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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Rabbits fed a 1% cholesterol diet with or without the antioxidant butylated hydroxytoluene (BHT) developed typical atherosclerotic lesions. The addition of BHTgave higher levels of total cholesterol (+40%), triglycerides (+250%), low density lipoprotein (LDL), and very low density lipoprotein (VLDL) in plasma. Despite the lower plasma lipid levels, the degree of atherosclerosis of the aortic surface was considerably higher in rabbits fed cholesterol than in the group treated with cholesterol and BHT. The mean atherosclerotic involvement was 18.6 ±4.4% in the former group and 5.9±1.7% in the latter group (p=0.02). In all animals, there was a high correlation between the area of the arterial lesion and cholesterol content (r=0.96). Serum levels of cholesterol autooxidation products (7-ketocholesterol and cholesterol 5tt,6«-epoxide) were lower in the group of rabbits treated with BHT (p<0.005). Serum levels of vitamin E were slightly higher in the BHT group. There was no significant difference in the clearance of /3-VLDL between the two treatment groups after using either 0-VLDL from cholesterol-fed animals or /3-VLDL from BHT-fed animals. The results are in accord with the contention that oxidative modification of lipoproteins is important for the development of atherosclerosis and that antioxidants may have a protective effect At present, however, other explanations cannot be completely excluded, for example, effects of antioxidants on immunologic factors or monocyte adhesion. [Arteriosclerosis and Thrombosis 1991;ll:15-22) R esults from several previous studies suggest that oxidative modification of low density lipoprotein (LDL) may enhance its atherogenecity and contribute to development of atherosclerosis.1 Some of the intrinsic changes in LDL subjected to oxidative modification have been well characterized and consist of degradation of polyunsaturated fatty acids, conversion of phospholipids to their lysoderivatives, nonenzymatic degradation of apolipoprotein B-100, and conjugation of fatty aldehydes to lysine residues in the protein moiety. 2 -6 These changes result in an LDL that is recognized by the macrophage scavenger receptor and possibly also by other receptors, leading to increased macrophage uptake of the modified LDL. 7 -8 In parallel, there may be a change in the monocyte and macrophage distribution pattern in the vicinity of the arterial wall, Received August 11, 1989; revision accepted June 29, 1990. resulting in an increase in intimal macrophages. 910These profound changes have been attributed to the oxidation process, and the finding that the antioxidant, probucol, could prevent these changes in vitro gives further support to this hypothesis. 11 It has also been reported that treatment of Watanabe heritable hyperlipidemic (WHHL) rabbits with probucol can prevent progression of atherosclerosis.12 A complication in the evaluation of the mechanism behind the antiatherogenic effect of probucol in vivo, however, is that this drug has an intrinsic hypolipidemic effect, which in itself could be ...

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 (halflife 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.