Cholesterol homeostasis in the brain : importance of 24S-hydroxylation

Detta är en avhandling från Stockholm : Karolinska Institutet, Department of Laboratory Sciences and Technology

Sammanfattning: Brain cholesterol is characterized by a very low turnover with very little exchange with lipoproteins in the circulation. We have investigated whether side chain-hydroxylated cholesterol species are important for elimination of cholesterol from the brain. About 80% of 24S-hydroxycholesterol (24S-OH-Chol) present in the body is present in the brain. Plasma concentrations of 24S-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. 24S-OH-Chot is eliminated by the liver and uptake in the liver (about 7 mg/24 h) was similar to the flux from the brain (about 6 mg/24 h). Intravenously injected deuterium-labeled racemic 24-OH-Chol was eliminated from the circulation of two healthy volunteers with half-lives of 10 and 14h, respectively. Results of experiments with rats exposed to 1802 were also consistent with a flux of 24S-OH-Chol from the brain into the circulation. Investigations in rats in vivo using an 1802-inhalation technique and mass isotopomer distribution analysis revealed that cholesterol synthesis in the brain corresponds to about 0.03 % of the pool per hour and that the conversion of cholesterol into 24S-OH-Chol was of similar magnitude. Brain microsomes converted endogenous cholesterol into 24S-OH-Chol at a similar rate when incubated in the presence of NADPH. As judged by the dependence upon NADPH and oxygen, the enzyme is likely to be a species of cytochrome P-450. Infants and children have a 4-5 times higher circulating level of 24S-OH-Chol than adults. Serum concentrations of 24S-OH-Chol increase dramatically during the first months after birth. It is concluded that conversion of cholesterol into 24S-OH-Chol is a quantitatively important mechanism for elimination of cholesterol from the brain. In a pilot study we tested the hypothesis that plasma levels of 24S-OH-Chol could be used as a putative marker for an altered cholesterol homeostasis in the brain of patients with Alzheimer's disease (AD). The concentration of 24S-OH-Chol in AD patients was significantly higher than in healthy controls and in depressed patients, regardless of the Apo E genotype. The results are consistent with a significant role of the 24S-hydroxylase for cholesterol homeostasis in the brain.

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