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PubMed2001

Cholesterol and hydroxycholesterol sulfotransferases: identification, distinction from dehydroepiandrosterone sulfotransferase, and differential tissue expression.

In humans, the biotransformation of cholesterol and its hydroxylated metabolites (oxysterols) by sulfonation is a fundamental process of great importance. Nevertheless, the sulfotransferase enzyme(s) that carries out this function has never been clearly identified. Cholesterol is a relatively poor substrate for the previously cloned hydroxysteroid sulfotransferase (HST), i.e. dehydroepiandrosterone (DHEA) sulfotransferase (HST1). Recently, cloning of a single human gene that encodes for two proteins related to HST1 was reported. These newly cloned sulfotransferases (HST2a and HST2b), while exhibiting sequence similarity to other members of the soluble sulfotransferase superfamily, also contain unique structural features. This latter aspect prompted an examination of their substrate specificity for comparison with HST1. Thus, HST1, HST2a, and HST2b were overexpressed as fusion proteins and purified. Furthermore, a novel procedure for the isolation of cholesterol and oxysterol sulfonates was developed that was used in association with HPLC to resolve specific sterol sulfonates. HST1 preferentially sulfonated DHEA and, to a lesser extent, oxysterols; whereas cholesterol was a negligible substrate. The reverse, however, was the case for the HST2 isoforms, particularly HST2b, which preferentially sulfonated cholesterol and oxysterols, in contrast to DHEA, which served as a poor substrate for this enzyme. RT-PCR analysis revealed distinct patterns of HST1, HST2a, and HST2b expression. It was particularly notable that both HST2 isoforms, but not HST1, were expressed in skin, a tissue where cholesterol sulfonation plays an important role in normal development of the skin barrier. In conclusion, substrate specificity and tissue distribution studies strongly suggest that HST2a and HST2b, in contrast to HST1, represent normal human cholesterol and oxysterol sulfotransferases. Furthermore, this study represents the first example of the sulfonation of oxysterols by a specific human HST.

Amino Acid Sequence↗
PubMed1989

[The role of gonadotropins, cyclic AMP, 22-R-hydroxycholesterol and cofactors in regulating endocrine functions of the Leydig cells in rats. I. Effect of cofactors on the synthesis of steroid hormones in the interstitial gland of rats].

The authors evaluated the influence of NAD, NADP, G-6-P and G-6-PDH on the synthesis of steroid hormones in the interstitial gland of the rat. The animals were killed by decapitation, and sections of the nucleus weighing altogether 20 mg were incubated with NAD (0.4 mM), NADP (0.4 mM), G-6-P (3.5 mM) and G-6-PDH (2 j.m./ml) for 4 hours in CO2 incubator. Then the tissue was homogenized, removed by centrifugation and then from the homogenous supernatant the authors extracted steroids which were in the incubating medium and in the tissue. Steroid hormones examined were marked radioimmunologically, they were: pregnenolon as the first and testosterone as the second stage of synthesis of nucleus androgens. The search carried out shows that the strongest stimulator in biosynthesis of pregnenolon was NADP together with the reducing system (G-6-P and G-6-PDH). On the other hand, in case of testosterone the highest effectiveness was achieved by simultaneous use of the cofactors examined. Applying cofactors separately the authors were able to find that both NAD and NADP together with the reducing system were responsible for testosterone synthesis and their simultaneous applying in the incubating medium leads to a synergistic effect.

Animals↗
PubMed1986

Membrane properties of oxysterols. Interfacial orientation, influence on membrane permeability and redistribution between membranes.

