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PubMed2005

Apoptotic effects of 25-hydroxycholesterol in immature rat Sertoli cells: prevention by 17beta-estradiol.

The aim of the present study was to determine whether or not apoptosis occurs in Sertoli cells in presence of 25-hydroxycholesterol, an oxysterol derived from cholesterol-containing foods or endogenous oxidation. Here, we provide evidence that 25-hydroxycholesterol can induce cultured Sertoli cells of immature rat to undergo apoptosis. The cell death was identified by analysis of fragmented DNA detected using enzyme-immunoassay. After 48 h of treatment with 50 microM of 25-hydroxycholesterol, apoptosis increased by 70% in Sertoli cells. Moreover, 50 microM of 25-hydroxycholesterol inhibited the incorporation of [14C] acetate into cholesterol by 70%. Addition of mevanolate to prevent isoprenoid deficiency do not inhibit the apoptosis generated by 25-hydroxycholesterol. In contrast, this increase of DNA fragmentation was reversed by addition of caspase-3 inhibitors as Ac-DEVD-CHO or Ac-ESMD-CHO. Bcl-2 mRNA level in the Sertoli cells decreased by 60% after 24 h exposure to 25-hydroxycholesterol. In parallel, Bax mRNA level increased by 40% in the Sertoli cells incubated in presence of 50 microM of 25-hydroxycholesterol. Physiological concentrations of 17beta-estradiol (10 or 100 nM) elicited a significant protection on apoptosis generated by 25-hydroxycholesterol in Sertoli cells. Our results show that the 25-hydroxycholesterol would control the cholesterol synthesis without toxic effect in immature rat Sertoli cells, these cells being able to protect themselves by estradiol production.

Animals↗
PubMed1997

Studies on the relationships between 7 alpha-hydroxylation and the ability of 25- and 27-hydroxycholesterol to suppress the activity of HMG-CoA reductase.

The metabolism of 25-hydroxycholesterol in different cell types was studied and the role of 7 alpha-hydroxylation for the effect of 25-hydroxycholesterol on the activity of HMG-CoA reductase was determined. Human diploid fibroblasts (HDF) and the human melanoma cell line SK-MEL-2 converted 25-hydroxycholesterol into 7 alpha,25-dihydroxycholesterol and 7 alpha,25-dihydroxy-4-cholesten-3-one while the virus-transformed fibroblast line 90VA-VI, the colon carcinoma cell line WiDr and the breast cancer cell line MDA-231 did not express 7 alpha-hydroxylase activity. The 7 alpha-hydroxylation of 25-hydroxycholesterol in HDF could be stimulated by dexamethasone and cortisol and inhibited by metyrapone. An unidentified, possibly 4-hydroxylated, metabolite was formed by 90VA-VI cells and a polar, probably conjugated, metabolite was formed by WiDr cells. The 7 alpha-hydroxylated metabolites of 25-hydroxycholesterol suppressed the activity of HMG-CoA reductase to a similar extent as 25-hydroxycholesterol in HDF but not in 90VA-VI cells, while the 7 alpha-hydroxylated metabolites of 27-hydroxycholesterol suppressed the activity of HMG-CoA reductase also in 90VA-VI cells. The suppression of HMG-CoA reductase activity by 25- and 27-hydroxycholesterol was decreased or abolished by dehydroepiandrosterone or pregnenolone which have little or no effect on the 7 alpha-hydroxylation. The results indicate that 7 alpha-hydroxylation is not directly involved, positively or negatively, in the action of 25- or 27-hydroxycholesterol as suppressors of HMG-CoA reductase activity.

Aryl Hydrocarbon Hydroxylases↗
PubMed1997

Importance of a novel oxidative mechanism for elimination of brain cholesterol. Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with 18O2 techniques in vivo and in vitro.

