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PubMed1997

Effect of 27-hydroxycholesterol on cellular sphingomyelin synthesis and Ca++ content in cultured smooth muscle cells.

The relationships among sphingomyelin synthesis cytosolic free Ca++ level and cytotoxicity in the presence of 27-hydroxycholesterol were investigated by measurement of [methyl-3H] choline incorporation into sphingomyelin, phosphatidylcholine, phosphocholine and cytidine choline 5'-diphosphate, 45Ca++ uptake, cytosolic free Ca++ levels and viable cell numbers. The results indicated that 27-hydroxycholesterol at higher than normal level induced increased [3H] choline incorporation in sphingomyelin accompanied by decreased radioactivity in phosphatidylcholine but did not alter [3H] choline content in phosphocholine and cytidine choline 5'-diphosphate. The increased radioactivity in sphingomyelin by 27-hydroxycholesterol was detected first, followed by detection of the enhanced Ca++ uptake and cytosolic free Ca++. Finally, a decrease in viable cell number occurred. We suggest that the increased transfer from phosphatidylcholine to sphingomyelin by 27-hydroxycholesterol may be related to enhanced cytosolic free Ca++.

Calcium↗
PubMed1996

Endogenous 7-oxocholesterol is an enzymatic product: characterization of 7 alpha-hydroxycholesterol dehydrogenase activity of hamster liver microsomes.

Previously, we described a new metabolite derived from endogenous cholesterol in the presence of hamster liver microsomal protein and NADPH (Song et al., 1991, Biochem. Pharmacol. 41, 1439-1447). Through gas chromatography/mass spectral analysis of the metabolite and its methoxime-3-dimethyl-t-butylsilyl ether derivative, this metabolite has been definitively identified as 7-oxocholesterol. Isotope incorporation experiments using molecular 18O2 demonstrated that no oxygen atoms from molecular oxygen were incorporated into the product, 7-oxocholesterol, when 7 alpha-hydroxycholesterol was used as substrate. In contrast, one atom of 18O was incorporated into cholesterol from 18O2 during its metabolism to form 7 alpha-hydroxycholesterol. Formation of 7-oxocholesterol was dependent upon the presence of NADP+, 7 alpha-hydroxycholesterol, and hamster liver microsomes. This enzyme appears to be a membrane-bound protein and its activity was most abundant in liver microsomal fractions and to a lesser extent in mitochondrial fractions; little or no activity was observed in nuclei or cytosol. The enzyme activity was present in highest content in the livers of hamsters and was also observed in human and bovine liver microsomes, but not those of mouse, rabbit, or rat. The reaction was inhibited by 2'-AMP, but not by anti-NADPH:cytochrome-P450 oxidoreductase globulin, carbon monoxide, metyrapone, nor miconazole. In contrast to the previously characterized 3 beta-hydroxy-delta 5-C27-steroid oxidoreductase activity, NAD+ did not serve as an effective cofactor for 7-oxocholesterol formation. The ability of NADPH to partially serve as a cofactor in this reaction was shown to be due to a high NADPH-oxidase activity of hamster liver microsomes, thereby providing sufficient NADP+ to serve as the oxidizing pyridine nucleotide for the reaction. These results document the existence of a non-P450, NADP(+)-dependent 7 alpha-hydroxycholesterol dehydrogenase in liver microsomes which catalyzes this reaction. The product, 7-oxocholesterol, is produced enzymatically in the livers of hamsters and other mammals and may regulate bile acid metabolism or other processes due to its action as an oxysterol.

Animals↗
PubMed1986

Effects of 25-hydroxycholesterol, cholesterol, and isoprenoid derivatives on the G1 progression in Swiss 3T3 cells.

The effect of inhibition of 3-Hydroxy-3-methylglutaryl Coenzyme A reductase (HMG CoA reductase) on cell cycle progression in proliferating 3T3 cells was studied. It was found that short transient exposures to the HMG CoA reductase inhibitor 25-hydroxycholesterol temporarily blocked the cell cycle traverse in the postmitotic half of G1 (G1pm), whereas cells in the subsequent cell cycle phases were unaffected. The kinetics of the cell cycle delay, induced by 25-hydroxycholesterol, resembled the kinetics of the delay induced by serum depletion, which also inhibited the activity of HMG CoA reductase. In contrast to the case of serum depletion, platelet derived growth factor (PDGF), which efficiently prevented the decrease of HMG CoA reductase in serum-free medium, was not capable of preventing the growth inhibitory effect following treatment by 25-hydroxycholesterol. However, cholesterol and two isoprenoids, dolichol and coenzyme Q, were effective in this respect. In addition, dolichol counteracted the cell cycle delay following short periods of serum starvation.

