Formation of oxysterols from different pools of cholesterol as studied by stable isotope technique: cerebral origin of most circulating 24S-hydroxycholesterol in rats, but not in mice

Abstract

In order to study the origin of different oxysterols in the circulation, in particular 24S-hydroxycholesterol, different pools of cholesterol in rat and mouse were labelled by feeding the animals with a diet supplemented with 0.3 or 0.5% hexadeuterium-labelled cholesterol, respectively, for 10 days. The incorporation of deuterium label in cholesterol and different oxysterols was measured by combined gas chromatography-mass spectrometry in selected tissues and in the circulation. In both rat and mouse, a high incorporation of label was found in cholesterol present in serum and liver (up to 77%). Incorporation of label was similar in 7 alpha- and 7 beta-hydroxycholesterol of the same origin. There was no significant incorporation of deuterium in brain cholesterol, and little or no incorporation in the brain oxysterols investigated, in both animals. In the testis, the incorporation of the deuterium label in cholesterol was less than half of that in the liver, with similarly reduced labelling of the testicular oxysterols. 24S-Hydroxycholesterol in the circulation contained a deuterium content that was about 50% of that of serum and liver cholesterol in the mouse experiment and about 30% in the rat experiment. Thus, about 50% of circulating 24S-hydroxycholesterol in the mouse and about 70% of this fraction in the rat must originate from pools of cholesterol that are not in equilibrium with plasma and liver cholesterol. The liver is probably responsible for a considerable part of the extracerebral formation of 24S-hydroxycholesterol, since this organ contained detectable amounts of 24S-hydroxycholesterol with a relatively high incorporation of deuterium in both animal species. The results are consistent with a cerebral origin of more than half of the 24S-hydroxycholesterol in the circulation of rats, but not in mice.