The brain is the most cholesterol-rich organ in the body. Brain cholesterol is characterized by a very low turnover with very little exchange with lipoproteins in the circulation. Very recently we showed that there is a continuous age-dependent flux of 24(S)-hydroxycholesterol from the human brain into the circulation (Lütjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Sidén, A., Diczfalusy, U., and Björkhem, I. (1996) Proc. Natl. Acad. Sci. U. S. A. 93, 9799-9804). Here we measured the rate of synthesis of cholesterol as well as the conversion of cholesterol into 24(S)-hydroxycholesterol in rat brain in vivo with use of an 18O2 inhalation technique and mass isotopomer distribution analysis. Cholesterol synthesis was found to correspond to 0.03 +/- 0.01% of the pool per h. Conversion of cholesterol into 24(S)-hydroxycholesterol was of a similar magnitude, about 0.02% of the pool per h. Brain microsomes converted endogenous cholesterol into 24(S)-hydroxycholesterol at a similar rate when incubated in the presence of NADPH. When incubated with whole homogenate and subcellular fractions of rat brain, there was no significant conversion of tritium-labeled 24-hydroxycholesterol into more polar products. Plasma from 18O2-exposed rats contained 24(S)-hydroxycholesterol with an enrichment of 18O similar to that in 24(S)-hydroxycholesterol in the brain. The results suggest that the present 24(S)-hydroxylase mediated mechanism is most important for elimination of cholesterol from the brain of rats. There is a slow conversion of brain cholesterol into 24(S)-hydroxycholesterol with a rapid turnover of the small pool of the latter oxysterol due to leakage to the circulation (half-life of brain 24(S)-hydroxycholesterol is about 0.5 days as compared with 2-4 months for brain cholesterol). It is evident that the 24(S)-hydroxylation greatly facilitates transfer of cholesterol over the blood-brain barrier and that this hydroxylation may be critical for cholesterol homeostasis in the brain.

Animals↗
PubMed2000

24-hydroxycholesterol is a substrate for hepatic cholesterol 7alpha-hydroxylase (CYP7A).

(24S)-Hydroxycholesterol is formed from cholesterol in the brain and is important for cholesterol homeostasis in this organ. Elimination of (24S)-hydroxycholesterol has been suggested to occur in the liver but little is known about the metabolism of this oxysterol. In the present investigation, we report formation of 7alpha, 24-dihydroxycholesterol in pig and human liver. 7alpha-hydroxylase activity toward both isomers of 24-hydroxycholesterol [(24S) and (24R)] was found in a partially purified and reconstituted cholesterol 7alpha-hydroxylase (CYP7A) enzyme fraction from pig liver microsomes. In contrast, a purified enzyme fraction of pig liver oxysterol 7alpha-hydroxylase with high activity toward 27-hydroxycholesterol did not show any detectable activity toward 24-hydroxycholesterol. 7alpha-Hydroxylation of 24-hydroxycholesterol was strongly inhibited by 7-oxocholesterol, a known inhibitor of CYP7A. Human CYP7A, recombinantly expressed in Escherichia coli and in simian COS cells, showed 7alpha-hydroxylase activity toward both cholesterol and the two isomers of 24-hydroxycholesterol, with a preference for the (24S)-isomer. Our results show that 24-hydroxycholesterol is metabolized by CYP7A, an enzyme previously considered to be specific for cholesterol and cholestanol and not active toward oxysterols. Because CYP7A is the rate-limiting enzyme in the major pathway of bile acid biosynthesis, the possibility is discussed that at least part of the 24-hydroxycholesterol is converted into 7alpha-hydroxylated bile acids by the enzymes involved in the normal biosynthesis of bile acids.

Animals↗
PubMed1995

Serum concentration of 7 alpha-hydroxycholesterol as an indicator of bile acid synthesis in humans.

