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PubMed1994

Local administration of 7 beta-hydroxycholesteryl-3-oleate inhibits growth of experimental rat C6 glioblastoma.

The effect of 7 beta-hydroxycholesteryl-3-oleate on rat brain C6 glioblastoma cells was studied. Three days after the inoculation of 2 x 10(5) C6 cells into the frontal cortex of 6-day-old Wistar rats, two types of liposomes [consisting of either phosphatidylcholine and monosialoganglioside (PG:GM1, 10:1 mol/mol) only, or containing 7 beta-hydroxycholesterol, 7 beta-hydroxycholesteryl-3-oleate, 7 alpha-hydroxycholesteryl-3-oleate, or 7-ketocholesteryl-3-oleate] were injected into the xenograft. Ten days later, the animals were sacrificed, the tumors were stained with cresyl violet or hematoxylin/eosin, their volumes determined by image analysis, and their development followed by magnetic resonance imaging. The mean (+/- SE) tumor volume was 4.4 +/- 1.0 mm3. The injection of liposomes without oxysterol had no effect on tumor growth, whereas injection of liposomes containing 7 beta-hydroxycholesteryl-3-oleate (36 nmol) gave rise to a marked decrease in tumor volume (from 4.4 +/- 1.0 to 0.7 +/- 0.4 mm3). Seven nmol had no effect on tumor growth, 72 nmol were as efficient as 36 nmol, and 144 nmol attenuated the tumor volume by 50% only. Liposomes containing 72 nmol of oleic acid enhanced the tumor volume 4-fold. These findings were confirmed by magnetic resonance imaging. Thus, following induction of tumors in both the right and left sides of the cortex and treatment of the right side, magnetic resonance imaging indicated a significant decrease in tumor volume on the right side only. When C6 cells and 7 beta-hydroxycholesteryl-3-oleate were simultaneously injected, tumors did not develop in 80% of the animals. The clearance of [3H]7 beta-hydroxycholesteryl-3-oleate, of which 75% was converted to cholesterol, reached 99% after 48 h. Other oxysterols did not affect the tumor volume except that 7-keto-cholesteryl-3-oleate decreased the tumor volume by 50%. Thus, the 3-fatty acyl ester and 7 beta-hydroxyl groups are apparently required for the antitumor growth effect. Taken together, these data suggest that 7 beta-hydroxycholesteryl-3-oleate might be useful for local glioblastoma chemotherapy.

Administration, Topical↗
PubMed1993

Tocotrienols regulate cholesterol production in mammalian cells by post-transcriptional suppression of 3-hydroxy-3-methylglutaryl-coenzyme A reductase.

Tocotrienols are natural farnesylated analogues of tocopherols which decrease hepatic cholesterol production and reduce plasma cholesterol levels in animals. For several cultured cell types, incubation with gamma-tocotrienol inhibited the rate of [14C]acetate but not [3H] mevalonate incorporation into cholesterol in a concentration- and time-dependent manner, with 50% inhibition at approximately 2 microM and maximum approximately 80% inhibition observed within 6 h in HepG2 cells. 3-Hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase total activity and protein levels assayed by Western blot were reduced concomitantly with the decrease in cholesterol synthesis. In HepG2 cells, gamma-tocotrienol suppressed reductase despite strong blockade by inhibitors at several steps in the pathway, suggesting that isoprenoid flux is not required for the regulatory effect. HMG-CoA reductase protein synthesis rate was moderately diminished (57% of control), while the degradation rate was increased 2.4-fold versus control (t1/2 declined from 3.73 to 1.59 h) as judged by [35S]methionine pulse-chase/immunoprecipitation analysis of HepG2 cells treated with 10 microM gamma-tocotrienol. Under these conditions, the decrease in reductase protein levels greatly exceeded the minor decrease in mRNA (23 versus 76% of control, respectively), and the low density lipoprotein receptor protein was augmented. In contrast, 25-hydroxycholesterol strongly cosuppressed HMG-CoA reductase protein and mRNA levels and the low density lipoprotein receptor protein. Thus, tocotrienols influence the mevalonate pathway in mammalian cells by post-transcriptional suppression of HMG-CoA reductase, and appear to specifically modulate the intracellular mechanism for controlled degradation of the reductase protein, an activity that mirrors the actions of the putative non-sterol isoprenoid regulators derived from mevalonate.