Cell Cycle↗
PubMed2005

High preoperative recipient plasma 7beta-hydroxycholesterol is associated with initial poor graft function after liver transplantation.

Oxidative stress is implicated in the pathogenesis of hepatic ischemia-reperfusion injury, a major determinant of initial poor graft function (IPGF) after orthotopic liver transplantation (OLT). We prospectively investigated the association between the recipient plasma preoperative oxidative stress and the occurrence of IPGF after deceased-donor OLT and indirectly studied the source-hepatic or extra-hepatic-of systemic oxidative stress in vivo in cirrhosis. We used a recently developed specific and sensitive mass spectrometry assay to measure 7beta-hydroxycholesterol and 7-ketocholesterol (oxysterols), markers of oxidative stress, in biological matrices. At univariate analysis, preoperative recipient 7beta-hydroxycholesterol plasma concentration was significantly higher in transplants with subsequent IPGF (n = 9) compared with those with initial good graft function (IGGF; n = 23) [mean +/- SD: 30.63 +/- 26.42 and 11.57 +/- 15.76 ng/mL, respectively] (P = 0.017). In a logistic regression model, which included also the Model for End-Stage Liver Disease (MELD) score, 7beta-hydroxycholesterol plasma concentration was an independent predictor of IPGF with an odds ratio of 1.17 (95% CI, 1.02-1.33, P = 0.028). Patients with cirrhosis (n = 32) had increased oxysterol plasma levels compared with healthy controls (n = 49); livers with cirrhosis (n = 21), however, had oxysterol content comparable with normal livers obtained from organ donors (n = 19). Oxysterols persisted elevated in plasma 1 month after OLT (n = 23). In conclusion, cirrhosis presents upregulated systemic oxidative stress likely of extrahepatic source that is associated with graft failure after OLT.

Biomarkers↗
PubMed1988

Effects of cholesterol and 25-hydroxycholesterol on smooth muscle cell and endothelial cell growth.

Auto-oxidation products of cholesterol may play a role in atherogenesis. In order to determine whether cholesterol or 25-hydroxycholesterol, a cholesterol auto-oxidation product, affected growth of vessel wall cells, sparse and confluent cultures of rabbit thoracic aorta smooth muscle cells and human umbilical vein endothelial cells were exposed to these compounds for 88 hr. The compounds were administered at 10(-4), 10(-5), 10(-6) or 10(-7) M in either ethanol or fetal bovine serum (FBS) vehicle. Cells were counted electronically, and the results were expressed as the percent growth in experimental vs control wells. Cholesterol did not inhibit cell growth under any experimental condition. 25-Hydroxycholesterol had the following effects: inhibited confluent smooth muscle cell growth at 10(-4) M in ethanol vehicle only; inhibited sparse smooth muscle cell growth in a dose-related manner at 10(-4), 10(-5) and 10(-6) M in ethanol vehicle, but in FBS vehicle inhibited at only 10(-4) and 10(-5) M; inhibited confluent human umbilical vein endothelial cells at 10(-4) M in ethanol vehicle only; and inhibited sparse human umbilical vein endothelial cell growth at 10(-4) and 10(-5) M in ethanol vehicle only. Thus, rabbit aortic smooth muscle cell growth was more sensitive to inhibition by 25-hydroxycholesterol than human umbilical vein endothelial cell growth was.

Animals↗
PubMed2001

Neurotoxicity of 24-hydroxycholesterol, an important cholesterol elimination product of the brain, may be prevented by vitamin E and estradiol-17beta.

24-Hydroxycholesterol, the main cholesterol elimination product of the brain is increased in serum of Alzheimer patients. This oxysterol behaves neurotoxic towards the human neuroblastoma cell line, SH-SY5Y. Here we demonstrate, that 24-hydroxycholesterol-induced neurotoxicity in differentiated SH-SY5Y cells was due to apoptosis, as indicated by DNA-fragmentation, caspase-3 activation and a decrease of the mitochondrial membrane potential. Free radicals were generated, resulting in the death of 75% of the cells within 48h; neurotoxicity in differentiated SH-SY5Y cells was partially prevented by physiological concentrations of vitamin E (50-100 microM) in that 75% of the cells survived. Physiological concentrations of estradiol-17beta (1-100nM) elicited a protective effect in differentiated cells, which was not significant; however, in undifferentiated cells a significant protection was noted by this steroid hormone. Vitamin C and melatonin did not prevent 24-hydroxycholesterol-induced neurotoxicity. These in vitro data support the in vivo observed beneficial effects reported as circumstantial evidence of vitamin E and estradiol-17beta treatment in the prevention and therapy of neurodegenerative disease.

