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)

apoE deficiency causes hyperlipidemia and premature atherosclerosis. To determine if macrophage-specific expression of apoE would decrease the extent of atherosclerosis, we expressed human apoE in macrophages of apoE-null mice (apoE-/-) and assessed the effect on lipid accumulation in cells of the arterial wall. Macrophage-specific expression of human apoE in normal mice was obtained by use of the visna virus LTR. These animals were bred with apoE-/- mice to produce animals hemizygous for expression of human apoE in macrophages in the absence of murine apoE (apoE-/-,hTgE+/0). Low levels of human apoE mRNA were present in liver and spleen and high levels in lung and peritoneal macrophages. Human apoE was secreted by peritoneal macrophages and was detected in Kupffer cells of the liver. Human apoE in the plasma of apoE-/-,hTgE+/0 mice (n = 30) was inversely correlated (P < 0.005) with the plasma cholesterol concentration. After 15 wk on a normal chow diet, atherosclerosis was assessed in apoE-/-,hTgE+/0 animals and in apoE-/-,hTgE0/0 littermates matched for plasma cholesterol level (approximately 450 mg/dl) and lipoprotein profile. There was significantly less atherosclerosis in both the aortic sinus and in the proximal aorta (P < 0.0001) in the animals expressing the human apoE transgene. In apo-E-/-,hTgE+/0 animals, which had detectable atherosclerotic lesions, human apoE was detected in the secretory apparatus of macrophage-derived foam cells in the arterial wall. The data demonstrate that expression of apoE by macrophages is antiatherogenic even in the presence of high levels of atherogenic lipoproteins. The data suggest that apoE prevents atherosclerosis by promoting cholesterol efflux from cells of the arterial wall.
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PMID:Macrophage-specific expression of human apolipoprotein E reduces atherosclerosis in hypercholesterolemic apolipoprotein E-null mice. 759 2

We have developed a procedure to quantify apolipoprotein (apo) B-100, apoB-48, and apoE in human triglyceride-rich lipoproteins. This procedure permits delipidation of small amounts of triglyceride-rich lipoproteins without appreciable losses, and quantification of these apolipoproteins in samples containing as little as 10 micrograms of protein. Delipidated triglyceride-rich lipoproteins are subjected to sodium dodecyl sulfate polyacrylamide slab gel electrophoresis, and the mass of apolipoproteins is estimated after densitometric scanning and volume integration of Coomassie blue-stained bands. The chromogenicities of apoB-100 and apoB-48 are virtually identical, and twofold lower than that of apoE. The standard curve for each apolipoprotein follows a power function over a wide protein range, permitting quantification of as little as 0.2 microgram of apoB-48 and as much as 30 micrograms of apoB-100 from a single application of triglyceride-rich lipoproteins to the gels. This method is suitable for routine use in studies of the intestinal and hepatic contributions to triglyceride-rich lipoproteins and their responses to postprandial lipemia.
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PMID:Quantification of apolipoproteins B-100, B-48, and E in human triglyceride-rich lipoproteins. 761 30

It has been widely accepted that the remnants of the intestinally-derived lipoprotein chylomicrons, i.e., chylomicron remnants (CMR), are cleared from the circulation by a receptor genetically distinct from the well-known LDL-receptor. This second receptor was initially considered as a receptor specific for apo E, in contrast to the LDL-receptor, which binds both apo B and apoE. This article critically examines the current dogma of the putative CMR receptor, as well as both supporting and conflicting evidence for the recently-proposed identity of this receptor with the LDL-receptor related protein (LRP). Next, we introduce the lipolysis-stimulated receptor, LSR, which bears all the biochemical characteristics of the CMR receptor. In addition, the apparent number of LSR expressed in the liver is inversely correlated with nonfasting levels of plasma triglycerides. A change in LSR expression and parallel inverse change in plasma triglycerides is observed in rats treated with hyperlipidemic (retinoic acid) or hypolipidemic (fish oil in MaxEPA) agents, indicating that LSR represents a definite target for pharmacological management of hyperlipidemia. In support of this notion is the observation that MaxEPA, which causes an increase in LSR expression, also reduces both plasma triglyceride and cholesterol levels in the thus far intractable homozygous Watanabe heritable hyperlipidemic rabbit.
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PMID:Lipolysis-stimulated receptor: a newcomer on the lipoprotein research scene. 762 72