The membrane properties of cholesterol auto-oxidation products, 7-ketocholesterol, 7 beta-hydroxycholesterol, 7 alpha-hydroxycholesterol and 25-hydroxycholesterol were examined. Monolayer studies show that these oxysterols are perpendicularly orientated at the interphase. Only 7 beta-hydroxycholesterol and 7 alpha-hydroxycholesterol are tilted at low surface pressures. In mixed monolayers with dioleoylphosphatidylcholine, 7-ketocholesterol, 7 beta-hydroxycholesterol and 7 alpha-hydroxycholesterol show a condensing effect in this order, although to a lesser extent that that observed for cholesterol. In liposomes these oxysterols also reduce glucose permeability and in the same order as their condensing effect. On the other hand 25-hydroxycholesterol shows no condensing effect in monomolecular layers whereas glucose permeability in liposomes is enormously increased. The permeability increase is already maximal at 2.5 mol% 25-hydroxycholesterol. Differential scanning calorimetry experiments reveal that all four oxysterols tested reduce the heat content of the gel----liquid-crystalline phase transition. It is concluded that 7-ketocholesterol, 7 beta-hydroxycholesterol and 7 alpha-hydroxycholesterol have a cholesterol like effect, although less efficient than cholesterol, whereas 25-hydroxycholesterol showing no condensing effect acts as a spacer molecule. Packing defects in the hydrophobic core of the bilayer due to the presence of the C-25 hydroxyl group are believed to cause the permeability increase. The transfer of radiolabelled (oxy)sterols from the monolayer to lipoproteins or vesicles in the subphase was studied. The transfer rate increases in the following order 7-ketocholesterol, 7 beta-hydroxycholesterol, 7 alpha-hydroxycholesterol, 25-hydroxycholesterol. The difference in rate between 7-ketocholesterol and 25-hydroxycholesterol is 20-fold. A higher rate of transfer is observed in the presence of high density lipoproteins and small unilamellar vesicles. A transfer rate for cholesterol is hardly measurable under these conditions. The transfer measured is consistent with the involvement of a water-soluble intermediate.

Cell Membrane Permeability↗
PubMed1995

Toxicity of oxysterols to human monocyte-macrophages.

We have investigated the toxicity of the cholesterol oxidation products (oxysterols), 7 alpha-hydroxycholesterol, 7 beta-hydroxycholesterol, 7-ketocholesterol, 25-hydroxycholesterol and 26-hydroxycholesterol to human monocyte-macrophages in vitro. The 7-position derivatives are present in low density lipoprotein (LDL) oxidised with copper (II) sulphate and macrophages, and in extracts of human atherosclerotic lesions, which also contain 26-hydroxycholesterol. We have also assessed 25-hydroxycholesterol for toxicity because it has often been used in studies of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibition and LDL receptor down-regulation. Measurement of radioactivity release from monocyte-macrophages preloaded with tritiated adenine, as a means of assessing cytotoxicity that all the oxysterols showed time- and concentration-dependent toxicity. The cytotoxic potency of 26-hydroxycholesterol was the greatest. The 7-position derivatives also produced marked cell damage, though at higher concentrations than for 26-hydroxycholesterol. Of the oxysterols assessed, the toxicity of 25-hydroxycholesterol was the least. The cytotoxicity of 7 beta-hydroxycholesterol and 26-hydroxycholesterol was also shown using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) dye reduction assay which confirmed that 26-hydroxycholesterol was more toxic than 7 beta-hydroxycholesterol. Incubation of monocyte-macrophages with cholesterol added to the different oxysterols gave varying results. Cholesterol, which was not itself toxic, inhibited the toxicity of 25-hydroxycholesterol and 26-hydroxycholesterol, but the toxicity of the 7-position derivatives was not affected. The possible relevance of these molecules to the death of macrophages seen in atherosclerosis is discussed.

Cells, Cultured↗
PubMed2004

Identification of naturally occurring spirostenols preventing beta-amyloid-induced neurotoxicity.

