24‐Hydroxycholesterol levels in human brain<sup>1</sup>

Smith, Leland L.; Ray, Deepshikha; Moody, James A.; Wells, J. D.; Lier, Johan E. van

doi:10.1111/j.1471-4159.1972.tb01406.x

Cited by 35 publications

(28 citation statements)

References 13 publications

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“…do not exclude a bidirectional flux, in favor of the flux from the brain. The concentrations of 24-OH-Chol in the brain and adrenals were found to be similar to those reported previously (11)(12)(13)(14)(15)17) and were 30-to 1500-fold higher than in any other organ. It may be mentioned that 24-OH-Chol has been denoted "cerebrosterol" in previous literature due to its occurrence in the brain (11).…”

Section: Discussionsupporting

confidence: 89%

“…It should be mentioned that ne P450 containing sterol 27-hydroxylase purified to in a study by Smith et al (17), there was no clear effect of age homogeneity from pig liver mitochondria has a low on the concentration of 24-OH-Chol in human brain. Howficant capacity to catalyze 24-hydroxylation of choever, in that study, no brain samples were analyzed from 28).…”

Section: Discussionmentioning

confidence: 93%

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Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.

Lütjohann

Breuer

Ahlborg

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

620

575

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We have investigated whether side chainhydroxylated cholesterol species are important for elimination of cholesterol from the brain. Plasma concentrations of 24-hydroxycholesterol (24-OH-Chol) in the internal jugular vein and the brachial artery in healthy volunteers were consistent with a net flux of this steroid from the brain into the circulation, corresponding to elimination of -4 mg cholesterol during a 24-h period in adults. Results of experiments with rats exposed to '802were also consistent with a flux of 24-OH-Chol from the brain into the circulation. No other oxysterol measured showed a similar behavior as 24-OH-Chol. These results and the finding that the concentration of 24-OH-Chol was 30-to 1500-fold higher in the brain than in any other organ except the adrenals indicate that the major part of 24-OH-Chol present in the circulation originates from the brain. Both the 24-OH-Chol present in the brain and in the circulation were the 24S-stereoisomer. In contrast to other oxysterols, levels of plasma 24-OH-Chol were found to be markedly dependent upon age. The ratio between 24-OH-Chol and cholesterol in plasma was -5 times higher during the first decade of life than during the sixth decade. There was a high correlation between levels of 24-OH-Chol in plasma and cerebrospinal fluid. It is suggested that the flux of 24-OHChol from the brain is important for cholesterol homeostasis in this organ. The brain is the most cholesterol-rich organ in the body. However, surprisingly little is known about the mechanism regulating cholesterol homeostasis in this organ. Very little cholesterol is taken up from circulating lipoproteins due to the efficient blood-brain barrier (1). The local synthesis of cholesterol is also very low, and it has been reported that only -0.1% of newly synthesized cholesterol in adult monkeys is present in the brain (2). If this is valid also in adult humans, only 1-2 mg of cholesterol would be synthesized each day. From in vitro experiments on slices of rat brain, it was calculated that the half-life of cholesterol is -6 months (3). However, the very low uptake and synthesis of cholesterol in the brain must be balanced by some mechanism for removal of cholesterol. If very little high-density lipoprotein-dependent cholesterol transport occurs, the possibility should be considered that there is a conversion of cholesterol into metabolites that may pass the blood-brain barrier more easily than cholesterol itself.Recently, we described a new mechanism for elimination of intracellular cholesterol in macrophages, involving conversion of cholesterol into 27-hydroxycholesterol (27-OH-Chol; also denoted (25R)-cholest-5-ene-3/3,26-diol) and 3,B-hydroxy-5-cholestenoic acid (4). These compounds are more polar than cholesterol and easily transported out from the cells (4, 5). We have also shown that there is a continuous flux of 27-OH-Chol and other 27-oxygenated steroids from extrahepatic sources to the liver, where these compounds are rapidly metabolized into bile acids (5).We have previous...

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Section: Discussionsupporting

confidence: 89%

Section: Discussionmentioning

confidence: 93%

Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.

Lütjohann

Breuer

Ahlborg

et al. 1996

Proc. Natl. Acad. Sci. U.S.A.

620

575

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“…24-Hydroxycholesterol can be formed from cholesterol by rat brain microsomal preparations [41] and by pig and mouse liver mitochondria [42,43]. The highest levels of 24-hydroxycholesterol in any organ are found in the brain [18]. Our finding of 0n49-0n66 nmol of 24-hydroxycholesterol\mg of microsomal protein confirms an early report of a microsomal location in bovine brain [44].…”

Section: Discussionsupporting

confidence: 86%

“…27-Hydroxycholesterol has been found in the brain where 24-hydroxycholesterol is the major hydroxycholesterol [18]. The possibility that bile acids are formed in the brain has been suggested [19,20].…”

