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At least 199 records · Page 11Linked to original sources
PubMed1987

Differentiation of human keratinocytes: changes in lipid synthesis, plasma membrane lipid composition, and 125I-EGF binding upon administration of 25-hydroxycholesterol and mevinolin.

We have studied the relationship between differentiation capacity, plasma membrane composition, and epidermal growth factor (EGF) receptor expression of normal keratinocytes in vitro. The plasma membrane composition of the cells was modulated experimentally by cholesterol depletion, using specific inhibitors of cholesterol synthesis, such as 25-hydroxycholesterol and mevinolin. Exposure of the cells towards these inhibitors resulted in a drastic decrease of cholesterol biosynthesis, as determined from 14C-acetate incorporation into the various lipid fractions. This effect on cholesterol biosynthesis was reflected by changes in plasma membrane composition, as determined by lipid analysis of isolated plasma membrane fractions, these resulting in a decreased cholesterol-phospholipid ratio. The experimental modulation of plasma membrane composition by 25-hydroxycholesterol or mevinolin were accompanied by a decreased cornified envelope formation and by high expression of EGF binding sites. These phenomena were more pronounced in cells induced to differentiate by exposure of cells grown under low Ca2+ to normal Ca2+ concentrations, as compared to cells grown persistently under low Ca2+ concentrations. These results suggest a close correlation between plasma membrane composition, differentiation capacity, and EGF receptor expression.

Anticholesteremic Agents↗
PubMed1988

25-Hydroxycholesterol promotes myelin basic protein-induced leakage of phospholipid vesicles.

Among several cholesterol oxidation products, 25-hydroxycholesterol is particularly potent in enhancing basic protein-induced carboxyfluorescence leakage from liposomes. Both myelin basic protein and poly(L-arginine) are effective at submicromolar concentrations in stimulating this vesicle rupture. Leakage is greatly augmented by the presence of only 1% of the 25-hydroxycholesterol. The possible relevance of these findings to myelin pathology is discussed.

Cholesterol↗
PubMed1980

Studies on the mechanisms of the rapid modulation of 3-hydroxy-3-methylglutaryl coenzyme A reductase in intact liver by mevalonolactone and 25-hydroxycholesterol.

A rapid, biphasic inhibition of rat hepatic 3-hydroxy-3-methylglutaryl coenzyme A reductase (mevalonate:NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34) was induced by intragastric administration of R,S-mevalonolactone. The initial phase had a t1/2 of 5.3 min. 30 min after drug administration the inhibition could be reversed in vitro by cytosol or a partially purified cytosolic activator. The reactivation was prevented by 50mM NaF. Thus the initial inhibition appeared to be the result of reversible inactivation possibly by phosphorylation of the enzyme. Consistent with this was the finding that the net reductase activator (phosphatase) activity present in cytosol was decreased 64% in these animals. The rapid reversible inhibition could not be reproduced in vitro by incubating microsomes or postmitochondrial supernatants with mevalonate suggesting the intact cell was necessary for expression of the effect. The second phase of inhibition due to mevalonate administration had a t1/2 of 1.3 h and was not reversible. It was attributed to inhibition of synthesis of reductase probably as the result of sterol accumulation in the cell. Perfusion of 25-hydroxycholesterol through livers isolated from animals at the circadian peak of cholesterol biosynthesis resulted in a rapid, 75-80% inhibition of 3-hydroxy-3-methylglutaryl coenzyme A reductase. This inhibition was not reversed by incubation with cytosol or partially purified activator. Further, there was no apparent change in net activator levels in cytosol from the livers perfused with 25-hydroxycholesterol. This suggests the effect of this sterol on reductase does not involve reversible phosphorylation-dephosphorylation. On the basis of this study it is postulated that there are at least two mechanisms by which 3-hydroxy-3-methylglutaryl coenzyme A reductase activity can be rapidly suppressed in the intact liver. One is reversible and appears to be the result of alteration in the reductase kinase-phosphatase system. The second is irreversible and may be due to acceleration of the normal degradation system.

Animals↗
PubMed1984

Rapid synthesis of 26-hydroxycholesterol from mevalonic acid in the Syrian hamster.