Acetates↗
PubMedDate not supplied

Effect of oxysterol derivatives on the time course development of hepatocarcinoma in transgenic mice.

Among their biological properties, several oxysterols display a stronger toxicity towards tumor cells than towards normal cells. Water-soluble phosphodiesters of 7 beta-hydroxycholesterol (JB69 and XA29), that were proved to retain a specific antitumoral activity in vitro, have been recently developed, allowing in vivo studies. They have been assayed on transgenic mice expressing the Large T antigen of SV40 in their liver and developing systematically hepatocarcinoma within 8 months. We show that JB69 and XA29 administered intraperitoneally into transgenic mice, before the onset of adenoma, may prevent or delay the tumor development. Consequently, oxysterol derivatives might constitute new efficient prodrugs against naturally occurring tumors.

Adenoma↗
PubMed1995

Identification and quantitation of cholest-5-ene-3 beta,4 beta-diol in rat liver and human plasma.

Cholest-5-ene-3 beta,4 beta-diol (4 beta-hydroxycholesterol) was identified in human plasma and rat liver by gas-liquid chromatography-mass spectrometry. An assay based on isotope dilution-mass spectrometry with a deuterium-labeled internal standard was developed for quantitation of this compound. The concentration of cholest-5-ene-3 beta,4 beta-diol in plasma from healthy subjects was 36 +/- 4.3 ng/ml (mean +/- SD, n = 8). The concentration in rat liver was 0.62 +/- 0.19 microgram/g wet weight (mean +/- SD, n = 6). These levels are of the same order of magnitude as other common oxysterols.

Adult↗
PubMed1996

Inhibition of acyl-CoA: cholesterol acyltransferase decreases apolipoprotein B-100-containing lipoprotein secretion from HepG2 cells.

There is evidence that the overproduction of apoB-100-containing lipoproteins by the liver is the underlying event in some forms of dyslipoproteinemia. This metabolic status is associated to an increased risk of developing premature coronary artery disease CAD. The conclusions from previous studies suggested that the availability to the hepatocytes of cholesterol that is readily esterified is an important determinant for VLDL and LDL secretion. In the present study, we set out to investigate the effect of the specific stimulation and inhibition of the rate-limiting enzyme of the cholesterol esterification, acyl-CoA:cholesterol acyltransferase (ACAT, E.C. 2.3.1.26), on the lipid and on the apoB-100 secretion rate from a human hepatoma cell line (HepG2). When the specific ACAT inhibitor FCE 27677 (10-5 M) was added to the cultures, a decrease of the cellular cholesteryl ester content and at the same time a significant reduction of the neutral lipids and of the apoB-100 secretion rate were noticed. The stimulation of ACAT by 25-hydroxycholesterol (20 microgram/ml) caused a 4-fold increase of the cellular cholesteryl ester content and a 2-fold increase of the lipoprotein secretion rate. FCE 27677 (10-5 M to 10-7 M) prevented the effects elicited by the oxysterol. On the contrary, lovastatin (10-6 M) and gemfibrozil (10-6 M) had no effect. The analysis of the lipid and of the apolipoprotein composition of the lipoproteins secreted in the medium revealed that ACAT inhibition had the dual effect of both decreasing the number of apoB-100-containing lipoproteins secreted as well as their cholesteryl ester load. Altogether, these data support the idea of a close relationship between ACAT activation, leading to increased cholesteryl ester availability, and apoB-100-containing lipoprotein secretion. It is speculated that ACAT inhibitors may prove useful for the treatment of human dyslipoproteinemias caused by the hepatic overproduction of apoB-100-containing lipoproteins.

Albumins↗
PubMed1996

Esterification of oxysterols in human serum: effects on distribution and cellular uptake.