The serum concentration of 7 alpha-hydroxycholesterol as an indicator of total bile acid synthesis was investigated under different experimental conditions in humans. 7 alpha-Hydroxycholesterol was measured by gas-liquid chromatography-mass spectrometry, using [2H7]7 alpha-hydroxycholesterol and/or 5 alpha-cholestane-3 beta, 6 beta-diol as internal standards, and bile acid synthesis was estimated by the fecal balance method. Intraindividual variation was small when the concentration of 7 alpha-hydroxycholesterol was determined twice in the same subject 2 days to 11 months apart (7.3 +/- 6.5%, n = 52). In patients with advanced cirrhosis of the liver (n = 22) 7 alpha-hydroxycholesterol was 3.4-fold lower (22 ng/ml +/- 8) compared to matched controls (75 ng/ml +/- 19). Administration of cholestyramine (4 g b.i.d.) for 14 days increased 7 alpha-hydroxycholesterol concentration in five healthy volunteers from 40 +/- 11 ng/ml to 181 +/- 95 ng/ml (P = 0.02) and fecal excretion of acidic sterols from 254 +/- 60 mg/d to 1336 +/- 344 mg/d (P < 0.01). Although a significant correlation was found between 7 alpha-hydroxycholesterol in serum and bile acid synthesis in patients with hypercholesterolemia (r = 0.847, P < 0.001, n = 17), it was impossible to accurately determine bile acid synthesis from the serum levels of 7 alpha-hydroxycholesterol. Thus, determination of 7 alpha-hydroxycholesterol concentrations in serum can be used to assess changes in bile acid synthesis rates over short and long term periods under various experimental conditions, but not to calculate bile acid synthesis correctly.

Bile Acids and Salts↗
PubMed1998

Cholesterol homeostasis in human brain: turnover of 24S-hydroxycholesterol and evidence for a cerebral origin of most of this oxysterol in the circulation.

We have previously demonstrated that the brain contains about 80% of the 24S-hydroxycholesterol in the human body and that there is a net flux of this steroid from the brain into the circulation (Lütjohann, D. et al. 1996. Proc. Natl. Acad. Sci. USA. 93: 9799-9804). Combining previous data with new data on 12 healthy volunteers, the arteriovenous difference between levels of this oxysterol in the internal jugular vein and in a peripheral artery was found to be -10.2 +/- 2.8 ng/ml (mean +/- SEM) corresponding to a net flux of 24S-hydroxycholesterol from the brain of about 6.4 mg/24 h. The arteriovenous difference between levels of 24S-hydroxycholesterol in the hepatic vein and a peripheral artery of 12 other volunteers was found to be 7.4 +/- 2.2 ng/ml, corresponding to a hepatic uptake of about 7.6 mg/24 h. The concentrations of 24S-hydroxycholesterol in the renal vein were about the same as those in a peripheral artery, indicating that a renal elimination is not of importance. Intravenously injected deuterium-labeled racemic 24-hydroxycholesterol was eliminated from the circulation of two human volunteers with half-lives of 10 h and 14 h, respectively. A positive correlation was found between the levels of circulating cholesterol and 24S-hydroxycholesterol. The results are consistent with a cerebral origin of most of the circulating 24S-hydroxycholesterol and suggest that the liver is the major eliminating organ. It is concluded that conversion into 24S-hydroxycholesterol is a quantitatively important mechanism for elimination of cholesterol from human brain. The possibility is discussed that circulating levels of 24S-hydroxycholesterol can be used as a marker for pathological and/or developmental changes in the brain.

Adult↗
PubMed1994

Serum 7 alpha-hydroxycholesterol reflects hepatic bile acid synthesis in patients with obstructive jaundice after external biliary drainage.

