Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Apolipoprotein E (apoE) is a polymorphic gene involved in lipid metabolism with three common variant alleles (epsilon2, epsilon3, and epsilon4). The epsilon4 allele has been associated with elevated levels of cholesterol as well as greater risk of coronary heart disease and Alzheimer's disease. In this case-control study we examined whether apoE genotype affected the association between serum lipids and breast cancer risk. In a subset of a study in western New York, 260 women with incident, primary breast cancer and 332 community controls were interviewed and provided blood samples. Polymerase chain reaction-restriction fragment length polymorphism analyses of the apoE polymorphism were performed. Participants were classified as apoE2 (epsilon2, epsilon2 or epsilon2, epsilon3), apoE3 (epsilon3, epsilon3), or apoE4 (epsilon4, epsilon4 or epsilon4, epsilon3). No unconditional logistic regression was used to compute adjusted odds ratios (ORs) and 95% confidence intervals (CI). Compared with women with the apoE3 genotype, there were no associations with risk for women with the apoE2 (OR=1.0; 95% CI=0. 91-1.64) or apoE4 genotype (OR=0.97; 95% CI=0.63-1.54). Higher serum levels of total cholesterol, HDL cholesterol, and LDL cholesterol were not associated with risk, either in the total sample or among subgroups of women defined by apoE genotype. Women with the highest serum triglyceride levels had an increase in risk (OR=1.63; 95% CI=1. 03-2.59) compared to women with the lowest levels. This effect was not apparent among women with the apoE2 or apoE3 genotype, but much stronger among women with the apoE4 genotype (OR=4.69; 95% CI=1. 49-14.7). These data suggest that the apoE4 genotype may modify the association between serum triglycerides and breast cancer risk.
Mol Carcinog 2000 Jan
PMID:Apolipoprotein E genetic polymorphism, serum lipoproteins, and breast cancer risk. 1064 31

The localization in the brain and metabolism of 3H-labeled corticosterone (B) and 11-dehydrocorticosterone (A) of high specific radioactivity was determined after stereotaxic injection into the hippocampus of anesthetized rats. [3H]B was cleared very rapidly with, on average, only about 7% being recovered after 5 min and 0.5% after 30 min. Most of this 3H-radioactivity was localized in the area surrounding the site of injection with little diffusion to adjacent areas. These findings make it possible to compare the short term metabolism of [3H]A and [3H]B in different lobes of the hippocampus in the same animal and establish their local equilibrium point in vivo. Under these conditions, about 5% conversion of each steroid to the other was observed in contrast to the situation in cultured hippocampal cells where 11beta-hydroxysteroid dehydrogenase (11-HSD) has been shown by others to act primarily as a reductase catalyzing the conversion of A to B. This method can also be used to study the effect of inhibitors such as 11alpha-hydroxyprogesterone, applied locally in the brain, on the metabolism of corticosteroids. The rate of conversion [3H]B or [3H]A to their dihydro- and tetrahydro-derivatives capable of modulating the GABAa receptor in the hippocampus was much lower than their interconversion. Thus, factors which influence the direction of the 11-HSD catalyzed reaction are important in regulating not only salt appetite and blood pressure but also the levels of neuroactive metabolites of corticosterone.
J Steroid Biochem Mol Biol 1999 Dec 15
PMID:11beta-hydroxysteroid dehydrogenase functions reversibly as an oxidoreductase in the rat hippocampus in vivo. 1065 2