Oxysterols, oxidized derivatives of cholesterol, may enter the circulation as contaminants of cholesterol-containing food, arise through peroxidation of lipoproteins, or be generated by enzymatic reactions. They are found in serum associated either with lipoproteins or with albumin. In these studies, 25-hydroxycholesterol (25OHC) was used as a model oxysterol to investigate the effect of esterification on the association of oxysterols with serum components and their delivery to cultured cells. 25OHC added in vitro to fresh human serum was readily esterified during incubation at 37 degrees C, most likely by serum lecithin:cholesterol acyltransferase (LCAT) as it was blocked by known inhibitors of LCAT. The 25OHC-esters formed were identified as monoesters by comparing their elution on high performance liquid chromatography and thin-layer chromatography with that of chemically synthesized 25OHC mono- and diesters. Esterification doubled the percentage of 25OHC associated with lipoproteins, concomitantly decreasing the amount associated with albumin. Whereas unesterified 25OHC readily transferred between isolated lipoproteins, 25OHC-esters remained associated with donor lipoproteins unless human lipoprotein-deficient serum was added. That cholesteryl ester transfer protein (CETP) mediated transfer of 25OHC-esters was demonstrated by the ineffectiveness of rat lipoprotein-deficient serum as well as by the ability of IC-4, an anti-CETP monoclonal antibody, to suppress the transfer. Esterification of 25OHC in serum limited its entry into human erythrocytes and fibroblasts (GM 3468A cells) in vitro. Up-regulation of fibroblast low density lipoprotein (LDL)-receptors enhanced the uptake of esterified 25OHC from medium, but did little to enhance the total uptake of 25OHC. Thus, esterification of oxysterols in serum shifts their distribution away from albumin into LDL and high density lipoprotein (HDL) and limits their availability to cells in culture.

Biological Transport↗
PubMed1996

Inhibitory effect of cholesterol oxides on low density lipoprotein receptor gene expression.

The effects of the cholesterol oxides on low density lipoprotein receptor (LDLR) gene expression were investigated. Cultured rabbit aortic smooth muscle cells were incubated with 1, 2, and 5 micrograms/ml culture medium concentrations of pure cholesterol, 25-hydroxycholesterol (25-OH), 7-ketocholesterol (7-keto), cholestane-3 beta, 5 alpha, 6 beta-triol (triol) and cholesterol-5 alpha, 6 alpha-epoxide (epoxide) for 12 hours and with vehicle only as control. Total mRNAs were extracted and electrophoresed. Northern blot hybridization analyses were performed. The results showed mRNA expressions of LDLR gene were inhibited to 16.1 +/- 4.4%, 33.8 +/- 0.6%, 42.8 +/- 1.8% and 46.9 +/- 3.9% of control by 25-OH, 7-keto, epoxide and triol respectively. Pure cholesterol showed only minimal inhibition. The inhibitions were time dependent. Although cholesterol oxides have been shown to alter many membrane-related functions and the LDLR domain are located in the cell membrane. The findings of this study suggested that the cholesterol oxides exerted their repressive actions on LDLR function primarily by down-regulating LDLR gene expression rather than directly upon cell membrane.

Animals↗
PubMedDate not supplied

[Hypocholesterolemic effect of hepatic microsomal enzymes in rats].

An inductor of microsomal enzymes 9-acetate-16alpha-isothiocyanogen pregnenolone (ATCP), administered into rats within 5 days after termination of feeding with an atherogenic diet, caused normalization of cholesterol content in blood, of beta-lipoproteins spectrum as well as the structure of liver cells. At the same time, in animals, which were not treated with ATCP, high level of cholesterol was maintained in blood serum; reducing smooth endoplasmic reticulum and a decrease in content of glycogen in hepatocytes were also observed. Enzymatic oxidation of cholesterol into 7alpha-hydroxycholesterol, distinctly stimulated by ATCP, appears to be the cause of increased elimination of cholesterol from the organism. ATCP might be used as a drug decreasing the content of cholesterol in blood of patients with hypercholesterolemia.

Animals↗
PubMed1997

Raman microspectroscopy of intracellular cholesterol crystals in cultured bovine coronary artery endothelial cells.