To examine the hypothesis that serum levels of 7 alpha-hydroxycholesterol reflect bile acid synthesis in the liver, we analyzed serum 7 alpha-hydroxycholesterol and bile acid output in 13 patients with obstructive jaundice after relief of biliary obstruction. Before biliary drainage, the serum level of 7 alpha-hydroxycholesterol was 92 +/- 12 pmol/ml (mean +/- S.E.M.) and was significantly lower than the control value (226 +/- 26 pmol/ml, p < 0.01). After biliary drainage, serum 7 alpha-hydroxycholesterol level and biliary bile acid outputs began to rise in some patients, indicating reversible liver dysfunction. In other patients, serum 7 alpha-hydroxycholesterol levels and bile acid outputs did not increase, suggesting severe or irreversible liver dysfunction. On and after the third day of biliary decompression, serum 7 alpha-hydroxycholesterol levels correlated well with bile acid excretion (p < 0.01, r = 0.93). Other liver function parameters, such as serum bilirubin, serum bile acids, albumin, and bile flow, also revealed significant correlation with serum 7 alpha-hydroxycholesterol levels. We conclude that the serum 7 alpha-hydroxycholesterol level clearly reflects bile acid synthesis in the liver and that it may serve as a useful parameter for the assessment of hepatic functional recovery in patients with obstructive jaundice after biliary drainage.

Aged↗
PubMed1990

26-hydroxycholesterol-stimulated DNA synthesis in smooth muscle cells and induction of endothelial injury using a coculture technique.

We investigated the effects of 0.5, 2.5, and 10 micrograms/ml of cholesterol or 26-hydroxycholesterol on bovine aortic ECs and SMCs. Suppression of viable cell density and cytotoxic changes in both cells were induced by 2.5 and 10 micrograms/ml 26-hydroxycholesterol. ECs were more severely damaged than SMCs in the presence of 26-hydroxycholesterol. Levels of up to 10 micrograms/ml cholesterol had no effect on ECs or SMCs growth or cytotoxicity. Confluent ECs exposed to 2.5 or 10 micrograms/ml of 26-hydroxycholesterol secreted significant amounts of 6-ketoprostaglandin F1 alpha after a 24-hr incubation. An equivalent concentration of cholesterol had no such effect. SMCs cocultured with ECs exposed to 10 micrograms/ml 26-hydroxycholesterol, when compared with an equivalent level of cholesterol, synthesized DNA in significantly greater amounts during a 24-hr incubation. The cocultured ECs incubated in the presence of 2.5 and 10 micrograms/ml 26-hydroxycholesterol were partially detached due to cell death. However, no difference was observed in the DNA content of SMCs cultured without ECs in the presence of cholesterol or 26-hydroxycholesterol. The results suggest that 26-hydroxycholesterol produced not only cytotoxicity to ECs and SMCs but also stimulated DNA synthesis in SMCs through endothelial injury.

Animals↗
PubMed2002

Analysis of oxidative processes and of myelin figures formation before and after the loss of mitochondrial transmembrane potential during 7beta-hydroxycholesterol and 7-ketocholesterol-induced apoptosis: comparison with various pro-apoptotic chemicals.

Among oxysterols oxidized at C7 (7alpha-, 7beta-hydroxycholesterol, and 7-ketocholesterol) 7beta-hydroxycholesterol and 7-ketocholesterol are potent inducers of cell death and probably play central roles in atherosclerosis. As suggested by our previous investigations, 7-ketocholesterol might be a causative agent of vascular damage by inducing apoptosis and enhancing superoxide anion (O2*-) production. To determine the precise relationships between cytotoxicity and oxidative stress, the ability of oxysterols oxidized at C7 to induce apoptosis, to stimulate O2*- production and to promote lipid peroxidation was compared with different pro-apoptotic chemicals: antitumoral drugs (VB, Ara-C, CHX, and VP-16) and STS. All compounds, except 7alpha-hydroxycholesterol, induced apoptosis characterized by the occurrence of cells with fragmented and/or condensed nuclei, loss of mitochondrial potential, caspase-3 activation, PARP degradation, and internucleosomal DNA fragmentation. The highest proportion of apoptotic cells was found with antitumoral drugs and STS, whereas the highest overproduction of O2*- detected before and after the loss of mitochondrial potential was obtained with 7beta-hydroxycholesterol and 7-ketocholesterol. Overproduction of O2*- was always correlated with enhanced lipid peroxidation. Vit E was only capable to significantly counteract apoptosis and oxidative stress induced by 7beta-hydroxycholesterol, 7-ketocholesterol, VB and STS. By electron and fluorescence microscopy, myelin figures evocating autophagic vacuoles were barely observed under treatment with 7beta-hydroxycholesterol and 7-ketocholesterol, and their formation occurring before the loss of mitochondrial potential was reduced by Vit E. In the presence of 7alpha-hydroxycholesterol, no enhancement of O2*- production, no lipid peroxidation, and no formation of myelin figures were observed. Collectively, our data demonstrate, that there can be a more or less important stimulation of oxidative stress during apoptosis. They also suggest that enhancement of O2*- production associated with lipid peroxidation during 7beta-hydroxycholesterol and 7-ketocholesterol-induced apoptosis could contribute to in vivo vascular injury, and that myelin figures could constitute suitable markers of oxysterol-induced cell death.