22R-Hydroxycholesterol is an intermediate in the steroid biosynthesis pathway shown to exhibit a neuroprotective property against beta-amyloid (1-42) (Abeta) toxicity in rat PCl2 and human NT2N neuronal cells by binding and inactivating Abeta. In search of potent 22R-hydroxycholesterol derivatives, we assessed the ability of a series of naturally occurring entities containing the 22R-hydroxycholesterol structure to protect PC12 cells against Abeta-induced neurotoxicity, determined by measuring changes in membrane potential, mitochondrial diaphorase activity, ATP levels and trypan blue uptake. 22R-Hydroxycholesterol derivatives sharing a common spirost-5-en-3-ol or a furost-5-en-3-ol structure were tested. Although some of these compounds were neuroprotective against 0.1 microM Abeta, only three protected against the 1-10 microM Abeta-induced toxicity and, in contrast to 22R-hydroxycholesterol, all were devoid of steroidogenic activity. These entities shared a common structural feature, a long chain ester in position 3 and common stereochemistry. The neuroprotective property of these compounds was coupled to their ability to displace radiolabeled 22R-hydroxycholesterol from Abeta, suggesting that the Abeta-22R-hydroxycholesterol physicochemical interaction contributes to their beneficial effect. In addition, a 22R-hydroxycholesterol derivative inhibited the formation of neurotoxic amyloid-derived diffusible ligands. Computational docking simulations of 22R-hydroxycholesterol and its derivatives on Abeta identified two binding sites. Chemical entities, as 22R-hydroxycholesterol, seem to bind preferentially only to one site. In contrast, the presence of the ester chain seems to confer the ability to bind to both sites on Abeta, leading to neuroprotection against high concentrations of Abeta. In conclusion, these results suggest that spirost-5-en-3-ol naturally occurring derivatives of 22R-hydroxycholesterol might offer a new approach for Alzheimer's disease therapy.

Amyloid beta-Peptides↗
PubMed2003

Changes in the levels of cerebral and extracerebral sterols in the brain of patients with Alzheimer's disease.

24S-hydroxycholesterol is a side-chain oxidized oxysterol formed in the brain that is continuously crossing the blood-brain barrier to reach the circulation. There may be an opposite flux of 27-hydroxycholesterol, which is formed to a lower extent in the brain than in most other organs. Here we measured cholesterol, lathosterol, 24S- and 27-hydroxycholesterol, and plant sterols in four different brain areas of deceased Alzheimer's disease (AD) patients and controls. 24S-hydroxycholesterol was decreased and 27-hydroxycholesterol increased in all the brain samples from the AD patients. The difference was statistically significant in four of the eight comparisons. The ratio of 27-hydroxycholesterol to 24S-hydroxycholesterol was significantly increased in all brain areas of the AD patients and also in the brains of aged mice expressing the Swedish Alzheimer mutation APP751. Cholesterol 24S-hydroxylase and 27-hydroxylase protein was not significantly different between AD patients and controls. A high correlation was observed between the levels of 24S-hydroxycholesterol and lathosterol in the frontal cortex of the AD patients but not in the controls. Most probably the high levels of 27-hydroxycholesterol are due to increased influx of this steroid over the blood-brain barrier and the lower levels of 24S-hydroxycholesterol to decreased production. The high correlation between lathosterol and 24-hydroxycholesterol is consistent with a close coupling between synthesis and metabolism of cholesterol in the frontal cortex of the AD brain.

Aged↗
PubMed2002

On the rate of translocation in vitro and kinetics in vivo of the major oxysterols in human circulation: critical importance of the position of the oxygen function.

Oxysterols possess powerful biological activities. Some of their effects on the regulation of key enzymes are similar to those of cholesterol, but are much more potent. One of the critical properties of oxysterols is their ability to pass lipophilic membranes at a high rate. Transfer of unesterified 25-hydroxycholesterol from red blood cells to plasma has been reported to occur more than 1,000 times faster than cholesterol. Here we have measured the relative rate of such translocation of the three major oxysterols in human circulation: 27-hydroxycholesterol, 24S-hydroxycholesterol, and 4beta-hydroxycholesterol. The distance from the 3beta-hydroxyl group to the additional hydroxyl group is the greatest possible in 27-hydroxycholesterol and the least possible in 4beta-hydroxycholesterol. The rate of exchange between erythrocytes and plasma was found to be high for 27-hydroxycholesterol and 24S-hydroxycholesterol, and hardly possible to measure for 4beta-hydroxycholesterol and cholesterol. When injected intravenously into humans, deuterium labeled 24- and 27-hydroxycholesterol caused an immediate high enrichment of the corresponding plasma sterols followed by a decay. After injection of labeled 4beta-hydroxycholesterol, the maximum deuterium enrichment occurred after 2-3 h, when secretion of the oxysterol from the liver is likely to be the limiting factor. When radiolabeled cholesterol was injected under the same conditions, maximum appearance of label occurred after about 2 days. The results illustrate the importance of the position of the additional oxygen in oxysterols and are discussed in relation to the rate of metabolism and biological effects of these oxysterols.