Raman microspectroscopy is presented as a promising technique for the in situ characterization of intracellular cholesterol crystals. Crystal characterization is the first step in investigating the effects of various stimuli on their formation and in determining their role in the development of atherosclerosis. Treatment of cultured bovine coronary artery endothelial cells with 22-hydroxycholesterol (220HC) stimulated the production of intracellular crystals, a phenomenon that did not occur in the absence of viable cells. These crystals were identified as a combination of the 220HC starting material and cholesterol. The best fit to the average Raman spectrum of the microscopic crystals was achieved with a combination of 70% Raman contribution from 220HC and 30% from cholesterol. GC/MS analysis of the crystals confirmed the presence of both compounds. These results demonstrate the potential of Raman microspectroscopy as a powerful tool in lipid research, particularly for the in situ characterization of intracellular crystals.

Animals↗
PubMed1997

[Elimination of cholesterol in human endothelial cells].

OBJECTIVE: To investigate what role the endothelial cell interfacing with blood components to play in cholesterol metabolism. METHODS: Isotopelabeling technique, Gas Chromatography/Mass Spectrometry and Western blotting were used to measure the presence of 27-oxygenated cholesterol in medium and the presence of sterol 27-hydroxylase in endothelium. RESULTS: When human endothelial cells were cultured in a medium containing fetal calf serum, there was a significant accumulation of 27-hydroxycholesterol and 3 beta-hydroxy-5-cholesteneic acid, products of cholesterol metabolism, in the medium. The rate of formation of these products almost increased linearly with time of cultivation. After addition of 100 micrograms of extraneous cholesterol to the medium, the accumulation of 27-hydroxy-cholesterol and 3 beta-hydroxy-5-cholesteneic acid increased significantly. Addition of more cholesterol did not further increase the formation of 27-hydroxy-cholesterol and caused a decrease in the formation of 3 beta-hydroxy-5 cholesteneic acid. The presence of sterol-27-hydroxylase in the endothelium was demonstrated by Western blotting. CONCLUSION: Cultured human endothelium from umbilical veins are able to convert exogenous cholesterol into 27-hydroxy-cholesterol and 3 beta-hydroxy-5-cholesteneic acid. Furthermore, the cells are able to transport these products from the cells into the medium.

Cells, Cultured↗
PubMed1998

Dietary oxysterols are incorporated in plasma triglyceride-rich lipoproteins, increase their susceptibility to oxidation and increase aortic cholesterol concentration of rabbits.

Early fatty streaks and advanced lesions are characterized by the deposition of cholesterol and cholesterol oxidation products (oxysterols). Oxysterols have been shown to be cytotoxic and pro-atherogenic compared to cholesterol and are found in cholesterol-rich processed foods. The consumption of dietary oxysterols may be significant in the onset and development of vascular disease. In order to study the short term effects of low levels of ingested dietary oxysterols on lipoprotein and aortic cholesterol and oxysterol levels, rabbits were fed either standard chow, chow supplemented with 1.0% oxidized cholesterol (containing 6% oxysterols), or 1.0% purified cholesterol (control). To determine the distribution and uptake of oxysterols after a 2-week dietary period, triglyceride-rich plasma lipoproteins, low density lipoproteins and aorta were analyzed by GC-MS. The concentration of 7beta-hydroxycholesterol was similar in all groups but the oxidized cholesterol-fed animals showed five times the concentration of 5alpha,6alpha-epoxycholesterol and double the level of 7-ketocholesterol in triglyceride-rich lipoproteins compared to the purified cholesterol-fed animals. The presence of 7-ketocholesterol in LDL was exclusive to animals fed the oxidized cholesterol diet. In addition, oxidation of triglyceride-rich lipoproteins was significantly greater in rabbits fed oxidized cholesterol compared to the pure cholesterol-fed animals. The oxidized cholesterol-fed animals also had a 64% increase in total aortic cholesterol, despite lower plasma cholesterol levels compared to the pure cholesterol control animals. Taken together these results suggest that dietary oxysterols may substantially increase the atherogenicity of lipoproteins.

Animals↗
PubMed1998

Inhibition of p42/p44 mitogen-activated protein kinase by oxysterols in rat astrocyte primary cultures and C6 glioma cell lines.