Analysis of Variance↗
PubMed1997

Activation of acyl-CoA: cholesterol acyltransferase in rat liver microsomes by 25-hydroxycholesterol.

25-Hydroxycholesterol stimulated acyl-CoA:cholesterol acyltransferase (ACAT) activity in rat liver microsomes in vitro with half-maximal stimulation at 16.8 microM oxysterol and a maximal activity that was three times that in its absence. The current study was conducted to determine the effect of 25-hydroxycholesterol on rates and extent of intervesicular cholesterol transfers within microsomes and to determine whether this activation of ACAT could be accounted for on the basis of increased cholesterol availability for the enzyme. Cholesterol transfer kinetics were assessed in systems that either enriched or depleted microsomal cholesterol. Incubation of microsomes at 37 degrees C with phosphatidylcholine:cholesterol liposomes or purified plasma membranes resulted in enrichment of microsomal cholesterol. Incubation of microsomes with just phosphatidylcholine liposomes resulted in depletion of cholesterol. The extent of cholesterol enrichment or depletion depended on incubation time and the initial concentration of cholesterol in donor and acceptor vesicles. The rate and extent of cholesterol transfer from liposomes to microsomes were slightly increased when 25-hydroxycholesterol was present during the transfer process. Irrespective of the treatment, 25-hydroxycholesterol continued to stimulate the ACAT activity of the treated microsomes. Microsomes that were enriched or depleted of cholesterol in the absence of 25-hydroxycholesterol yielded as much enzyme activities when assayed in the presence of 25-hydroxycholesterol as with the systems that contained 25-hydroxycholesterol during both the transfer process and enzyme assays. The results suggest that a major part of the activation of microsomal ACAT by 25-hydroxycholesterol is not ascribable to increased substrate availability for the enzyme.

Animals↗
PubMedDate not supplied

24S-hydroxycholesterol in cerebrospinal fluid is elevated in early stages of dementia.

The brain is the most cholesterol-rich organ in the human body. Accumulation of excess cholesterol in hippocampal neurons promotes the cleavage of the amyloid precursor protein (APP) into amyloidogenic components with the consequence of the acceleration of neuronal degeneration. Conversion of cholesterol to 24S-hydroxycholesterol mediated by cholesterol 24S-hydroxylase (CYP46) is the major pathway for the elimination of brain cholesterol and the maintenance of brain cholesterol homeostasis. We examined whether cerebrospinal fluid (CSF) 24S-hydroxycholesterol levels differ between patients with dementia, patients with mild cognitive impairment (MCI), and cognitively intact control subjects. Plasma and CSF concentrations of 24S-hydroxycholesterol and cholesterol in 32 patients with Alzheimer's disease (AD), 11 patients with vascular dementia, seven patients with MCI, and seven cognitively intact control subjects were measured by combined gas-chromatography/mass spectrometry. We show elevated concentrations of 24S-hydroxycholesterol in the CSF of AD patients and we interpret this finding as a consequence of increased cholesterol turnover in the central nervous system during neurodegeneration. The observed influence of the apolipoprotein E epsilon4 (APOE4) allele on CSF 24S-hydroxycholesterol concentrations with a gene-dosage effect suggests the existence of a link between the AD risk factor APOE4 and CNS cholesterol metabolism. The elevation of CSF 24S-hydroxycholesterol appears to occur early in the disease process, since patients with mild cognitive impairment had also increased CSF concentrations of this compound. We believe that the CSF concentration of 24S-hydroxycholesterol is altered in AD-related neurodegeneration and thus, CSF 24S-hydroxycholesterol may be a marker for monitoring the onset and progression of the disease.