Erythrocytes↗
PubMed1980

Regulation of cholesterol esterification and biosynthesis in monolayer cultures of normal adult rat hepatocytes.

Adult rat parenchymal liver cells were isolated and cultured in monolayers. Cholesterol esterification in the intact cultured cells was determined by measuring incorporation of tritiated oleic acid into cell cholesterol ester. Addition of 10 microgram/ml of 25-hydroxycholesterol to the medium gave a 3- to 6-fold increase in cholesterol esterification, while the incorporation of oleic acid into phospholipids and triglycerides remained unaltered. Similar stimulation of cholesterol esterification by 25-hydroxycholesterol was also found if [14C]mevalonolactone or [3H]cholesterol (the latter presented to the cells in high density lipoproteins) were used as precursors. The stimulatory effect of 25-hydroxycholesterol was maximal after only 15-min incubation and was independent of protein synthesis. After 4 to 6 h of incubation with 25-hydroxycholesterol, its stimulatory effect was reduced significantly, and after 18 h of incubation no stimulation was observed. Thus, the liver cells in some fashion adapt to the continuing presence of 25-hydroxycholesterol. Isolated microsomes prepared from cells previously incubated with 25-hydroxycholesterol showed acyl-CoA:cholesterol acyltransferase activity 3 times that of microsomes from control cells. Incubation of isolated microsomes with 25-hydroxycholesterol increased acyl-CoA:cholesterol acyltransferase activity 2-fold. The net cellular content of ester cholesterol increased after 2 to 6 h incubation of hepatocytes with 25-hydroxycholesterol; there was a net decrease in cellular free cholesterol. Mevalonolactone (10 mM) also stimulated cholesterol esterification and inreased the cellular content of ester cholesterol (3- to 4-fold). The effectiveness of mevalonolactone did not diminish with longer periods of preincubation. Furthermore, the stimulatory effects of 25-hydroxycholesterol and mevalonolactone added together were at least 50 to 100% greater than the effects of either agent alone, suggesting that the mechanisms by which they increase cellular cholesterol esterification are different. Both 25-hydroxycholesterol and mevalonolactone rapidly inhibited microsomal 3-hydroxy-3-methylglutaryl-CoA reductase activity. Pure cholesterol had no effect on cellular cholesterol esterification or on 3-hydroxy-3-methylglutaryl-CoA reductase activity at concentrations up to 10 microgram/ml.

Animals↗
PubMed2001

Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study.

The major oxysterols in human circulation are 7 alpha-, 27-, and (24S)-hydroxycholesterol. Two unique experiments were performed to elucidate their origin and kinetics. A volunteer was exposed to (18)O(2)-enriched air. A rapid incorporation of (18)O in both 7 alpha- and 27-hydroxycholesterol and disappearance of label after exposure were observed. The half-life was estimated to be less than 1 h. Incorporation of (18)O in (24S)-hydroxycholesterol was not significant. In the second experiment a volunteer was infused with liposomes containing 10 g of [(2)H(6)]cholesterol. This resulted in an enrichment of plasma cholesterol with (2)H of up to 13%, and less than 0.5% in cerebrospinal fluid cholesterol. The content of (2)H in circulating 7 alpha-hydroxycholesterol remained approximately equal to that of plasma cholesterol and decreased with a half-life of about 13 days. The (2)H content of circulating 27-hydroxycholesterol was initially lower than that of cholesterol but in the last phase of the experiment it exceeded that of cholesterol. No significant incorporation of (2)H in (24S)-hydroxycholesterol was observed. It is evident that 7 alpha-hydroxycholesterol must originate from a rapidly miscible pool, about 80% of 27-hydroxycholesterol from a more slowly exchangeable pool, and more than 90% of (24S)-hydroxycholesterol from a nonexchangeable pool, presumably the brain. The results are discussed in relation to the role of oxysterols in cholesterol homeostasis and their use as markers for pathological conditions. - Meaney, S., M. Hassan, A. Sakinis, D. Lütjohann, K. von Bergmann, A. Wennmalm, U. Diczfalusy, and I. Björkhem. Evidence that the major oxysterols in human circulation originate from distinct pools of cholesterol: a stable isotope study. J. Lipid Res. 2001. 42: 70;-78.

Blood Circulation↗