From brain to bile -: Evidence that conjugation and ω-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans
From brain to bile -: Evidence that conjugation and ω-hydroxylation are important for elimination of 24S-hydroxycholesterol (cerebrosterol) in humans
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DOI：
10.1074/jbc.m103828200
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发表时间：
2001-10-05
影响因子：
4.8
通讯作者：
Einarsson, C
中科院分区：
文献类型：
--
作者：
Björkhem, I;Andersson, U;Einarsson, C
大脑几乎是人类24 S-羟基胆固醇形成的唯一场所，并且这种氧固醇持续穿过血脑屏障进入循环。本文通过三种不同的方法研究了24 S-羟基胆固醇的肝脏代谢：氚标记的24 S-羟基胆固醇与人原代肝细胞的孵育，氚标记的24 S-羟基胆固醇对人类志愿者的给药，以及回肠瘘患者回盲肠液中游离和结合的24 S-羟基胆固醇及其中性代谢物的定量。24 S-羟基胆固醇和24 R-羟基胆固醇在人肝细胞中转化为胆汁酸的速率约为胆汁酸合成中正常中间体7 α-羟基胆固醇的40%。24 S-羟基胆固醇也以类似于转化为胆汁酸的速率转化为5-异戊烯-3 β，24 S，27-三醇的缀合物。当给予人类志愿者时，标记的24 S-羟基胆固醇转化为胆汁酸的速率约为同时给予标记的7 α-羟基胆固醇的一半。在回盲部液中鉴别出游离、硫酸化和葡萄糖醛酸化的24 S-羟基胆固醇和5-异戊烯-3 β，24，27-三醇。这些类固醇的排泄量约为3.5 mg/24 h，占脑中24 S-羟基胆固醇总估计流量的50%以上。得出的结论是，24 S-羟基胆固醇是一种效率较低的前体胆汁酸，约有一半是共轭和消除胆汁本身或作为共轭的27-羟基化代谢产物。24 S-羟基胆固醇的代谢效率较低，这可能解释了循环中这种氧固醇的水平惊人地高，并且与24 S-羟基胆固醇作为胆固醇稳态调节剂的建议作用有关。
The brain is the almost exclusive site of formation of 24S-hydroxycholesterol in man, and there is a continuous flux of this oxysterol across the blood-brain barrier into the circulation. The hepatic metabolism of 24S-hydroxycholesterol was studied here by three different approaches: incubation of tritium-labeled 24S-hydroxycholesterol with human primary hepatocytes, administration of tritium-labeled 24S-hydroxycholesterol to a human volunteer, and quantitation of free and conjugated 24S-hydroxycholesterol and its neutral metabolites in ileocecal fluid from patients with ileal fistulae. 24S-Hydroxycholesterol as well as 24R-hydroxycholesterol were converted into bile acids by human hepatocytes at a rate of about 40% of that of the normal intermediate in bile acid synthesis, 7 alpha -hydroxycholesterol. There was also a conversion of 24S-hydroxycholesterol into conjugate(s) of 5-cholestene-3 beta ,24S,27-triol at a rate similar to the that of conversion into bile acids. When administered to a human volunteer, labeled 24S-hydroxycholesterol was converted into bile acids at about half the rate of simultaneously administered labeled 7 alpha -hydroxycholesterol. Free, sulfated, and glucuronidated 24S-hydroxycholesterol and 5-cholestene-3 beta ,24,27-triol were identified in ileocecal fluid. The excretion of these steroids was about 3.5 mg/24 h, amounting to more than 50% of the total estimated flux of 24S-hydroxycholesterol from the brain. It is concluded that 24S-hydroxycholesterol is a less efficient precursor to bile acids and that about half of it is conjugated and eliminated in bile as such or as a conjugate of a 27-hydroxylated metabolite. The less efficient metabolism of 24S-hydroxycholesterol may explain the surprisingly high levels of this oxysterol in the circulation and is of interest in relation to the suggested role of 24S-hydroxycholesterol as a regulator of cholesterol homeostasis.