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)

The effects of a novel acyl-CoA: cholesterol acyltransferase (ACAT) inhibitor, HL-004, on cholesterol metabolism were examined in mice peritoneal macrophages. Cholesteryl ester-rich foam cells were induced by incubating macrophages with acetylated LDL. HL-004 prevented the accumulation of cholesteryl ester in the presence of the cholesterol acceptor, HDL. In the absence of HDL, HL-004 generated large amounts of free cholesterol in the cell. Moreover, HL-004 stimulated the efflux of cholesterol from preestablished foam cells in the presence of HDL. These results suggest that the inhibition of foam cell formation and the stimulation of foam cell regression by HL-004 are attributed to intracellular ACAT inhibition, and that HL-004 would be expected to exhibit an antiatherosclerotic effect through direct action on arterial wall.
Cell Mol Biol (Noisy-le-grand) 1996 Sep
PMID:Effect of the ACAT inhibitor, HL-004, on cholesterol metabolism in macrophages. 889 54

At midgestation in the baboon, 11beta-hydroxysteroid dehydrogenase (11beta-HSD) catalysed interconversion of cortisol (F) and cortisone (E) during transuterine passage favors the formation of F. Because the site(s) of oxidation/reduction of F and E are not clear, the present study compared F-E interconversion in placenta, decidua and chorion in vitro. In addition, because the reduction of E to F is catalysed only by the 11beta-HSD-1, we also determined whether the mRNA for this enzyme was expressed in baboon placenta, including placental syncytiotrophoblast cells; the site of fetal-maternal exchange. Placentas were obtained on day 100 of gestation (term = day 184) and villous tissue, decidua and chorion isolated, minced in HBSS and incubated (300-400 mg) in duplicate for 0.1-24 h in Medium 199 containing 10% fetal bovine serum and [3H]F and [14C]E. Radiolabelled F and E were purified from incubates and the percentage conversion of F to E and E to F was calculated. In decidua, mean (+/- SE; n = 3) conversion of E to F (69 +/- 2%) was greater than oxidation of F to E (26 +/- 2%). Conversion of E to F in placenta (50 +/- 1%) and chorion (39 +/- 9%) was also extensive and greater than or equal to that for the oxidation of F to E (39 +/- 4% and 32 +/- 4%, respectively). The apparent ratio of 11beta-HSD reductive/oxidative activity was maintained when respective tissues from four baboons were incubated for 18 h with or without 4.4 microM excess radioinert substrate. Expression of 11beta-HSD-1 mRNA was determined by Northern blot by hybridization of poly (A) + -enriched RNA from tissues obtained at midgestation with [32P]labelled human 11beta-HSD-1 cDNA. This cDNA hybridized to a single mRNA species of 1.6 kb in decidua, whole placental villous tissue and syncytiotrophoblast cells, but not to RNA isolated from fetal baboon kidney. The results of the present study demonstrate that at midgestation in the baboon, 11beta-HSD activity in intact placenta and decidua in vitro favored the formation of F from E, presumably catalysed by the 11beta-HSD-1 enzyme protein, the mRNA for which is present in placental syncytiotrophoblasts. Moreover, based on overall mass and extensive vascularity, we suggest that the net formation of F from E during transuterine passage in vivo at this stage of gestation results from the 11beta-HSD-1 in the syncytiotrophoblast cells of the baboon placenta.
J Steroid Biochem Mol Biol 1996 Jul
PMID:Interconversion of cortisol and cortisone in the baboon placenta at midgestation: expression of 11beta-hydroxysteroid dehydrogenase type 1 messenger RNA. 890 24

Transient increases in triglycerides and cholesterol were found in rat liver immediately after birth. Plasma VLDL and HDL increased after birth and reached a plateau after one week of life. The content of cholesterol ester was low at birth in all lipoproteins and increased in LDL and HDL during the first week of life. After birth, VLDL became enriched in apolipoproteins C and E, whereas HDL was enriched in apolipoprotein C and depressed in apolipoprotein E. The developmental changes in plasma lipoprotein levels and compositions in rats during the first week of life are comparable to those described in humans.
Comp Biochem Physiol B Biochem Mol Biol 1996 Apr
PMID:Changes in plasma lipoproteins and liver lipids in neonatal rats. 892 46

Tamoxifen, a non-steroidal anti-oestrogen, is used in the treatment of breast cancer, both receptor positive and negative tumours. It also possesses weak oestrogenic activity which forms the basis of this study. Tamoxifen (2 different dosages) was administered through diet (10 mg/kg diet and 20 mg/kg diet) to experimental atherosclerosis induced female rats to assess the effect of tamoxifen on plasma lipid levels, lipoprotein cholesterol level and on the activity of lipid metabolising enzymes. The plasma total lipid level was increased in atherosclerosis suffering animals compared to control animals with concomitant changes in the activity of lipid metabolising enzymes. HDL-cholesterol was decreased while LDL-cholesterol and VLDL-cholesterol were increased in the atherosclerosis induced group. Cholesterol and free cholesterol were decreased in tamoxifen treated groups while the other lipids show a moderate increase. HDL-cholesterol was increased but LDL-cholesterol was decreased in the tamoxifen treated groups. The higher dosage tamoxifen given group animals show significantly favourable results from therapy stand point when compared to diseased group.
Mol Cell Biochem 1997 Mar
PMID:Effect of tamoxifen on lipids and lipid metabolising marker enzymes in experimental atherosclerosis in Wistar rats. 906 89

