochemical and clinical features of FDB with those of 101 Danish FH patients in whome FDB had been ruled out. Our data support, that the LDL cholesterol elevation is less pronounced in FDB than in FH and that the age-specific prevalence of atherosclerotic cardiovascular disease (CVD) is lower in FDB than in FH. In the compiled study of 205 FDB heterozygotes (V), we found that age, gender and genetic variation in the LDLR gene explained a considerable part of the between-individual variation in total and LDL cholesterol. We conducted a prospective study of the lipid lowering effect of pravastatin and gemfibrozil in 30 Danish FDB patients (VI). Together with other, retrospective, studies, we conclude that the cholesterol lowering effect of HMG-coA-reductase inhibitors, anion binding resins and nicotinic acid is fully comparable to that observed when treating FH patients and type IIa hypercholesterolemic patients, without clinical signs of FH.
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PMID:Familial defective apolipoprotein B-100. 977 89

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