Aged↗
PubMed2000

Plasma levels of 24S-hydroxycholesterol in patients with neurological diseases.

The brain is the exclusive or almost exclusive site of formation of 24S-hydroxycholesterol and we have shown that the circulating level of 24S-hydroxycholesterol is dependent upon the relation between cerebral production and hepatic clearance. In the present work we determined plasma levels of 24S-hydroxycholesterol in patients with various neurological diseases. Eleven subjects with brain death occurring 6-10 h before collection of the plasma samples had markedly reduced circulating levels of 24S-hydroxycholesterol (-43%, P<0.001). Patients with advanced Alzheimer's disease and cerebral inflammatory diseases had slightly lower levels of 24S-hydroxycholesterol in plasma when compared to matched controls. Patients with acute ischemic stroke, multiple sclerosis and primary brain tumors had levels not significantly different from those of controls. The conditions leading to reduced plasma levels of 24S-hydroxycholesterol had no significant effect on plasma levels of another side-chain oxidized oxysterol, 27-hydroxycholesterol. Except for conditions characterized by very marked destruction of the central nervous system, different severe neurological diseases seem to have relatively small effects on the flux of 24S-hydroxycholesterol from the brain.

Adult↗
PubMed2002

Conversion of 7 alpha-hydroxycholesterol to bile acid in human subjects: is there an alternate pathway favoring cholic acid synthesis?

Despite the fact that most human subjects synthesize about twice as much cholic acid as chenodeoxycholic acid, available evidence suggests that 7 alpha-hydroxycholesterol, the first intermediate in the major pathway for bile acid synthesis, is converted about equally to these two bile acids. Synthesis through the main alternate pathway can not explain this discrepancy because 27-hydroxycholesterol, the first intermediate in that pathway, is converted preferentially to chenodeoxycholic acid. To examine the validity of these contradictory observations, we administered (24-(14)C)-cholic acid and (24-(14)C)-chenodeoxycholic acid together with (7 beta-(3)H)-7 alpha-hydroxycholesterol on one occasion and (22,23-(3)H)-27-hydroxycholesterol on a separate occasion to eight normal human subjects. Synthesis of the two primary bile acids was determined by means of standard isotope dilution kinetics of the carbon 14-specific activities of biliary bile acids. Conversion of (7 beta-(3)H)-7 alpha-hydroxycholesterol and (22,23-(3)H)-27-hydroxycholesterol to bile acid was calculated from the tritium/carbon 14 ratio in cholic and chenodeoxycholic acid. For synthesis, the mean +/- SEM cholic/chenodeoxycholic ratio was 1.82 +/- 0.26. For apparent conversion of (7 beta-(3)H)-7 alpha-hydroxycholesterol to bile acid, the mean +/- SEM cholic/ chenodeoxycholic ratio was 1.02 +/- 0.09, whereas for (22,23(3)H)-27-hydroxycholesterol, the mean +/- SEM cholic/chenodeoxycholic ratio was 0.38 +/- 0.03. These data imply that, on average, more than 40% of cholic acid in these subjects was synthesized through a pathway that bypassed initial 7 alpha-hydroxylation. However, consideration of all potential candidates for such a pathway raises doubts that any of them contributes substantially to bile acid synthesis.

Adult↗
PubMed2002

25-hydroxycholesterol is produced by testicular macrophages during the early postnatal period and influences differentiation of Leydig cells in vitro.