Antioxidants↗
PubMed1979

Effects of various oxygenated sterols on cellular sterol biosynthesis in Chinese hamster lung cells resistant to 25-hydroxycholesterol.

The effects of a wide variety of oxygenated sterols upon sterol biosynthesis and hydroxymethylglutaryl-CoA reductase (mevalonate: NADP+ oxidoreductase (CoA-acylating), EC 1.1.1.34) activity in a wild-type clone and in a 25-hydroxycholesterol-resistant clone of Chinese hamster lung (Dede) cells are described. Derivatives of cholesterol which were oxygenated in the 6, 7 or 15 positions of the sterol nucleus or in the 20, 22, 24 or 25 positions of the sterol side chain were shown to be potent inhibitors of sterol synthesis and reductase activity in the wild-type cells but none of these substitutions had any effect on the 25-hydroxycholesterol-resistant A2 clone. A 32-hydroxylated derivative of lanosterol also suppressed sterol synthesis and reductase activity in wild-type cells but had no significant effect upon the A2 line. It was also appraent that a complete sterol side chain was necessary for inhibitory activity. Studies of a wide range of inhibitory sterols indicated that there was a close correlation between their effects upon sterol synthesis and reductase activity and that their inhibitory action was specific for sterol biosynthesis since little effect was observed upon fatty acid or CO2 synthesis. Previous studies had shown that the uptake of 25-hydroxycholesterol by the resistant A2 line was unimpaired and the present results indicate that metabolism of this oxygenated sterol is also unaltered. These results, in conjunction with previous studies, suggest that the resistant A2 line is defective in feedback regulation of cholesterol synthesis and that all of the oxygenated sterols tested suppress the biosynthetic pathway through at least one common step.

Acetates↗
PubMed1983

Esterification of cholesterol and 25-hydroxycholesterol by rat liver microsomes.

The properties of an enzyme in rat liver microsomes was described that catalyzed the formation of 25-hydroxycholesteryl ester in the presence of labeled sterol and oleoyl-CoA. The reaction was similar in several respects to that of cholesteryl ester formation by acyl-CoA: cholesterol acyltransferase. Trypsin pretreatment of microsomes inhibited the esterification of both sterols and a similar dose-dependent inhibition was produced by addition of progesterone and several androgens. Microsomes with an enhanced cholesterol content resulting from in vivo treatment with ethinyl estradiol showed increased esterifying activity towards both cholesterol and 25-hydroxycholesterol. Esterification of endogenous microsomal cholesterol was increased by the addition of 25-hydroxycholesterol, concomitant with 25-hydroxycholesteryl ester formation. To assess the relationship between the association of sterols with membranes and sterol ester formation, microsomes were preincubated with either sterol, reisolated by ultracentrifugation in a density gradient and then analyzed chemically or enzymatically. Cholesterol and 25-hydroxycholesterol both associated with microsomes and the added sterol was subsequently esterified. Maximal esterification was only partially dependent on the amount bound. Progesterone, which inhibited sterol esterification, did not bind to microsomes and no inhibition was observed in reisolated microsomes, indicating that the inhibition produced by progesterone was reversible.

Animals↗
PubMed1989

Treatment of CHO-K1 cells with 25-hydroxycholesterol produces a more rapid loss of 3-hydroxy-3-methylglutaryl-coenzyme A reductase activity than can be accounted for by enzyme turnover.