Obesity is frequently associated with insulin-resistance and abnormal glucose homeostasis. Recent evidence indicates that TNFalpha may play a role in mediating the insulin-resistance of obesity through its overexpression in adipose tissue. Previously, we have shown that human adipose stromal cells contain 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) mRNA and activity. The present study was designed to examine the effects of insulin on 11beta-HSD1 expression in human adipose stromal cells under basal and TNFalpha-stimulated conditions. The cells were obtained from breast adipose tissue by collagenase digestion, and grown to confluence under replicating conditions in 10% fetal bovine serum. The cells were transferred to serum-free medium for 24 h prior to treatment with either TNFalpha, insulin or both for a further 24 h. The level of 11beta-HSD1 reductase activity was determined by measuring the conversion of [(3)H]-cortisone to [(3)H]-cortisol at a substrate concentration of 10 nM. Treatment with TNFalpha at concentrations of 0.1-10 ng/ml resulted in a dose dependent increase in 11beta-HSD1 reductase activity from 1.5 to 10-fold. Insulin (0.1-100 nM) had no effect under basal conditions, but inhibited the stimulatory effects of TNFalpha (5 ng/ml) on 11beta-HSD1 reductase activity in a dose dependent fashion (8-66%) inhibition). Northern blot analysis revealed corresponding changes in the level of 11beta-HSD1 mRNA, suggesting that the effects of TNFalpha and insulin on 11beta-HSD1 activity are mediated at the level of gene transcription. The interaction between insulin and TNFalpha suggests that local and systemic factors may act in a concerted fashion to modulate glucocorticoid activity in adipose and other peripheral tissues.
J Steroid Biochem Mol Biol 2000 Mar
PMID:Insulin attenuates the stimulatory effects of tumor necrosis factor alpha on 11beta-hydroxysteroid dehydrogenase 1 in human adipose stromal cells. 1077 8

Some studies show that plasma triglyceride (TG) levels are a significant independent risk factor for cardiovascular disease (CVD). TG levels are inversely correlated with high density lipoprotein cholesterol (HDL-C) levels, and their metabolism may be closely interrelated. Therefore, the TG/HDL-C ratio may be a relevant CVD risk factor. Our analysis of families in the Framingham Heart Study gave a genetic heritability estimate for log(TG) of 0.40 and for log(TG/HDL-C) of 0.49, demonstrating an important genetic component for both. A 10 cM genome-wide scan for log(TG) level and log(TG/HDL-C) was carried out for the largest 332 extended families of the Framingham Heart Study (1702 genotyped individuals). The highest multipoint variance component LOD scores obtained for both log(TG) and log(TG/HDL-C) were on chromosome 7 (at 155 cM), where the results for the two phenotypes were 1.8 and 2.5, respectively. The 7q32.3-qter region contains several candidate genes. Four other regions with multipoint LOD scores greater than one were identified on chromosome 3 [LOD score for log(TG/HDL-C) = 1.8 at 140 cM], chromosome 11 [LOD score for log(TG/HDL-C) = 1.1 at 125 cM], chromosome 16 [LOD score for log(TG) = 1.5 at 70 cM, LOD score for log(TG/HDL-C) = 1.1 at 75 cM] and chromosome 20 [LOD score for log(TG/HDL-C) = 1.7 at 35 cM, LOD score for log(TG) = 1.3 at 40 cM]. These results identify loci worthy of further study.
Hum Mol Genet 2000 May 22
PMID:Evidence for a gene influencing the TG/HDL-C ratio on chromosome 7q32.3-qter: a genome-wide scan in the Framingham study. 1081 13

This study examined the enzymatic characteristics and steroid regulation of the glucocorticoid-metabolizing enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) in the human breast cancer cell line T-47D. In cell homogenates, exogenous NAD significantly increased the conversion of corticosterone to 11-dehydrocorticosterone, while NADP was ineffective. There was no conversion of 11-dehydrocorticosterone to corticosterone either with NADH or NADPH demonstrating the lack of reductase activity. In keeping with these results, RT-PCR analysis indicated a mRNA for 11beta-HSD2 in T-47D cells, while 11beta-HSD1 mRNA levels were undetectable. In T-47D cells treated for 24 h with medroxyprogesterone acetate (MPA), 11beta-HSD catalytic activity was elevated 11-fold, while estrone (E(1)), estradiol (E(2)) and the synthetic glucocorticoid dexamethasone (DEX) were ineffective. The antiprogestin mifepristone (RU486) acted as a pure antagonist of the progestin-enhanced 11beta-HSD activity, but did not exert any agonistic effects of its own. In addition, RT-PCR analysis demonstrated that MPA was a potent inducer of 11beta-HSD2 gene expression, increasing the steady-state levels of 11beta-HSD2 mRNA. Taken together, these results demonstrate that 11beta-HSD2 is the 11beta-HSD isoform expressed by T-47D cells under steady-state conditions and suggest the existence of a previously undocumented mechanism of action of progestins in breast cancer cells.
J Steroid Biochem Mol Biol 2000 Apr
PMID:Progestin regulation of 11beta-hydroxysteroid dehydrogenase expression in T-47D human breast cancer cells. 1082 13