Apolipoprotein (apo) E mediates the removal of chylomicron and VLDL remnants from plasma. In a proband with mild hyperlipidemia and a family history of premature coronary artery disease, we have identified a new mutant of apoE with an isoelectric point close to but distinct from that of apoE3. Sequencing of the apoE gene from this subject (JB) revealed that the subject was heterozygous for a G to A substitution in codon 136, resulting in the substitution of histidine for arginine; therefore, we have designated this isoform apoE3' (Arg136-->His). Examination of the proband's kindred revealed that the nine carriers (all heterozygotes) of the variant isoform displayed a twofold elevation in the concentration of very low density lipoprotein (VLDL) cholesterol (40 +/- 8 mg/dl) and triglyceride (109 +/- 19) compared to the nine noncarriers (19 +/- 3 and 55 +/- 13, respectively). In all carriers, the VLDL displayed an abnormal double pre-beta pattern upon electrophoresis. The low density lipoprotein receptor-binding activity of purified apoE3' (Arg136-->His) when complexed with DMPC was slightly defective (80% of the activity of normal apoE). The mutant apoE also displayed a reduced affinity for heparin compared to apoE3. As both of these biochemical parameters are known to be important in VLDL clearance, the defects associated with this variant are likely responsible for the increase in VLDL observed in carriers. None of the carriers displayed clinical features of type III hyperlipoproteinemia, suggesting that the relatively mild dyslipoproteinemic phenotype associated with this variant might be associated with recessive expression of this disorder. However, the abnormal VLDL phenotype appears to be dominantly expressed.
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PMID:Identification and characterization of a novel apolipoprotein E variant, apolipoprotein E3' (Arg136-->His): association with mild dyslipidemia and double pre-beta very low density lipoproteins. 770 48

To investigate the potential use of apoE in gene therapy of hyperlipidemias, an adenoviral vector was constructed that contained the human apoE3 cDNA under the control of the RSV promoter (Av1RE). Transduction of HepG2 cells resulted in the overexpression of human apoE secreted into the culture medium. Intravenous injection of 5 x 10(11) Av1RE vector particles into apoE-deficient mice resulted in expression of human apoE3 in mouse plasma at levels of 1.2 +/- 0.4 micrograms/L (mean +/- SEM, n = 5) 7 days after injection. Mice injected with the control vector Av1Lacz4 did not express detectable levels of human apoE. Average plasma cholesterol concentrations were reduced approximately eightfold from 737.5 +/- 118 mg/dL (mean +/- SEM, n = 6) to 98.2 +/- 4.4 mg/dL (mean +/- SEM, n = 5) and were unaffected in the control vector group. Expression of human apoE resulted in a shift in the plasma lipoprotein distribution from primarily VLDL and LDL in the control mice to predominantly HDL in the Av1RE-treated group. Western blot analysis of fast protein liquid chromatography-fractionated mouse plasma showed that the human apoE protein was associated with VLDL, LDL, and HDL. Correction of the hyperlipidemic condition found in the apoE-knockout mouse strain by direct in vivo gene transfer establishes the potential of this approach for treatment of hyperlipidemia caused by apoE deficiency or malfunction in human disease.
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PMID:Phenotypic correction of hypercholesterolemia in apoE-deficient mice by adenovirus-mediated in vivo gene transfer. 774 59

Although lipoprotein abnormalities of the nephrotic syndrome are assumed to be related to the presence of proteinuria, this topic has not been investigated extensively. We measured lipoproteins from 19 nonuremic patients during and after remission of the nephrotic syndrome in an effort to determine the extent of their putative atherogenicity. As expected, disturbances involved primarily the apoprotein B-containing lipoproteins. No patient showed serum lipoprotein(a) [Lp(a)] < 300 mg/L during the acute phase. Lp(a) concentrations correlated significantly with those of apoprotein B, and both values decreased dramatically with the remission of the nephrotic syndrome. Surprisingly, despite the resolution of proteinuria, concentrations of intermediate-density lipoproteins and Lp(a) remained above normal in hypertriglyceridemic patients, suggesting a residual effect of nephrosis in the overall lipoprotein transport. Accumulation of atherogenic remnants should be considered a characteristic of the hyperlipidemia of the nephrotic syndrome, and aggressive treatment to reduce proteinuria is mandatory.
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PMID:Accumulation of atherogenic remnants and lipoprotein(a) in the nephrotic syndrome: relation to remission of proteinuria. 776 11