A key enzyme in the regulation of mammalian cellular cholesterol biosynthesis is 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase). It is well established that treatment with the compound 25-hydroxycholesterol lowers HMG-CoA reductase activity in cultured Chinese hamster ovary (CHO-K1) cells. After brief incubation (0-4 h) with 25-hydroxycholesterol (0.5 microgram/ml), cellular HMG-CoA reductase activity is decreased to 40% of its original level. This also occurs in the presence of exogenous mevinolin, a competitive inhibitor of HMG-CoA reductase which has previously been shown to inhibit its degradation. The inhibition of HMG-CoA reductase activity by 25-hydroxycholesterol is complete after 2 h. Radio-immune precipitation analysis of the native enzyme under these conditions shows a degradation half-life which is considerably longer than that of the observed inhibition. Studies with sodium fluoride, phosphatase 2A, bacterial alkaline phosphatase and calf alkaline phosphatase indicate that the observed loss of activity is not due to phosphorylation. These data are not consistent with described mechanisms of HMG-CoA reductase activity regulation by phosphorylation or degradation but are consistent with a novel mechanism that regulates the catalytic efficiency of this enzyme.

Alkaline Phosphatase↗
PubMed1983

The importance of serum lipoproteins in the cytolytic action of 7 beta-hydroxycholesterol on cultured hepatoma cells.

The toxicity of 7 beta-hydroxycholesterol for cultured HTC cells is 10 times greater if serum lipids and lipoproteins are absent from the culture medium. A water-soluble derivative of 7 beta-hydroxycholesterol, sodium 3,7-bishemisuccinate, showed the same toxicity as the original molecule and was also 8 times more toxic when serum lipids and lipoproteins were absent. But the rapid inhibition of DNA synthesis was similar in cells treated with both compounds, whether lipids and lipoproteins are present or not. Thus the absence of serum lipids and lipoproteins enhances the lytic effect of both substances but does not increase their intracellular action on DNA synthesis. This first parallel study on lipophilic 7 beta-hydroxycholesterol and its water-soluble homologue shows the importance of the serum lipids and lipoproteins in the cytotoxicity of such sterols.

Animals↗
PubMed1976

Effects of 25-hydroxycholesterol and aminoglutethimide in isolated rat adrenal cells. A model for congenital lipoid adrenal hyperplasia?

The production of corticosterone from 25-hydroxycholesterol by isolated rat adrenal cells is inhibited by aminoglutethimide phosphate (AGI); half-maximal inhibition is obtained at ca. 10 muM. AGI also inhibits ACTH-stimulated steroid production from endogeneous substrates; here half-maximal inhibition is obtained with ca. 40 muM AGI. In the presence of ACTH + AGI, 25-hydroxycholesterol causes additive inhibition. This effect of 25-hydroxycholesterol is dose-dependent. ACTH-stimulated steroid production from endogeneous substrates is partially inhibited by 5-cholene-3 beta,24-diol. These results may just reflect substrate competition for the side-chain cleaving system or may be due to some seocndary toxic effect on the cells.

Adrenal Glands↗
PubMed1993

Simultaneous determination of mevalonate and 7 alpha-hydroxycholesterol in human plasma by gas chromatography-mass spectrometry as indices of cholesterol and bile acid biosynthesis.

A very sensitive and specific method for the simultaneous determination of mevalonate and 7 alpha-hydroxycholesterol in human plasma is described. The assay is based on isotope dilution mass spectrometry: the extracts from plasma were treated with benzylamine followed by dimethylethylsilylimidazole, then the resulting dimethylethylsilyl ether derivatives of mevalonylbenzylamide and 7 alpha-hydroxycholesterol were determined by gas chromatography-mass spectrometry using high-resolution selected-ion monitoring. Simple regression analysis revealed significant correlations between the plasma level of mevalonate and the hepatic activity of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (EC 1.1.1.34) (r = 0.83, P < 0.01) and between the plasma level of free 7 alpha-hydroxycholesterol and the hepatic activity of cholesterol 7 alpha-hydroxylase (EC 1.14.13.7) (r = 0.76, P < 0.05).

Adult↗
PubMed2006

22-Hydroxycholesterols regulate lipid metabolism differently than T0901317 in human myotubes.

The nuclear liver X receptors (LXRalpha and beta) are regulators of lipid and cholesterol metabolism. Oxysterols are known LXR ligands, but the functional role of hydroxycholesterols is at present unknown. In human myotubes, chronic exposure to the LXR ligand T0901317 promoted formation of diacylglycerol (DAG) and triacylglycerol (TAG), 22-R-hydroxycholesterol (22-R-HC) had no effect, and 22-S-hydroxycholesterol (22-S-HC) reduced the formation. In accordance with this, 22-HC and T0901317 regulated the expression of fatty acid transporter CD36, stearoyl-CoA desaturase-1, acyl-CoA synthetase long chain family member 1 and fatty acid synthase (FAS) differently; all genes were increased by T0901317, 22-R-HC did not change their expression level, while 22-S-HC reduced it. Transfection studies confirmed that the FAS promoter was activated by T0901317 and repressed by 22-S-HC through an LXR response element in the promoter. Both 22-R-HC and T0901317 increased gene expression of LXRalpha, sterol regulatory element-binding protein 1c and ATP-binding cassette transporter A1, while 22-S-HC had little effect. In summary, 22-R-HC regulated lipid metabolism and mRNA expression of some LXR target genes in human myotubes differently than T0901317. Moreover, 22-S-HC did not behave like an inactive ligand; it reduced synthesis of complex lipids and repressed certain genes involved in lipogenesis and lipid handling.