The ligand-binding domain of low-density lipo-protein (LDL) is composed of seven 40-amino-acid repeats encoded by exons 2-6. Previous studies identified a missense mutation in codon 66 of exon 3, which resulted in the production of LDL receptor protein that is not processed to its mature form. In the current investigation, we documented the presence of two identical mutant LDL receptor alleles (Trp66-->Gly) in two familial hypercholesterolemia (FH) probands, II-1 and II-2, associated with markedly elevated plasma LDL cholesterol (17.22 +/- 0.78 and 11.95 +/- 0.24 mmol/liter, respectively). Functional assays of their fibroblast LDL receptor showed inefficient binding (39 and 50%), internalization (33 and 37%), and degradation (32 and 37%) compared with controls. The contribution of the apo B gene to variation in LDL levels was virtually eliminated given the normal ligand interaction with cell surface receptors and the absence of the mutation occurring in codon 3500 of the apo B gene. Similarly, the homozygous apo E3/E3 wildtype phenotype excluded any genetic contribution of apo E to the lipoprotein abnormalities. Furthermore, the LPL mutations commonly observed in French Canadians could not account for the observed lipid alterations. Several alterations in lipoprotein composition characterized VLDL, IDL, LDL, HDL2, and HDL3 fractions. Moreover, defective intestinal fat transport was observed in both probands (II-1 and II-2). Thus, the disturbance of lipoprotein concentration, composition, size, and metabolism may in part be related to the exon 3 mutation (Trp66-->Gly) of the LDL receptor gene. The biochemical phenotype was more severe in the father (I-1) than in the mother (I-2), and in the younger homozygous proband (II-1) than in the older (II-2). The greater severity was associated with a higher LDL cholesterol/HDL cholesterol ratio. Whether the differences between the two probands are due to polygenic factors or to a metabolic consequence of a major nonallelic trait is unknown. Nevertheless, the present biochemical findings stress the extent of the lipid abnormalities associated with homozygous FH and the importance of the phenotypic variability encountered even among subjects carrying the same mutation.
Biochem Mol Med 1997 Feb
PMID:Association of an exon 3 mutation (Trp66-->Gly) of the LDL receptor with variable expression of familial hypercholesterolemia in a French Canadian family. 906 82

11beta-hydroxysteroid dehydrogenase (11beta-HSD) catalyzes the interconversion of cortisol to hormonally inactive cortisone (corticosterone (B) to 11-dehydrocorticosterone (A) in rodents), and as such is established as a pre-receptor signalling pathway for corticosteroid hormone action. To further evaluate the role of this enzyme in adult and fetal life we have characterized two isoforms of 11beta-HSD in mouse tissues. Mouse 'liver' or type 1 11beta-HSD is a bi-directional dehydrogenase/oxo-reductase (K(m) for B 1.9 microM, K(m) for A 0.73 microM). Oxo-reductase activity utilized only NADPH as a co-factor, whilst dehydrogenase activity increased with both NAD or NADP. Mouse 'kidney' or 11beta-HS3D2 activity was NAD-dependent with a K(m) for B of 0.11 microM. Dexamethasone was not a substrate. Using an in-house mouse 11beta-HSD2 cDNA and NAD-dependent activity studies, 11 beta-HSD2 was expressed in epithelial cells of colon, renal collecting ducts, ovary, and adrenal, but was absent in liver, spleen, testis and heart. With the exception of gonadal tissues, activity and mRNA levels were consistently higher in adult male versus female tissues. In fetal kidney and colon there was absent/low levels of 11beta-HSD2 expression from fetal day 15 to term (day 19/20). Placental 11beta-HSD2 mRNA and activity were highest on fetal day 13/14 and fell progressively to undetectable levels by term. Two isoforms of 11beta-HSD are present in mouse tissues in accordance with other mammalian species. The sexual-dimorphic expression 11 beta-HSD2 in kidney and colon may reflect male-female differences in sodium homeostasis, and the absent expression of 11 beta-HSD2 in late gestation may facilitate glucocorticoid-dependent maturation of mouse fetal tissues.
Mol Cell Endocrinol 1997 Mar 28
PMID:Ontogeny and sexual dimorphic expression of mouse type 2 11beta-hydroxysteroid dehydrogenase. 909 7