Using isotope-ratio mass spectrometry, newly synthesized 26-hydroxycholesterol and its derivative, 3 beta-hydroxy-5-cholenoic acid, were detected in the liver and bile of animals within 2 h following intravenous administration of [5-13C]mevalonic acid. The findings indicate that 26-hydroxycholesterol merits further consideration as an in vivo modulator of HMG-CoA reductase activity.

Animals↗
PubMed1994

Ketoconazole and 25-hydroxycholesterol produce reciprocal changes in the rate of transcription of the human LDL receptor gene.

Sterol-dependent regulation of low-density lipoprotein (LDL) receptor gene expression was studied in the human hepatoma HepG2 cell line. Incubation of HepG2 cells with 20 microM ketoconazole increased the level of LDL receptor mRNA. After a lag of approx. 1.0 h the level rose 6.5-fold within 8.0 h and remained elevated for up to 24 h. Incubation with 10 micrograms 25-hydroxycholesterol/ml for 24 h produced a 40-50% reduction in the level of LDL receptor mRNA. Ketoconazole- and 25-hydroxycholesterol-induced changes in LDL receptor mRNA accumulation were due to alterations in the relative rate of LDL receptor gene transcription as measured by nuclear run-on transcription. Incubation with 20 microM ketoconazole for 4 h or 10 micrograms 25-hydroxycholesterol/ml for 24 h produced a 3.6-fold increase and a 40% reduction, respectively, in the transcription rate of LDL receptor gene. Removal of the Alu-like sequence elements within the LDL receptor cDNA was required to consistently measure changes in LDL receptor gene transcription. No significant changes were noted in the half-life of LDL receptor mRNA in ketoconazole or 25-hydroxycholesterol-treated cells. These data demonstrate that sterol-dependent changes in the level of LDL receptor mRNA can be completely accounted for by changes in the rate of LDL receptor gene transcription.

Base Sequence↗
PubMed1989

Evidence for the formation of 26-hydroxycholesterol by cytochrome P-450 in pig kidney mitochondria.

Pig kidney mitochondria were found to catalyze the formation of 26-hydroxycholesterol, an inhibitor of cholesterol biosynthesis. The cholesterol 26-hydroxylase was purified 600-fold. It was present in a mitochondrial enzyme fraction enriched in cytochrome P-450. The cytochrome P-450 fraction required NADPH, mitochondrial ferredoxin and ferredoxin reductase for 26-hydroxylase activity. The mitochondria and the purified 26-hydroxylase preparation also catalyzed 26-hydroxylation of 5 beta-cholestane-3 alpha, 7 alpha, 12 alpha-triol, and intermediate in cholic acid biosynthesis, and of 25-hydroxyvitamin D3. The role of extra-hepatic formation of 26-hydroxycholesterol is discussed.

Animals↗
PubMed1983

Suppression of endocytosis in polyclonally activated Con A-stimulated T lymphocytes by 25-hydroxycholesterol.

Endocytosis in polyclonally activated, Con A-stimulated spleen cell cultures was analyzed. It was found that as lymphocytes differentiate to acquire cytotoxic capability their endocytic activity also increases, reaching a plateau at 48 hr. Inhibition of sterol synthesis reduced endocytic rates by as much as 50% when 25-hydroxycholesterol was added during the first 24 hr of culture, the time at which sterol synthesis is at its maximum. When 25-hydroxycholesterol was added after the cycle of sterol synthesis, little or no suppression of endocytosis was seen. Compactin, which is an allosteric, competitive inhibitor of HMG-CoA reductase (the rate-limiting enzyme in the sterol biosynthetic pathway), produced a similar abrogation of endocytic rate. The effect of inhibition of sterol synthesis on endocytosis can be counteracted by the addition of cholesterol to the cultures. It is hypothesized that the dynamic process of endocytosis plays a role in the reorganization of membrane components necessary for the expression of the differentiated state of cytotoxicity.

Animals↗
PubMed1987

Regulation of low density lipoprotein metabolism by 26-hydroxycholesterol in human fibroblasts.

Oxygenated derivatives of cholesterol are believed to play a role in cellular cholesterol homeostasis through the feed-back control of its biosynthesis. We report that 26-hydroxycholesterol inhibits the specific binding, uptake and degradation of 125I-LDL in human fibroblasts. The effect is dose-dependent, and saturation kinetics indicates a reduction of LDL-binding sites with no effect on ligand affinity. The results support a possible role of 26-hydroxycholesterol, a physiological oxysterol, in the regulation of cellular cholesterol homeostasis.