Animals↗
PubMed2004

Significance of plasma 7alpha-hydroxy-4-cholesten-3-one and 27-hydroxycholesterol concentrations as markers for hepatic bile acid synthesis in cholesterol-fed rabbits.

Plasma 7alpha-hydroxy-4-cholesten-3-one has been used as an index of hepatic bile acid synthesis. The aim of the current study was to ascertain whether the level of this oxysterol reflects hepatic cholesterol 7alpha-hydroxylase activity when plasma cholesterol concentrations are markedly changed. In addition, the relationship of hepatic sterol 27-hydroxylase activity with plasma concentrations of 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid was studied. We used New Zealand white rabbits fed 2% cholesterol for 5 or 10 days and/or constructed bile fistula. Feeding cholesterol markedly increased and bile drainage reduced plasma cholesterol concentrations. Initially, in these models there was no correlation between plasma 7alpha-hydroxy-4-cholesten-3-one concentrations and hepatic cholesterol 7alpha-hydroxylase activities (r = -0.24, n = 10). Cholesterol feeding was associated with downregulated 7alpha-hydroxylase activities, while plasma 7alpha-hydroxy-4-cholesten-3-one concentrations were elevated in the presence of increased plasma cholesterol levels. However, this discrepancy was overcome and significant correlation was observed (r = 0.73, P <.05, n = 10) by expressing 7alpha-hydroxy-4-cholesten-3-one levels relative to cholesterol. In contrast, hepatic sterol 27-hydroxylase activities were not significantly correlated with plasma absolute (r = 0.23, difference not significant [NS], n = 10) nor cholesterol-related levels of 27-hydroxycholesterol (r = -0.13, NS, n = 10), or 3beta-hydroxy-5-cholestenoic acid concentrations (r = 0.30, NS, n = 10). In conclusion, plasma 7alpha-hydroxy-4-cholesten-3-one concentrations reflected hepatic cholesterol 7alpha-hydroxylase activities when the sterol levels were adjusted to plasma cholesterol concentrations in rabbits with hypercholesterolemia. The results suggest that plasma 7alpha-hydroxy-4-cholesten-3-one relative to cholesterol is a better marker for hepatic cholesterol 7alpha-hydroxylase activity than the absolute concentration when hypercholesterolemia is present. In contrast, 27-hydroxycholesterol and 3beta-hydroxy-5-cholestenoic acid levels in plasma did not reflect hepatic sterol 27-hydroxylase activities even if the levels were adjusted to plasma cholesterol concentrations.

Animals↗
PubMed1998

Different patterns of IL-1beta secretion, adhesion molecule expression and apoptosis induction in human endothelial cells treated with 7alpha-, 7beta-hydroxycholesterol, or 7-ketocholesterol.

Among oxysterols oxidized at C7 (7alpha-, 7beta-hydroxycholesterol, and 7-ketocholesterol), 7beta-hydroxycholesterol and 7-ketocholesterol involved in the cytotoxicity of oxidized low density lipoproteins (LDL) are potent inducers of apoptosis. Here, we asked whether all oxysterols oxidized at C7 were able to trigger apoptosis, to stimulate interleukin (IL)-Ibeta and/or tumor necrosis factor (TNF)-alpha secretion, and to enhance adhesion molecule expression (intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and E-selectin) on human umbilical venous endothelial cells (HUVECs). Only 7beta-hydroxycholesterol and 7-ketocholesterol were potent inducers of apoptosis and of IL-1beta secretion. TNF-alpha secretion was never detected. Depending on the oxysterol considered, various levels of ICAM-1, VCAM-1 and E-selectin expression were observed. So, oxysterols oxidized at C7 differently injure and activate HUVECs, and the alpha- or beta-hydroxyl radical position plays a key role in apoptosis and IL-1beta secretion.

