Activation of the Liver X Receptor Stimulates Trans-intestinal Excretion of Plasma Cholesterol
Activation of the Liver X Receptor Stimulates Trans-intestinal Excretion of Plasma Cholesterol
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DOI：
10.1074/jbc.m109.014860
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发表时间：
2009-07-17
影响因子：
4.8
通讯作者：
Kuipers, Folkert
中科院分区：
文献类型：
--
作者：
van der Veen, Jelske N.;van Dijk, Theo H.;Kuipers, Folkert
最近的研究表明，血浆胆固醇的直接肠道分泌显著有助于小鼠粪便中性固醇的损失。这种新途径的生理相关性，它代表了胆固醇逆向转运途径的一部分，尚未在体内直接建立。我们已经开发了一种方法来量化的分数和绝对贡献的几个胆固醇流量总粪便中性固醇损失在小鼠体内，通过评估的动力学口服和静脉给药稳定的同位素标记的胆固醇结合同位素的方法来评估从头合成的胆固醇的命运。我们的研究结果表明，经肠胆固醇排泄显著有助于清除C57 B16/J小鼠的血液来源的游离胆固醇（231 μ mol/kg/d的33%），T0901317对LXR的药理学激活强烈刺激了这一途径（706 μ mol/kg/d的63%）。在缺乏Abcg 5（~ 4%）的小鼠中，跨肠胆固醇排泄受损，表明胆固醇转运Abcg 5/Abcg 8异二聚体参与该途径。我们的数据表明，肠道排泄代表了一个定量的重要途径，粪便中的中性固醇的胆汁分泌无关的小鼠。该途径对LXR系统的药理学激活敏感。这些数据支持肠实质上有助于胆固醇逆向转运的概念。
Recent studies have indicated that direct intestinal secretion of plasma cholesterol significantly contributes to fecal neutral sterol loss in mice. The physiological relevance of this novel route, which represents a part of the reverse cholesterol transport pathway, has not been directly established in vivo as yet. We have developed a method to quantify the fractional and absolute contributions of several cholesterol fluxes to total fecal neutral sterol loss in vivo in mice, by assessing the kinetics of orally and intravenously administered stable isotopically labeled cholesterol combined with an isotopic approach to assess the fate of de novo synthesized cholesterol. Our results show that trans-intestinal cholesterol excretion significantly contributes to removal of blood-derived free cholesterol in C57B16/J mice (33% of 231 mu mol/kg/day) and that pharmacological activation of LXR with T0901317 strongly stimulates this pathway (63% of 706 mu mol/kg/day). Trans-intestinal cholesterol excretion is impaired in mice lacking Abcg5 (-4%), suggesting that the cholesterol transporting Abcg5/Abcg8 heterodimer is involved in this pathway. Our data demonstrate that intestinal excretion represents a quantitatively important route for fecal removal of neutral sterols independent of biliary secretion in mice. This pathway is sensitive to pharmacological activation of the LXR system. These data support the concept that the intestine substantially contributes to reverse cholesterol transport.