Leydig cells develop inappropriately in animals lacking testicular macrophages. We have recently found that macrophages from adult animals produce 25-hydroxycholesterol, an oxysterol involved in the differentiation of hepatocytes and keratinocytes. Therefore, we hypothesized that testicular macrophages also produce 25-hydroxycholesterol during the early postnatal period and that this oxysterol plays a role in the differentiation of Leydig cells. We assessed the production of 25-hydroxycholesterol and 25-hydroxylase mRNA by cultured testicular macrophages from rats at 10, 20, and 40 days of age. We also tested the long-term effects of 25-hydroxycholesterol on basal and LH-stimulated testosterone production, and 3beta-hydroxysteroid dehydrogenase activity as end points of Leydig cell differentiation in vitro. We found that testicular macrophages from animals at all ages produced both 25-hydroxycholesterol and 25-hydroxylase mRNA, with macrophages from 10-day-old animals having the highest steady-state levels of message. We also found that chronic exposure of Leydig cells to 25-hydroxycholesterol increased basal production of testosterone but decreased LH-stimulated steroidogenesis at all ages. Finally, 25-hydroxycholesterol increased 3beta-hydroxysteroid dehydrogenase activity in both progenitor and immature Leydig cells. These findings support the hypothesis that testicular macrophages play an important role in the differentiation of Leydig cells through the secretion of 25-hydroxycholesterol.

3-Hydroxysteroid Dehydrogenases↗
PubMed2005

Crossing the barrier: net flux of 27-hydroxycholesterol into the human brain.

Side chain oxidized oxysterols have a unique ability to traverse lipophilic membranes. We tested the hypothesis that there is a net flux of 27-hydroxycholesterol from the circulation into the brain using plasma samples collected from the internal jugular vein and an artery of healthy male volunteers. Two independent studies were performed, one in which total levels of 27-hydroxycholesterol were measured and one in which the free fraction of 27-hydroxycholesterol was measured. In the majority of subjects studied, the level of 27-hydroxycholesterol was higher in the artery than in the vein, and uptake from the circulation was calculated to be about 5 mg/24 h. The distribution of 27-hydroxycholesterol in human brain was found to be consistent with an extracerebral origin, with a concentration gradient from the white to the gray matter--a situation opposite that of 24S-hydroxycholesterol, which os exclusively formed in brain. In view of the fact that the blood-brain barrier is impermeable to cholesterol and that 27-hydroxycholesterol is a potent regulator of several cholesterol-sensitive genes, the flux of 27-hydroxycholesterol into the brain may be and important link between intra- and extracerebral cholesterol homeostasis.

Animals↗
PubMed2004

The effects of gender and CYP46 and apo E polymorphism on 24S-hydroxycholesterol levels in Alzheimer's patients treated with statins.

To examine the effect of gender and polymorphisms of CYP46 and apo E on plasma levels of 24S-hydroxycholesterol in Alzheimer's disease (AD) patients and to determine whether these factors contribute to the variability in responses to statin treatment. Fifty-three AD patients had measurement of plasma levels of 24S-hydroxycholesterol, plasma and lipoprotein cholesterol and genotyping of CYP46 and apo E. Thirty-nine of the subjects subsequently participated in a statin trial for 6 weeks, and had a repetition of the baseline measurements. Baseline levels of 24S-hydroxycholesterol were higher in women than in men. There was a positive and significant correlation of plasma oxysterol levels with levels of total plasma cholesterol (women: r = .72, P < .0001; men: r = .47, P = .02) and non-HDL cholesterol (women: r = .68, P < .0001; men: r = 0.51, P = .01) (and LDL cholesterol) but not HDL cholesterol levels. There was no association of CYP46 or apo E polymorphisms with plasma levels of 24S-hydroxycholesterol. AD subjects treated with statins had a similar percent reduction in lathosterol, 24S-hydroxycholesterol, total cholesterol and non-HDL (and LDL) cholesterol regardless of gender and polymorphisms of CYP46. Subjects with the 4/4 polymorphism had less reduction in the ratios of 24S-hydroxycholesterol-LDL cholesterol. Women with AD had higher levels of plasma 24S-hydroxycholesterol levels than men. Women also showed a very strong correlation of plasma levels of 24S-hydroxycholesterol-to-total and non-HDL cholesterol. This may suggest that the oxysterol may be an important marker of AD risk instead of total cholesterol, as suggested by others. Polymorphisms of CYP46 or apo E do not explain levels of oxysterol or non-HDL cholesterol or the responsiveness to statin treatment in this study.