We previously demonstrated that oxysterols inhibit the growth of experimental glioblastoma induced in the rat brain cortex. Mechanism of action of these compounds remains obscure. In this study, we investigated the effect of 7beta-hydroxycholesterol (7beta-OHCH) and 7ketocholesterol (7k-CH) on the growth and MAP kinase activity in three in vitro biological models: rat astrocyte primary cultures, primary cultures treated by dibutyryl-cAMP (reactive cells), and the C6 glioma cell line. The oxysterols are not lethal to primary astrocytes, even if MAP kinase activity is decreased, particularly when cells were treated with 7k-CH. Both oxysterols are toxic to reactive astrocytes, and as compared with untreated primary cultures, they amplified the MAP kinase activity decrease. However, the mechanism of action of oxysterols on reactive astrocytes seems not to be linked to the MAP kinase pathway. In highly proliferating C6 cell lines, only 7beta-OHCH has an antiproliferative effect and is cytotoxic. The inhibition of MAP kinase activity is a function of 7beta-OHCH concentration. PD098059, a MAP kinase pathway inhibitor, has only a time-limited antiproliferative effect on C6 cell growth. We conclude that in C6 cells, the MAP kinase activity decrease is correlated with the toxic effect of 7beta-OHCH and occurs at first stages of 7beta-OHCH action.

Animals↗
PubMed1999

Spermatogonia of rainbow trout: II. in vitro study of the influence of pituitary hormones, growth factors and steroids on mitotic activity.

At the present time, in spite of recent advances, knowledge about the factors regulating germ cell proliferation in the teleost testis is limited. This study was designed to investigate, in vitro, the ability of various hormones, growth factors, and steroids to influence the proliferation of trout spermatogonia (Go) present in mixed cultures of somatic and germ cells prepared from testes, either prespermatogenetic or spermatogenetic. The tested molecules were usually present for the duration of culture (4.5 days) and 3H-thymidine (3H-Tdr) for the last day in culture. In our cell culture conditions, homologous gonadotropin I (tGTH-I) and growth hormone (tGH) moderately stimulated 3H-Tdr incorporation by Go, with ED50 equal to 5.5 +/- 3.0 and 1.8 +/- 0.4 ng/ml respectively. Insulin growth factor I (rhIGF-I) and fibroblast growth factor (rhFGF-2) stimulated 3H-Tdr incorporation by Go from spermatogenetic testes only, with ED50 equal to 16.2 +/- 9.3 and 2.4 +/- 0.3 ng/ml respectively. The effects of the most efficient concentrations of rhIGF-I combined with those of either tGTH-I or tGH were additive. Seventy to one hundred microM suramin stimulated 3H-Tdr incorporation by Go from testes at all maturation stages and this effect was additive with that of tGTH-I. We assume that this effect of suramin could result from the inhibition of an unidentified antimitogenic factor. No effect was observed with homologous prolactin, human epidermal growth factor, activin A and B, transforming growth factor-beta1, testosterone, 11-ketotestosterone, 17beta-estradiol, pregnenolone, 11beta-hydroxyprogesterone, and 22-hydroxycholesterol. In conclusion, our in vitro results suggest that GTH-I, GH, IGF-I, and FGF-2, are potent in situ modulators of the proliferative activity of trout Go at the time of induction, speeding up, then slowing down spermatogenesis, through direct or indirect additive and/or antagonistic influences.

Animals↗
PubMed2002

Treatment with simvastatin in normocholesterolemic patients with Alzheimer's disease: A 26-week randomized, placebo-controlled, double-blind trial.

In a randomized, placebo-controlled, double-blind study, we investigated whether statins alter cholesterol metabolites and reduce Abeta levels in the cerebrospinal fluid of 44 patients with Alzheimer's disease. Individuals were given up to 80mg simvastatin daily or placebo for 26 weeks. Overall, simvastatin did not significantly alter cerebrospinal fluid levels of Abeta40 and Abeta42. In post hoc analysis, simvastatin significantly decreased Abeta40 levels in the cerebrospinal fluid of patients with mild Alzheimer's disease. The reduction of Abeta40 correlated with the reduction of 24S-hydroxycholesterol. These changes were not observed in more severely affected patients.

Aged↗
PubMed2005

Methodology for multi-site ligand-protein docking identification developed for the optimization of spirostenol inhibition of beta-amyloid-induced neurotoxicity.