Cells, Cultured↗
PubMed1983

The synthesis and metabolism of [6-3H]-25-hydroxycholesterol in rat adrenal tumor cells.

The synthesis of [6-3H]-25-hydroxycholesterol from 26-norcholest-5-en-3 beta-ol-25-one is described. The metabolism of the radiolabeled hydroxysterol in rat adrenocortical carcinoma cells and in mitochondria-enriched preparations of rat adrenal tissue was investigated. We found that [6-3H]-25-hydroxycholesterol was metabolized efficiently to [3H]-pregnenolone in both preparations of rat adrenal tissue.

Adrenal Cortex Neoplasms↗
PubMed1984

Identification of 24-hydroxycholesterol in bovine adrenals in both free and esterified forms and in bovine brains as its sulfate ester.

24-Hydroxycholesterol was found to be present in bovine adrenals in a concentration of 2-3 micrograms/kg and in larger amounts (10-12 micrograms/kg) as a saponifiable ester. No solvolyzable sulfate ester was detected. In bovine brains, however, the sulfate ester of this sterol was found in a concentration of 84 micrograms/kg. A procedure for the synthesis of [7-3H] 24S-hydroxycholesterol is described.

Adrenal Glands↗
PubMed1992

7 beta-hydroxycholesterol and 7 beta-hydroxycholesteryl-3-esters reduce the extent of reactive gliosis caused by an electrolytic lesion in rat brain.

Electrolytic lesions performed in brain cortex of six-day-old or adult rats resulted in the appearance of many reactive astrocytes around the injury site after a postoperative delay of eight days. They were revealed by immunohistochemistry using antibodies against glial fibrillary acidic protein. Injection of tritiated thymidine 24 h prior to autopsy indicated that, in neonates, 50% of the reactive astrocytes were proliferating. Infusion of 2 microliters of liposome suspension made of phosphatidylcholine and a monosialoganglioside, in the injury site, immediately after the electrolytic lesion did not modify the extent of the reactive gliosis. Liposomes containing 3 nmol of either 7 beta-hydroxycholesterol, 7 beta-hydroxycholesteryl-3-stearate or 7 beta-hydroxycholesteryl-3-oleate reduced by about 50% the intensity of the reactive gliosis in the frontal cortex of six-day-old rats and by 40% the number of dividing astrocytes. In the adult rat cortex the intensity of the glial reaction was also decreased by 30% by 15 nmol 7 beta-hydroxycholesteryl-3-oleate. Further investigations demonstrated that it is the 7 beta-hydroxy function which is needed for the biological activity of these oxysterols. These findings, which demonstrate anti-proliferative and anti-inflammatory properties of 7 beta-hydroxycholesterol on astrocytes, facilitate the future investigation of the influence of reactive gliosis on functional recovery following brain injury. This anti-proliferative property could also be used in other kinds of pathologies involving glial cell proliferation, such as glioblastomas.

Animals↗
PubMed1993

Differences in 27-hydroxycholesterol concentrations in plasma and liver of baboons with high and low responses to dietary cholesterol and fat.

Selective breeding has produced baboon progeny that have low or high response in plasma low-density lipoprotein (LDL) cholesterol when fed a high cholesterol and high fat (HCHF) diet. We examined differences in bile acid metabolism between low and high responding baboons by measuring the most abundant oxysterol in plasma and liver. Low responding baboons had higher concentrations of plasma and liver 27-hydroxycholesterol than high responding baboons on the HCHF diet but not on the chow diet. The increased hepatic 27-hydroxycholesterol in low responders was associated with an increase in sterol 27-hydroxylase activity as compared to high responders. These studies suggest that the hepatic sterol 27-hydroxylase is induced by dietary cholesterol and this induction is much higher in low responding baboons.

Animals↗
PubMed1997

Induction of apoptosis and of interleukin-1beta secretion by 7beta-hydroxycholesterol and 7-ketocholesterol: partial inhibition by Bcl-2 overexpression.

