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

Abstract

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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“…The crucial step in excreting excess cholesterol synthesized in the brain is by conversion to 24 (S)-hydroxycholesterol, which, unlike cholesterol, can easily cross the blood-brain barrier (Lutjohann et al 1996). Roughly two-thirds of excess cholesterol is removed from the brain in this manner; the fate of the remainder is uncertain.…”

Bioconversion of 3β-hydroxy-5-cholenoic acid into chenodeoxycholic acid by rat brain enzyme systems

“…These facts may indicate that 24-hydroxycholesterol acts as an intermediate of the synthetic pathway from cholesterol to 3␤-hydroxy-5-cholenoic acid. 24S-Hydroxycholesterol synthesized in the brain is excreted into the peripheral bloodstream for transfer to the liver (29,30) and is then converted into bile acids in human hepatocytes (31). In addition, increased levels of oxysterols, such as 24-hydroxycholesterol, induce liver bile acid biosynthesis and degradation of cholesterol via binding to the oxysterol receptor (32).…”

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