Spirostenol steroids have been found to inhibit beta-amyloid-induced neurotoxicity. We have evaluated in parallel experimental and molecular-modeling studies the relative effectiveness of 17 (22R)-hydroxycholesterol derivatives in binding to the target peptide. Our results support the previous evidence that beta-amyloid offers multiple docking sites for these steroids. Molecular modeling allowed for the correlation of spirostenol candidate structural differences with a choice of proposed active sites. A multi-site identification technique based on a Site-Identifier Matrix (SIM) was developed that clearly showed the uniqueness of our lead (maximum neurotoxicity inhibition) candidate SP233, with a nearly equal docking affinity for two sites.

Amyloid beta-Peptides↗
PubMedDate not supplied

Accumulation of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one in patients with cerebrotendinous xanthomatosis: effect of treatment with chenodeoxycholic acid.

Evidence was recently presented that an essential part of the accumulation of cholestanol in patients with cerebrotendinous xanthomatosis is due to acceleration of a novel pathway, involving 7 alpha-hydroxylated intermediates in bile acid biosynthesis as precursors (J. Clin. Invest. 1985; 75:448-456). Such intermediates accumulate in patients with cerebrotendinous xanthomatosis due to lack of the mitochondrial 26-hydroxylase involved in the major pathway for bile acid biosynthesis. The new pathway may involve the following steps: 7 alpha-hydroxycholesterol----7 alpha-hydroxy-4-cholesten-3-one----cholesta-4,6- dien-3-one----4-cholesten-3-one----cholestanol. Accurate methods have been developed for assay of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one in serum, based on isotope dilution-mass spectrometry. The serum levels of 7 alpha-hydroxy-4-cholesten-3-one as well as those of cholesta-4,6-dien-3-one were found to be markedly elevated in the three patients with cerebrotendinous xanthomatosis. Treatment of two of the patients with chenodeoxycholic acid reduced the serum levels of the two steroids by more than 80%. The concentration of cholestanol was reduced by 72% in one patient and by 48% in the other. The possibility is discussed that accumulation of cholestanol in patients with cerebrotendinous xanthomatosis is secondary to accumulation of 7 alpha-hydroxy-4-cholesten-3-one and cholesta-4,6-dien-3-one.

Brain Diseases↗
PubMed1991

Angiotoxicity and atherogenicity of cholesterol oxides.

Cholesterol in the diet can readily autoxidize and be absorbed and transported in plasma lipoproteins. Cholesterol oxides can also be endogenously produced in tissues via free-radical-induced reactions. Some cholesterol oxides, notably cholestane-3 beta, 5 alpha, 6 beta-triol and 25-hydroxycholesterol, have been shown to cause injury to vascular endothelial and smooth muscle cells, to alter LDL receptor function, to enhance cholesteryl ester accumulation, to inhibit prostacyclin production, and to induce experimental atherosclerosis alone or in combination with cholesterol. An epidemiological study examining relationships between atherosclerosis and plasma levels of cholesterol oxides as independent risk factors may provide additional insights regarding the roles of cholesterol oxides in atherogenesis.

Animals↗
PubMed1975

Regulation of sterol synthesis in cultured cells by oxygenated derivatives of cholesterol.

Sterol synthesis in liver in vivo is regulated at the site of the reaction catalyzed by 3-hydroxy-3-methylglutaryl-CoA reductase through a feedback system thought to involve either cholesterol or one or more of the products of its metabolism. Cholesterol feeding results in repression of the synthesis of the enzyme, but inactivation of the enzyme seems to precede repressroblasts is not inhibited by purified exogenous cholesterol. However, derivatives of cholesterol produced by the introduction of a ketone or hydroxyl function in the 7, 20, 22 or 25 positions effectively inhibit sterol synthesis by specifically depressing the level of HMG CoA reductase activity. As a result of this specific effect prolonged incubation of an inhibitory sterol with growing L cells results in depletion of cellular sterol. Growth of the culture then ceases and the cells die unless an appropriate sterol or a sterol precursor is supplied in the medium. The inhibitory sterols, 25-hydroxycholesterol and 7-ketocholesterol appear to be taken up by L cells through processes that involve their specific interactions with saturable cellular receptors. The uptake of cholesterol by L cells appears to be by a different process--possibly through physical diffusion.

Animals↗