Apoptosis↗
PubMed1985

The analysis of 25-hydroxycholesterol in plasma and cholesterol-containing foods by high-performance liquid chromatography.

A method for the analysis of 25-hydroxycholesterol by high-performance liquid chromatography (HPLC) in a wide range of materials is described. Lipid extracts were initially purified on octadecyl silicic acid cartridges and by reversed-phase HPLC before quantitation by HPLC on a silicic acid column. The reproducibility of the method was confirmed by the analysis of plasma from rats fed 25-hydroxycholesterol. 25-Hydroxycholesterol was not detected in lard, cream, fresh egg yolk or spray-dried egg yolk powder. It was detected in egg yolk powder after heating at 110 degrees C for 4 days and its authenticity was confirmed by mass spectrometry.

Animals↗
PubMed1983

Chain length dependent modification of lipid organization by low levels of 25-hydroxycholesterol and 25-hydroxycholecalciferol. A laser Raman study.

We have used Raman spectroscopy to investigate the thermal transitions of multibilayered liposomes composed of lecithins, i.e., dilauroyllecithin, dimyristoyllecithin, dipalmitoyllecithin, distearoyllecithin, or egg lecithin, plus 5-cholesten-3,25-diol (25-hydroxycholesterol), 25-hydroxycholecalciferol, and vitamin D3. We recorded the CH-stretching (2800-3000-cm-1) regions of the Raman spectra at various temperatures and employed plots of temperature vs. the intensity of the 2880- or 2930-cm-1 bands relative to that of the 2850-cm-1 feature, i.e., the ratios I2880/I2850 and I2930/I2850, to estimate thermal transitions. These plots show multiple discontinuities, each of which may be ascribed to a state change of a separate phase with distinctive proportions of lecithins and cholesterol derivatives. Low concentrations of 25-hydroxycholesterol and 25-OH-D3 (greater than or equal to 0.2 mol%) abolish the pretransition and split the main transitions of dilauroyllecithin (4 degrees C) and dimyristoyllecithin (23 degrees C) into two. The midpoint of the new small transition centers at about 3-4 degrees C lower than those of the respective main transitions of dilauroyllecithin and dimyristoyllecithin. A further increase in the molar ratio of 25-hydroxycholesterol and 25-hydroxycholecalciferol decreases the amplitudes of the new and the main transitions (dilauroyl- and dimyristoyllecithin). The transitions of dipalmitoyllecithin and distearoyllecithin at 2 mol % concentrations of either sterol remain unaffected. There was no splitting in the main transition of either dipalmitoyllecithin or distearoyllecithin in the presence of these sterols. The perturbing effect of the 25-hydroxysterols follows the order dilauroyllecithin greater than dimyristoyllecithin greater than dipalmitoyllecithin greater than distearoyllecithin.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcifediol↗
PubMed2001

Control of apolipoprotein E secretion by 25-hydroxycholesterol and proinflammatory cytokines in the human astrocytoma cell line CCF-STTG1.

During the last few years the increased presence of proinflammatory cytokines and oxidation products in Alzheimer's disease (AD) has been largely described. Oxysterols, formed by hydroxylation of cholesterol, occur naturally in the brain and are increased in the serum of AD patients. Of these oxysterols, 25-hydroxycholesterol is the most potent regulator of gene transcription. It stimulates the synthesis of apolipoprotein E (apo E) in macrophages. Apo E plays a major role in the brain as a phospholipid and cholesterol carrier molecule in compensatory synaptogenesis. Cytokines might also be able to modulate apo E expression. Accordingly, this study examined the control of apo E secretion by several proinflammatory cytokines and oxysterols in the human astrocytoma cell line CCF-STTG1. A time-dependent stimulation of apo E secretion by 25-hydroxycholesterol was observed. Among several cytokines tested, only tumor necrosis factor (TNF)-alpha inhibited apo E secretion in basal conditions in CCF-STTG1 human astrocytoma cells. In the presence of 25-hydroxycholesterol, TNF-alpha reduced apo E secretion by 80%, while interleukins (IL) IL-1beta, IL-6, and IL-2 had no significant effects. In Alzheimer's disease, the increase in the concentrations of cytokines and the concomitant decrease of cholesterol concentration in the brain could contribute jointly to reduce apo E concentration, and in doing so accelerate neurodegeneration. Surprisingly, oxysterols would be able to limit this phenomenon.

Alzheimer Disease↗