Apo C-III plays an important role in the metabolism of plasma triglyceride, which can delay the catabolism of triglyceride-rich lipoproteins by interfering with apo E-mediated receptor clearance of remnant particles from plasma. The mechanism of the interference has not yet been defined. To further explore the role of apo C-III, we first injected mice with 125I-apo C-III. The measurement of radioactivity showed that liver took up 3.3-10 fold as much radioactivity as other organs such as heart, spleen, lung, kidney, stomach, large intestine, small intestine, and muscle. This was confirmed by incubating the tissue homogenates of the organs with 125I-apo C-III that the radiolabeled apo C-III specifically bound to only hepatic homogenate. To investigate which subcellular part or parts of hepatic cells play the role of binding to apo C-III, hepatic cell components of nucleus, mitochondria, microsomes and plasma membranes were then incubated with 125I-apo C-III. The radiolabeled apo C-III could specifically bind to only hepatic plasma membranes. Finally hepatic plasma membranes were purified to study the characteristics of the specific binding with apo C-III. Addition of increasing concentration of 125I-apo C-III to human hepatic plasma membranes revealed saturable binding to membranes with a Kd of 0.31 +/- 0.07 micromol/l. The maximum specific binding capacity was 1.74 +/- 0.45 microg apo C-III/mg membrane protein. In competition studies using unlabeled apo C-III and isolated lipoproteins HDL, LDL and VLDL, only apo C-III and VLDL effectively competed with 125I-apo C-III for membrane binding. The binding of 125I-apo C-III to human liver plasma membranes was Ca2+-independent, and was abolished when plasma membranes were treated with trypsin. The characteristics of 125I-apo C-III binding to mouse liver plasma membranes were similar to those of human liver plasma membranes with the exception of a binding maximum of 1.52 +/- 0.39 microg apo C-III/mg membrane protein. We conclude that apo C-III exhibits high-affinity binding to hepatic plasma membranes, which is saturable, reverse and specific.
Mol Cell Biochem 2000 Apr
PMID:Apolipoprotein C-III can specifically bind to hepatic plasma membranes. 1088 27

Many lines of evidence suggest that LDL is oxidized in vivo and that Ox-LDL is present in the artery wall. But the oxidation of VLDL and HDL in vivo has not yet been reported. In this study, the oxidative modification of serum LDL, VLDL, and HDL in patients with endogenous hypertriglyceridemia (HTG) and in serum of rabbits fed on high cholesterol diet were made. The serum LDL, VLDL and HDL were isolated by the density gradient ultracentrifugation. The oxidative modification of LDL, VLDL and HDL were identified by agarose eletrophoresis, absorbance at 234 nm and fluorescence of TBARS. The results showed that serum TC, TG and TBARS in the HTG group (n = 25) and in rabbits fed with a high fat diet (for 12 weeks, n = 8) were significantly higher than those of the corresponding control groups (normal subjects, n = 25; rabbits fed with a normal diet, n = 8; p < 0.01). The electrophoretic mobilities of LDL, VLDL and HDL were increased when compared with the controls, and absorbance at 234 nm and TBARS of LDL, VLDL and HDL in the HTG group and in the high fat diet rabbits were significantly higher than those of the controls (p < 0.01). These results suggest that not only LDL but also VLDL and HDL were oxidatively modified in vivo in the patients with HTG and in the rabbits fed with a high cholesterol diet.
Mol Cell Biochem 2000 Apr
PMID:Oxidative modification of lipoproteins in hypertriglyceridemic patients and hypercholesterolemic rabbits in vivo. 1088 38