Despite the definite etiologic link between apolipoprotein (apo) E mutations and type III hyperlipoproteinemia (HLP), it is not clear what additional factors are involved in the development of florid hyperlipidemia and how to explain the wide variability in the expression of the hyperlipidemic phenotype in carriers of receptor binding-defective apoE variants. The present study was designed to determine whether the overexpression of cholesteryl ester transfer protein (CETP), a plasma protein that transfers cholesteryl esters from the high density lipoproteins (HDL) to the very low density lipoproteins (VLDL) and whose activity is increased in hyperlipidemic states, plays a role in the development of hyperlipidemia and beta-VLDL accumulation in type III HLP. We produced double-transgenic mice that co-expressed high levels of simian CETP and either high or low levels of a human receptor binding-defective apoE variant, apoE(Cys-142). We previously reported that apoE(Cys-142) high-expresser mice showed spontaneous hyperlipidemia and accumulation of beta-VLDL, whereas the low-expresser mice showed only a modest increase in VLDL cholesterol. Co-expression of CETP induced a massive transfer of cholesteryl esters from the HDL to the VLDL in both lines of double-transgenic mice. As a result, HDL cholesterol and apoA-I levels were reduced to about 50% of normal, VLDL cholesterol increased 2.5-fold, and the cholesteryl ester content of VLDL reached values similar to those observed in human beta-VLDL. The ratio of defective to normal apoE in VLDL was unaffected by CETP co-expression and was higher in animals expressing high apoE levels. Finally, in spite of an increased accumulation of beta-VLDL in the high-expresser mice, the VLDL of the low-expresser mice maintained pre-beta mobility upon co-expression of CETP. The results of this study demonstrate that the ratio of defective to normal apoE on the VLDL, rather than the cholesteryl ester content of VLDL, is the major factor determining the development of severe hyperlipidemia and the formation and accumulation of beta-VLDL in type III HLP.
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PMID:Co-expression of cholesteryl ester transfer protein and defective apolipoprotein E in transgenic mice alters plasma cholesterol distribution. Implications for the pathogenesis of type III hyperlipoproteinemia. 779 36

1. Secondary hyperparathyroidism in chronic renal failure may contribute to abnormalities of lipid metabolism and glucose tolerance. Amelioration of secondary hyperparathyroidism has been reported to mitigate the hyperlipidaemia and improve glucose tolerance experimentally. 2. The effect of the partial suppression of hyperparathyroidism by intravenous calcitriol on lipid levels and glucose tolerance was studied in 15 haemodialysis patients with secondary hyperparathyroidism. All received intravenous calcitriol 1 microgram at the end of haemodialysis thrice weekly for eight weeks. Oral glucose tolerance test and plasma lipid profiles including triglyceride, total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), apoprotein A-I and apoprotein B were determined simultaneously before and after eight weeks of therapy. 3. Before calcitriol treatment, uraemic patients with secondary hyperparathyroidism displayed a significant higher triglyceride and a significant lower HDL-C and apoprotein A-I as well as marked glucose intolerance with an increment of the area below the glucose curve when compared with healthy control subjects. 4. After eight weeks of calcitriol treatment, there was a significant decrement in serum intact parathyroid hormone (476.45 +/- 48.33 versus 191.37 +/- 30.17 ng/l, P < 0.001) and plasma triglyceride (2.24 +/- 0.34 versus 1.80 +/- 0.29 mmol/l, P < 0.05) as well as a significant increment of plasma apoprotein A-I (38.13 +/- 2.14 versus 44.19 +/- 2.18 mumol/l, P < 0.05), whereas there was no significant change in serum total cholesterol, LDL-C, HDL-C, and apoprotein B.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of intravenous calcitriol on lipid profiles and glucose tolerance in uraemic patients with secondary hyperparathyroidism. 787 41

While determining the apolipoprotein-E (apo-E) genotype of 22 patients with type III hyperlipidemia (HLP III) by restriction isotyping, we identified a new mutant form of apo-E by its unusual DNA restriction fragment length polymorphism pattern. DNA sequence analysis of a polymerase chain reaction-amplified portion of the proband's apo-E gene revealed the substitution of cysteine (TGC) for arginine (CGC) at position 136 in the mutant allele (designated R136C). Lipoproteins containing this mutant protein bound defectively to macrophages in vitro, confirming the contribution of R136C to the expression of HLP III in the proband. The proband's two siblings carried the mutant allele and were also heterozygous for E2. Each also had dysbetalipoproteinemia (indicated by the presence of beta-very low density lipoprotein), but neither was hyperlipidemic, attesting to the importance of other factors for the full expression of HLP III. The mutant allele appears to contribute to the inheritance of HLP III in a recessive fashion. Restriction isotyping facilitates the diagnosis of subjects with HLP III, aids in the identification of affected individuals through family screening, and can contribute to the discovery of new mutations that help explain the pathogenesis of HLP III.
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PMID:Detection of a new apolipoprotein-E mutation in type III hyperlipidemia using deoxyribonucleic acid restriction isotyping. 790 41

A 7-year-old boy with a 5-year history of steroid-unresponsive nephrotic syndrome due to minimal change disease presented with acute myocardial infarction. Angiography was suggestive of a dissected atherosclerotic plaque at the initial and mid portions of the right coronary artery, as well as a lesion in the mid portion of the circumflex artery. The child had a long history of extreme hypercholesterolemia and hypertriglyceridemia, along with apolipoprotein-E 4/3 phenotype. The mother, who also has apolipoprotein-E 4/3 phenotype, has mild hypercholesterolemia. The case suggests that children with long-lasting nephrotic syndrome and even mild familial propensity for hyperlipidemia may be at increased risk for ischemic cardiovascular events. The literature is reviewed regarding the relationship between nephrotic syndrome and the incidence of ischemic heart disease.
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PMID:Acute myocardial infarction in a young boy with nephrotic syndrome: a case report and review of the literature. 791 53


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