In the baboon, the 11beta-hydroxysteroid dehydrogenase (11beta-HSD)-catalyzed metabolism of maternal cortisol and cortisone by the placenta is an important component in the sequence of events regulating the function of the fetal pituitary-adrenocortical axis. The present study was designed to isolate and sequence the promoter region of the baboon 11beta-HSD-1 gene. The 11beta-HSD-1 genomic DNA was isolated from a baboon kidney genomic library using a human 11beta-HSD-1 cDNA as a probe. The sequence of a 1.7 kb fragment of the 5'-flanking region showed extensive homology (> 95) to that published by others for human 11beta-HSD-1 particularly in exons I and II (> 95%) and in the proximal promoter ( > 98%). Using total RNA from adult baboon liver annealed with a 22 bp antisense primer located at the 3' end of Exon I, parallel genomic sequencing reactions with the same primer confirmed that the baboon 11beta-HSD-1 gene has two transcriptional start sites 93 nucleotides apart and that both start sites are preceded by a CAAT box but not a TATA box. RNase protection assays confirmed that both transcription start sites are utilized in liver and near term baboon placenta and that transcripts emanating from the downstream start site dominate in the placenta in contrast to the preferential utilization of the upstream start site in adult liver.
Mol Cell Endocrinol 1997 Mar 28
PMID:Cloning and expression of the 11beta-hydroxysteroid dehydrogenase type 1 gene in the baboon. 909 15

It has been suggested that the association between the development of hypertension and a combination of low birth weight and high placental weight can be explained by variations in expression of NAD+-dependent 11beta-hydroxysteroid dehydrogenase (11-HSD2 or 11-HSD K) in the placenta. Enzymatic activity and mRNA levels of 11-HSD2 were measured in 111 human placentas taken from normal births. There were no correlations between either 11-HSD2 activity or mRNA levels and either fetal or placental weight. These studies suggest that variations in placental 11-HSD activity do not influence fetal or placental weight in humans.
Mol Cell Endocrinol 1997 Apr 04
PMID:Variation in placental type 2 11beta-hydroxysteroid dehydrogenase activity is not related to birth weight or placental weight. 914 81

Long-term treatment (21 days) of male rats with corticosterone in the drinking water caused a significant increase in the activity of the NADP-dependent form of 11beta-hydroxysteroid dehydrogenase (11-HSD1) in the pituitary, thymus, and spleen, (marginally in the hippocampus, amygdala and lymph nodes), without having any effect in a number of other central and peripheral tissues. In contrast, repeated restraint stress, although increasing plasma corticosterone to the same level as that observed after its administration, failed to change the activity of this key regulatory enzyme, which allows aldosterone to exert its specific effects in the presence of a large excess of corticosterone. This resistance to elevation in 11-HSD activity was also observed in the thymuses of subordinate rats during social stratification in a visible burrow system. In both cases, the circulating levels of corticosterone were much higher in stressed rats than in control animals. Factors which might account for these differences in response are discussed and compared with the situation in intact cells where, unlike in tissue homogenates, the reduction of 11-dehydrocorticosterone to corticosterone (reductase activity) appears to predominate.
J Steroid Biochem Mol Biol 1997 Mar
PMID:Long-term corticosteroid treatment but not chronic stress affects 11beta-hydroxysteroid dehydrogenase type I activity in rat brain and peripheral tissues. 921 23

Estrogen protects against developing premature coronary artery disease. However, the mechanism of protective effects of estrogen still remains poorly understood. One mechanism by which estrogen can have protective effects appears to be through modulation of plasma lipoproteins. We showed that the mouse can be used as animal model to study estrogen-mediated synthesis and secretion of lipoproteins since, unlike the rat, the mouse does not up-regulate LDL receptors (Srivastava et al. [4]). Since inbred strains of mice differ in their genetic background and show differing responsiveness to dietary lipids, we examined how various inbred strains of mice respond to estradiol administration, and whether some mouse strains show responses similar to rats. 17beta-estradiol was administered to male mice from 15 different inbred strains, and the changes in plasma levels of lipids, apoB, apoAI, and apoE were examined. Total cholesterol decreased in all but one strain, apoAI levels decreased in all but 3 strains while apoB levels and apoB/apoAI ratios increased in all but 2 strains, suggesting that in contrast to rats, the apoB-containing lipoproteins increased relative to HDL in all strains of mice examined. Basal and estradiol-induced changes in total cholesterol were significantly correlated with changes in apoAI, but not apoB, reflecting the predominance of HDL over other lipoproteins in mouse plasma. The effects of estrogen on plasma apoE levels varied among various inbred strains of mice tested. Plasma apoE levels increased in seven strains treated with estrogen, and remained unchanged in the rest. To examine whether changes of plasma apoproteins are associated with the changes in the respective hepatic mRNA levels, apoAI, B and E mRNA were quantified by RNase protection assay. Hepatic apoE mRNA did not show correlation with either basal or post treatment plasma apoE levels in any of the strains. Similarly, most of the mouse strains did not show correlation of plasma apoAI and apoB levels with the corresponding hepatic mRNA levels. These results suggest that estrogen regulates plasma lipoprotein concentrations primarily by posttranscriptional mechanisms, and there were strain-related differences in the estrogen-mediated regulation of lipoprotein metabolism.
Mol Cell Biochem 1997 Aug
PMID:Regulation of lipoprotein metabolism by estrogen in inbred strains of mice occurs primarily by posttranscriptional mechanisms. 927 67


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