Aged↗
PubMed1999

27-hydroxycholesterol: production rates in normal human subjects.

We attempted to quantitate production of bile acid via the 27-hydroxylation pathway in six human subjects. After bolus intravenous injection of known amounts of [24-14C]cholic acid and [24-14C]chenodeoxycholic acid, each subject underwent a constant intravenous infusion of a mixture of [22, 23-3H]-27-hydroxycholesterol and [2H]-27-hydroxycholesterol for 6;-10 h. Production rate of 27-hydroxycholesterol was calculated from the infusion rate of [2H]-27-hydroxycholesterol and the serum ratio of deuterated/protium 27-hydroxycholesterol, which reached a plateau level by 4 h of infusion. Conversion of 27-hydroxycholesterol to cholic and chenodeoxycholic acids was determined from the 3H/14C ratio of these two bile acids in bile samples obtained the day after infusion. In five of the six subjects, independent measurement of bile acid synthesis by fecal acidic sterol output was available from previous studies. Endogenous production of 27-hydroxycholesterol averaged 17.6 mg/day and ranged from 5.0 to 28.2 mg/day, which amounted to 8.7% (range 3.0;-17.9%) of total bile acid synthesis. On average 66% of infused 27-hydroxycholesterol was converted to bile acid, of which 72.6% was chenodeoxycholic acid. These data suggest that relatively little bile acid synthesis takes place via the 27-hydroxylation pathway in healthy humans. Nevertheless, even this amount, occurring predominantly in vascular endothelium and macrophages, could represent an important means for removal of cholesterol deposited in endothelium.

Adult↗
PubMed2000

Plasma levels of 24S-hydroxycholesterol reflect the balance between cerebral production and hepatic metabolism and are inversely related to body surface.

We have previously presented evidence that most of the 24S-hydroxycholesterol present in the circulation originates from the brain and that most of the elimination of this oxysterol occurs in the liver. Plasma 24S-hydroxycholesterol levels decline by a factor of about 5 during the first decades of life. The concentration of the enzyme cholesterol 24S-hydroxylase in the brain is, however, about constant from the first year of life, and reduced enzyme levels thus cannot explain the decreasing plasma levels during infancy. In the present work we tested the hypothesis that the plasma levels of 24S-hydroxycholesterol may reflect the size of the brain relative to the capacity of the liver to eliminate the substance. It is shown here that the age-dependent changes in absolute as well as cholesterol-related plasma level of 24S-hydroxycholesterol closely follow the changes in the ratio between estimated brain weight and estimated liver volume. The size of the brain is increased only about 50% whereas the size of the liver is increased by about 6-fold after the age of 1 year. Liver volume is known to be highly correlated to body surface, and in accordance with this the absolute as well as the cholesterol-related plasma level of 24S-hydroxycholesterol was found to be highly inversely correlated to body surface in 77 healthy subjects of varying ages (r(2) = 0.74). Two chondrodystrophic dwarves with normal size of the brain but with markedly reduced body area had increased levels of 24S-hydroxycholesterol when related to age but normal levels when related to body surface. It is concluded that the balance between cerebral production and hepatic metabolism is a critical determinant for plasma levels of 24S-hydroxycholesterol at different ages and that endocrinological factors are less important. The results are discussed in relation to the possibility to use 24S-hydroxycholesterol in the circulation as a marker for cholesterol homeostasis in the brain.

Adolescent↗