Section: Introductionmentioning

confidence: 99%

Metabolism of 27-, 25- and 24-hydroxycholesterol in rat glial cells and neurons

Zhang

Akwa

El‐Etr

et al. 1997

Biochemical Journal

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The metabolism of 27-, 25-and 24-hydroxycholesterol in cultures of rat astrocytes, Schwann cells and neurons was studied. 27-and 25-Hydroxycholesterol, but not 24-hydroxycholesterol, underwent 7α-hydroxylation with subsequent oxidation to 7α-hydroxy-3-oxo-∆% steroids in all three cell types. When cells were incubated for 24 h with 0n28 nmol of 27-hydroxycholesterol in 10 ml of medium, the rates of conversion into 7α-hydroxylated metabolites were 0n21, 0n12 and 0n02 nmol\24 h per 10' cells in the media of astrocytes, Schwann cells and neurons respectively. The corresponding values for 25-hydroxycholesterol were 0n26, 0n16 and 0n04. A minor fraction of 27-hydroxycholesterol and its 7α-hydroxylated metabolites was oxidized to 3β-hydroxy-5-cholestenoic acid, 3β,7α-dihydroxy-5-cholestenoic acid and 7α-hydroxy-3-oxo-4-cholestenoic acid. In addition to the two

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“…The relatively constant level of 24S-OH in different brain areas (21,42) implies that oxysterol-mediated regulation of liver-X-receptor activity within the brain may be largely dependent on the availability of ligands for its heterodimeric partner, the retinoid X receptor. This is particularly intriguing, because polyunsaturated fatty acids have been reported to activate retinoid X receptor (43,44) and have been associated with protection versus dementia, particularly Alzheimer disease (45).…”

Section: Discussionmentioning

confidence: 99%

Studies on the Transcriptional Regulation of Cholesterol 24-Hydroxylase (CYP46A1)

Ohyama

Meaney

Heverin

et al. 2006

Journal of Biological Chemistry

123

135

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Mammalian CNS contains a disproportionally large and remarkably stable pool of cholesterol. Despite an efficient recycling there is some requirement for elimination of brain cholesterol. Conversion of cholesterol into 24S-hydroxycholesterol by the cholesterol 24-hydroxylase (CYP46A1) is the quantitatively most important mechanism. Based on the protein expression and plasma levels of 24S-hydroxycholesterol, CYP46A1 activity appears to be highly stable in adults. Here we have made a structural and functional characterization of the promoter of the human CYP46A1 gene. No canonical TATA or CAAT boxes were found in the promoter region. Moreover this region had a high GC content, a feature often found in genes considered to have a largely housekeeping function. A broad spectrum of regulatory axes using a variety of promoter constructs did not result in a significant transcriptional regulation. Oxidative stress caused a significant increase in transcriptional activity. The possibility of a substrate-dependent transcriptional regulation was explored in vivo in a sterol-deficient mouse model (Dhcr24 null) in which almost all cholesterol had been replaced with desmosterol, which is not a substrate for CYP46A1. Compared with heterozygous littermates there was no statistically significant difference in the mRNA levels of Cyp46a1. During the first 2 weeks of life in the wild-type mouse, however, a significant increase of Cyp46a1 mRNA levels was found, in parallel with an increase in 24S-hydroxycholesterol level and a reduction of cholesterol synthesis. The failure to demonstrate a significant transcriptional regulation under most conditions is discussed in relation to the turnover of brain and neuronal cholesterol.Although the brain is the most cholesterol-rich organ in the body, relatively little is known about the mechanisms by which it maintains steady-state cholesterol levels (1, 2). This is in marked contrast to the situation in virtually every other tissue or organ. One finding that has been consistently confirmed is that, due to the efficiency of the bloodbrain barrier, the brain is unable to take up cholesterol from the circulation and relies on de novo synthesis to meet its substantial cholesterol requirements. However, the rate of cholesterol synthesis in the adult brain is very low, and the bulk of brain cholesterol has a half-life that is at least 100 times longer than that of cholesterol in most other organs (3).One consequence of this "uncoupling" of brain and whole body cholesterol homeostasis has been the evolution of specific mechanisms for maintenance of cerebral cholesterol levels. Two mechanisms for removal of brain cholesterol are currently recognized (1). The first is analogous to classic "reverse cholesterol transport" and is mediated by a flux of cholesterol present in apolipoprotein E containing lipoproteins through cerebrospinal fluid into the circulation (4, 5). In adults, this mechanism is believed to be responsible for elimination of 1-2 mg of cholesterol per 24 h. The details of this particular ...

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24‐Hydroxycholesterol levels in human brain¹

Cited by 35 publications

References 13 publications

Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.

Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.

Metabolism of 27-, 25- and 24-hydroxycholesterol in rat glial cells and neurons

Studies on the Transcriptional Regulation of Cholesterol 24-Hydroxylase (CYP46A1)

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24‐Hydroxycholesterol levels in human brain1

Cited by 35 publications

References 13 publications

Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.

Cholesterol homeostasis in human brain: evidence for an age-dependent flux of 24S-hydroxycholesterol from the brain into the circulation.

Metabolism of 27-, 25- and 24-hydroxycholesterol in rat glial cells and neurons

Studies on the Transcriptional Regulation of Cholesterol 24-Hydroxylase (CYP46A1)

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Product

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24‐Hydroxycholesterol levels in human brain¹