We investigated the effect of endogenous apolipoprotein (apo) E synthesis in mouse peritoneal macrophages on cholesterol efflux and intracellular cholesteryl ester hydrolysis mediated by high-density lipoprotein-3 (HDL3) and lipid-free apolipoproteins (apo). After loading with acetylated LDL (acLDL) peritoneal macrophages from wild-type (apoE(+/+)) and apoE-deficient (apoE(-/-)) mice were incubated with medium alone or with liposomes, HDL3, lipid-free apoA-I, or lipid-free apoE3. Cholesterol and cholesteryl esters in the cells and culture media were quantified by HPLC. Incubation of apoE(+/+) or apoE(-/-) macrophages for 18 h with medium alone or with liposomes did not cause significant changes in cellular cholesterol. Addition of HDL3, apoA-I, or apoE3 to the medium led to significant cholesterol efflux, which was less efficient in apoE(-/-) macrophages than in apoE(+/+) macrophages. HDL and lipid-free apolipoproteins were more effective in reducing the cellular content of cholesteryl esters of apoE(+/+) macrophages than of apoE(-/-) macrophages, suggesting that endogenous apoE stimulates cholesteryl ester hydrolysis. The difference in the mass of cholesteryl esters was more pronounced for cholesteryl arachidonate and linoleate than for cholesteryl oleate or palmitate. Furthermore, in [(14)C]arachidonate labeling experiments cholesterol arachidonate hydrolysis was higher in apoE(+/+) macrophages than in apoE(-/-) macrophages in the presence of cholesterol efflux mediated by HDL3 or apoA-I. In contrast, in the absence of cholesterol efflux cholesterol arachidonate synthesis was higher in apoE(+/+) macrophages than in apoE-/- macrophages. Taken together, our data suggest that endogenous apoE stimulates cholesterol efflux and intracellular cholesteryl ester hydrolysis mediated by HDL3 and lipid-free apolipoproteins in mouse peritoneal macrophages. This may contribute to the antiatherogenic effect of apoE.
J Mol Med (Berl) 2000
PMID:Endogenous apolipoprotein E modulates cholesterol efflux and cholesteryl ester hydrolysis mediated by high-density lipoprotein-3 and lipid-free apolipoproteins in mouse peritoneal macrophages. 1093 84

Cancer patients often present altered serum lipid profile including changes of HDL cholesterol level. The aim of our work was to evaluate serum level of HDL cholesterol in patients with squamous cell and small cell lung cancer and its dependence on histological type and clinical stage of lung cancer. Fasting serum level of HDL cholesterol was analysed in 135 patients with newly diagnosed lung cancer and compared to a control group of healthy men. All lung cancer patients, as well as subgroups of squamous cell and small cell lung cancer had statistically significantly lower HDL cholesterol concentration than controls. There were no statistically significant differences of HDL cholesterol level between the histological types or between clinical stages of each histological type of lung cancer.
Int J Mol Med 2000 Sep
PMID:Serum HDL cholesterol concentration in patients with squamous cell and small cell lung cancer. 1093 94

The levels of plasma apolipoprotein (apo) E, an anti-atherogenic protein involved in mammalian cholesterol transport, were found to be 2-3 fold lower in mice over-expressing human apoA-I gene. ApoE is mainly associated with VLDL and HDL-size particles, but in mice the majority of the apoE is associated with the HDL particles. Over-expression of the human apoA-I in mice increases the levels of human apoA-I-rich HDL particles by displacing mouse apoA-I from HDL. This results in lowering of plasma levels of mouse apoA-I. Since plasma levels of apoE also decreased in the apoA-I transgenic mice, the mechanism of apoE lowering was investigated. Although plasma levels of apoE decreased by 2-3 fold, apoB levels remained unchanged. As expected, the plasma levels of human apoA-I were almost 5-fold higher in the apoAI-Tg mice compared to mouse apoA-I in WT mice. If the over-expression of human apoA-I caused displacement of apoE from the HDL, the levels of hepatic apoE mRNA should remain the same in WT and the apoAI-Tg mice. However, the measurements of apoE mRNA in the liver showed 3-fold decreases of apoE mRNA in apoAI-Tg mice as compared to WT mice, suggesting that the decreased apoE mRNA expression, but not the displacement of the apoE from HDL, resulted in the lowering of plasma apoE in apoAI-Tg mice. As expected, the levels of hepatic apoA-I mRNA (transgene) were 5-fold higher in the apoAI-Tg mice. ApoE synthesis measured in hepatocytes also showed lower synthesis of apoE in the apoAI-Tg mice. These studies suggest that the integration of human apoA-I transgene in mouse genome occurred at a site that affected apoE gene expression. Identification of this locus may provide further understanding of the apoE gene expression.
Mol Cell Biochem 2000 Jun
PMID:Apolipoprotein E gene expression is reduced in apolipoprotein A-I transgenic mice. 1094 10


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