Importance of a novel oxidative mechanism for elimination of brain cholesterol - Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with O-18(2) techniques in vivo and in vitro
Importance of a novel oxidative mechanism for elimination of brain cholesterol - Turnover of cholesterol and 24(S)-hydroxycholesterol in rat brain as measured with O-18(2) techniques in vivo and in vitro
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DOI：
10.1074/jbc.272.48.30178
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发表时间：
1997-11-28
影响因子：
4.8
通讯作者：
Wennmalm, A
中科院分区：
文献类型：
--
作者：
Bjorkhem, I;Lutjohann, D;Wennmalm, A
脑是体内胆固醇最丰富的器官。脑胆固醇的特征在于非常低的周转率，与循环中的脂蛋白交换非常少。最近，我们表明，存在24（S）-羟基胆固醇从人脑进入循环的持续的年龄依赖性流量（Liitjohann，D.，Breuer，O.，Ahlborg，G.，内内斯莫岛Siden，A.，Diczfalusy，U.，和比约克赫姆岛等人（1996）Proc. Acad. Sci.联合S. A. 93，9799-9804），在此，我们使用O-18（2）吸入技术和质量同位素分布分析测量了胆固醇的合成速率以及大鼠脑中胆固醇向24（S）-羟基胆固醇的转化。发现胆固醇合成对应于每小时0.03 +/-0.01%的库。胆固醇转化为24（S）-羟基胆固醇的转化率相似，约为每小时总胆固醇的0.02%。在NADPH存在下孵育时，脑微粒体以相似的速率将内源性阿替醇转化为24（S）-羟基胆固醇。当与大鼠脑的整个匀浆和亚细胞组分一起孵育时，氚标记的24-羟基胆固醇没有显著转化为极性更强的产物。O-18（2）暴露大鼠血浆中含有24（S）-羟基胆固醇，脑中O-18的富集程度与24（S）-羟基胆固醇相似，提示24（S）-羟化酶介导的机制是清除脑中胆固醇的重要机制。脑胆固醇缓慢转化为24（S）-羟基胆固醇，后者的少量氧固醇由于泄漏到循环中而迅速周转（与脑胆固醇的2-4个月相比，脑24（S）-羟基胆固醇的半衰期为约0.5天）。显然，24（S）-羟基化极大地促进了胆固醇通过血脑屏障的转移，并且这种羟基化对于脑中的胆固醇稳态可能是关键的。
The brain is the most cholesterol-rich organ in the body, Brain cholesterol is characterized by a very Bow 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 (Liitjohann, D., Breuer, O., Ahlborg, G., Nennesmo, I., Siden, A., Diczfalusy, U., and Bjorkhem, 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 O-18(2) 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 cholestesol 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 O-18(2)-exposed rats contained 24(S)-hydroxycholesterol with an enrichment of O-18 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.