The oxysterols, 7beta-hydroxycholesterol and 7-ketocholesterol, are involved in the cytotoxicity of oxidized LDL. To elucidate their molecular mechanisms, the human promonocytic leukemia cells U937 and U4 were used. U4 cells overexpressing Bcl-2 were obtained by transfection of U937 cells. 7Beta-hydroxycholesterol and 7-ketocholesterol induced nuclear condensation and/or fragmentation, internucleosomal DNA fragmentation, and IL-1beta secretion, which were partially inhibited by Bcl-2 overexpression. These findings underline that these oxysterols could constitute major risk factors in atherosclerosis by their cytotoxicity and their ability to induce IL-1beta release which might favor the recruitment of immunocompetent cells in the atherosclerotic plaque.

Apoptosis↗
PubMed2001

25-hydroxycholesterol induces lipopolysaccharide-tolerance and decreases a lipopolysaccharide-induced TNF-alpha secretion in macrophages.

Several different oxysterols are formed when LDL is oxidized. The role of oxysterols in the inflammatory process in the atherosclerotic plaque is not totally elucidated. In this study we have investigated the effect of four different oxysterols on an LPS-induced TNF-alpha secretion in human macrophages. Cultured human macrophages were incubated with 7-keto-, 7beta-hydroxy-, 27-hydroxy- and 25-hydroxycholesterol for 24 h before exposure to endotoxin (LPS) for 3 h. All oxysterols, except 7-ketocholesterol, significantly decreased an LPS-induced TNF-alpha secretion. The most pronounced effect was obtained with 25-hydroxycholesterol, where the TNF-alpha secretion was reduced to 8%. This decreased effect was also found on the TNF-alpha mRNA level. The decreased LPS-induced TNF-alpha secretion coincided with an increased binding of the transcription factors Sp1 and Sp3 to the TNF-alpha promoter. In vitro studies of the TNF-alpha promoter suggests possible interactions between Sp1 and Sp3 and the NF-kappaB transcription factor complex that might affect the transcriptional initiation.

Carotid Artery Diseases↗
PubMed2000

Oxysterols: 27-hydroxycholesterol and its radiolabeled analog.

We describe a convenient and stereoselective route to the synthesis of 27-hydroxycholesterol. Also its radiolabeled analog, 22, 23 di [(3)H]-27-hydroxycholesterol with high specific radioactivity (55 Ci/mmol) was synthesized by this method. Julia condensation of steroidal 22-sulfone with aldehyde, led to the addition of the 23-27 carbon side chain building block to the steroid backbone. Formed in this reaction beta-hydroxysulfone moiety was reduced by sodium amalgam generate 22-23 unsaturated bond. Further reduction either by hydrogen or tritium furnished substrates for the synthesis of title compounds.

Chromatography, High Pressure Liquid↗
PubMed2003

Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients.

The serum concentration of 24S-hydroxycholesterol reflecting brain cholesterol turnover may be a possible marker for neurodegeneration and demyelination in multiple sclerosis. Serum was analyzed for cholesterol precursors and oxysterols in multiple sclerosis patients of different clinical subtypes (n=20 each subtype) and in 37 healthy controls. Serum 24S-hydroxycholesterol levels were lower in primary progressive and in older relapsing remitting multiple sclerosis patients. Furthermore, serum levels of lathosterol were decreased in all clinical subtypes. The results are important given recent interest in statin treatment in multiple sclerosis, which will further decrease the cholesterol precursor and oxysterol levels. The decreased levels of brain specific and peripheral sterols indicate a role for cholesterol homeostasis in relation to the pathology of multiple sclerosis, at least in the primary progressive clinical subtype.

Adult↗
PubMed2003

The detection of 20S-hydroxycholesterol in extracts of rat brains and human placenta by a gas chromatograph/mass spectrometry technique.

The presence of 20(S)-hydroxycholesterol in rat brains and human placenta has been established using the gas chromatography/mass spectrometry (GC/MS) select ion monitoring (SIM) technique. Identification was ensured by three criteria: the specific retention time when the compound emerges from the gas chromatogram and the two m/z ions (201 and 461amu) which are characteristic of its mass spectrum. The possible role of 20(S)-hydroxycholesterol in steroid hormone biosynthesis and in other biological processes is discussed.

Animals↗